Cancer
Conditions
Keywords
MEK inhibitor, anti-EGFR antibody, colorectal cancer, BRAF inhibitor
Brief summary
This was a four part, phase I/II study aimed to evaluate the safety, tolerability and efficacy of combination of an anti-EGFR antibody panitumumab (P) either with a BRAF inhibitor (dabrafenib (D); GSK2118436) alone or with the combination of a BRAF inhibitor and a MEK inhibitor (trametinib (T); GSK1120212) in patients with BRAF-mutant V600E advanced or mCRC. The goal was to: 1) Determine RP2R/MTD for doublet (D+P) and triplet (D+T+P) combinations in Part 1; 2) Assess clinical activity for these combinations in Part 2; 3) Determine RP2R/MTD for double (T+P) combination in Part 4A, and assess clinical activity of this combination in two patient populations in Part 4B (patients with BRAF-V600E mutation-positive advanced or metastatic CRC and patients with advanced or metastatic CRC with secondary resistance to anti-EGFR therapy).
Detailed description
Part 1: Dose escalation This was a dose escalation part intended to evaluate safety, tolerability, PK, PD, clinical activity and determine RP2R/MTD for the doublet (D+P) and the triplet (D+T+P) combinations in patients with BRAF-mutation V600E positive advanced or metastatic CRC. A 3+3 dose escalation procedure was followed. Dosing for dabrafenib and trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for dose-limiting toxicities (DLTs) during the first 28 days of treatment. Part 2A: This was a cohort expansion part to assess the safety and preliminary clinical activity of the optimal safe and tolerable dose combinations (D+P)/(D+T+P) defined in Part 1. Part 2B: In this part, additional patients were enrolled into the triplet (D+T+P) combination at two dose levels in to further explore safety, tolerability and clinical activity. Up to 10 patients each with no prior treatment (First Line Population), and up to 20 patients each with at least one prior treatment (Second to Fourth Line Population) were planned to be enrolled in dose Cohorts 3A and 4. Part 3: Randomized Phase 2 Study The randomized phase 2 portion (Phase 3) of the study was not pursued as the observed responses in any of the cohorts did not meet the predefined criteria at the time of the preliminary analysis (data cut-off date: 06-May-2016). Part 4 This part was designed to identify the RP2R/MTD and initial clinical activity for the doublet (T+P) combination in patients BRAF-mutation V600E positive advanced or metastatic CRC, and advanced or metastatic CRC with secondary resistance to prior anti-EGFR therapy. Part 4A: Dose Escalation This was a dose escalation part intended to determine RP2R/MTD for the doublet (T+P) combination in patients with BRAF-mutation V600E positive advanced or metastatic CRC. Approximately 18 patients (\ 6 each cohort) were planned to be enrolled in Part 4A. A 3+3 dose escalation procedure was followed. Dosing for trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for DLTs during the first 28 days of treatment. Part 4B: Cohort Expansion This was a cohort expansion part intended to evaluate safety and efficacy of the doublet (T+P) combination. Up to 20 patients in each of two expansion cohorts were planned to be enrolled at the starting dose cohort or MTD from Part 4A.
Interventions
DRUGDabrafenib
Each capsule contains 50 mg or 75 mg of GSK2118436; 50 mg strength capsules are Swedish orange (dark red) opaque hypromellose size 2 capsules and 75 mg strength capsules are pink opaque hypromellose size 1 capsules. The initial dosing regimen will be twice daily (BID) continuous oral daily dosing.
DRUGTrametinib
Each tablet contains 0.5mg or 2.0 mg GSK1120212; 0.5 mg is yellow modified oval biconvex film-coated tablets of size 4.8 mm X 8.9 mm and 2 mg as pink round biconvex film coated tablets;7.5 mm in diameter. The initial dosing regimen will be once daily continuous oral daily dosing.
DRUGPanitumumab
Panitumumab is a sterile, colorless, translucent-to-white amorphous, proteinaceous powder available as 100 mg panitumumab in 5 mL (20 mg/mL) single-use vial; 200 mg panitumumab in 10 mL (20 mg/mL) single-use vial; 400 mg panitumumab in 20 mL (20 mg/mL) single-use vial; to be administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes.
DEVICE5-fluorouracil
5-fluorouracil-based chemotherapy
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The original intention of the study was to include a randomized phase 2 portion of the study as a Part 3; however, a preliminary analysis did not meet predetermined criteria for efficacy. As a result, Part 3 of the study was not initiated.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects eligible for enrolment in this study must meet all of the following criteria * Provided written informed consent, * Male or female \>=18 years of age and able to swallow and retain orally administered study treatment and does not have any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels. * Part 1 and Part 2: Histologically- or cytologically-confirmed diagnosis of advanced or metastatic BRAF V600E mutation positive CRC * Part 4A and 4B ONLY: Histologically- or cytologically-confirmed diagnosis of advanced or metastatic CRC that either harbours the BRAF V600E -mutation, as determined by relevant genetic testing OR has developed secondary resistance to anti-EGFR therapy, defined as patients that derived benefit (disease control based on investigator assessment for \>6 months OR partial response \[confirmed or unconfirmed\] based on RECIST 1.1) from prior anti-EGFR-containing therapy (as defined below) and then subsequently progressed on therapy. The anti-EGFR therapy must have been the most recent therapy and the patient must have progressed based on investigator assessment within 3 months of screening. Acceptable prior anti-EGFR-containing therapies include: a. Monotherapy anti-EGFR, including cetuximab or panitumumab OR b. irinotecan/anti-EGFR combo after previously having disease progression (based on investigator assessment) on an irinotecan-containing regimen * Part 3: Histologically- or cytologically-confirmed diagnosis of BRAFV600E mutation positive advanced or metastatic colorectal cancer (CRC who are eligible to receive fluoropyrimidine-containing chemotherapy regimen that have experienced documented radiographic progression on one prior line of fluoropyrimidine-containing chemotherapy (previous anti-EGFR therapy is excluded), Second-line for advanced/metastatic disease, having failed or been intolerant to at least one regimen of fluoropyrimidine-containing chemotherapy including irinotecan or oxaliplatin in the advanced/metastatic setting. Enrollment in Part 3 may only occur following confirmation of KRAS wild-type cancer. * Archival tissue is required; if archival tissue is not available or found to not contain tumor tissue, a fresh biopsy is required. * Measurable disease per RECIST version 1.1. * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. * Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use one of the contraception methods listed in protocol. * Female subjects are eligible if: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or post-menopausal female defined as 12 months of spontaneous amenorrhea to be verified with a follicle-stimulating hormone (FSH) level \>40 Milli-international units per milliliter (MIU/mL) and estradiol level \<40 picogram per milliliter (pg/mL). Child-bearing potential and agrees to use one of the contraceptive methods listed in protocol. * Female subjects must agree to use contraception from 7 days prior to the first dose of study drug(s) until 6 months after the last dose of panitumumab, until 4 months after the last dose of trametinib, or 4 weeks after the last dose of dabrafenib, whichever is longer. Additionally, women of childbearing potential must have had a negative serum pregnancy test within 7 days prior to the first dose of study drug(s). * Adequate organ system function as defined in absolute neutrophil count greater than or equal to 1.2X10\^9/Liter (L), hemoglobin greater than or equal to 9 grams per deciliter (g/dL) or 5.6 millimoles per litre (mmol/L), platelets greater than or equal to 75 × 10\^9/L, Prothrombin Time / International Normalized Ratio (PT/INR) and Partial Thromboplastin Time (PTT) less than or equal to 1.5X upper limit of normal (ULN); serum magnesium greater than or equal to the lower limit of normal (LLN); albumin greater than or equal to 2.5 g/dL or 25 grams per liter (g/L), total bilirubin less than or equal to 1.5XULN, and Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) less than or equal to 2.5X ULN; creatinine less than or equal to 1.5XULN or calculated creatinine clearance greater than or equal to 50mL/min; left ventricular ejection fraction (LVEF) greater than or equal to the LLN by echocardiography (ECHO) or multigated acquisition scan (MUGA). * Subjects enrolled in France or Italy: In France or Italy, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.
Exclusion criteria
Subjects meeting any of the following criteria must not be enrolled in the study * History of prior malignancy, other than colorectal cancer. * Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures. * Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per investigator's assessment). * History of sensitivity to heparin or heparin-induced thrombocytopenia. * Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy or biologic therapy). * Prior exposure to a MEK inhibitor. * Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Prior exposure to a BRAF inhibitor. * Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Known presence of KRAS-mutation based on previous KRAS-testing. Note: Prospective KRAS testing is not required. However, if the results of previous KRAS testing are known, they must be used in assessing eligibility. KRAS testing will be performed retrospectively for all patients. * Part 3: Prior exposure to EGFR inhibitors or an anti-EGFR antibody * Received an investigational or approved anti-cancer drug within 4 weeks, or within 5 half-lives (whichever is shorter) of the first dose of study drug(s). At least 14 days must have passed between the last dose of prior investigational agent and the first dose of study drug(s). * Part 3: Received more than one prior anti-cancer therapy in the metastatic setting, exclusive of previous adjuvant regimens. Previous investigational anti-cancer therapy in the metastatic setting is prohibited. * Current use of a prohibited medication or requirement to dose with any of these medications during treatment with study drug(s). * Known Hepatitis B, or Hepatitis C infection. * Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first dose of study drug(s). Limited radiotherapy with in the 2 weeks prior to first dose of study drug(s). * Chemotherapy regimens with delayed toxicity within the 3 weeks prior to first dose of study drug(s). Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within 2 weeks prior to first dose of study drug(s). * Unresolved toxicity greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 Grade 1 from previous anti-cancer therapy, with the exception of Grade 2 alopecia, Grade 2 neuropathy, or laboratory values that are allowed per inclusion criteria. * History of retinal vein occlusion (RVO). * Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism or excretion of drugs. Previous colectomy is acceptable. * Subjects with brain metastases are excluded, unless: All known lesions must be previously treated with surgery or stereotactic radio-surgery, and Brain lesion(s), if present, must be confirmed stable (i.e., no increase in lesion size) for \>=90 days prior to first dose of study drug(s). This must be documented with two consecutive MRI or CT scans using contrast, and Asymptomatic with no corticosteroids requirement for \>=30 days prior to first dose of study drug(s), and No enzyme-inducing anticonvulsants for \>=14 days prior to first dose of study drug(s). In addition, for subjects that had brain metastases but currently have no evidence of disease (NED), NED for \>=12 weeks is required and must be confirmed by two consecutive MRI or CT scans (using contrast) separated by \>=6 weeks, prior to randomization. Enrollment of a subject with brain metastases who meet the above criteria requires approval of a GlaxoSmithKline (GSK) Medical Monitor. * Psychological, familial, sociological or geographical conditions that do not permit compliance with the protocol. * History or evidence of cardiovascular risk including any of the following: LVEF\<LLN; A QT interval corrected for heart rate using the Bazett's formula (QTcB;) ≥ 480 milliseconds (msec);.History or evidence of current clinically significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation for \>30 days prior to randomization are eligible. History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization. History or evidence of current \>= Class II congestive heart failure as defined by New York Heart Association (NYHA). Treatment refractory hypertension defined as a blood pressure of systolic\> 140 millimeter of mercury (mm Hg) and/or diastolic \> 90 mm Hg which cannot be controlled by anti-hypertensive therapy; Subjects with intra-cardiac defibrillators or permanent pacemakers; Known cardiac metastases * Unstable pulmonary embolism, deep vein thrombosis, or other significant arterial/venous thromboembolic event \<=30 days before randomization. If on anticoagulation, subject must be on stable therapeutic dose prior to randomization. * Subjects with a history of pneumonitis or interstitial lung disease (ILD). * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug(s) or their excipients. * Pregnant or lactating female. * Unwillingness or inability to follow the procedures outlined in the protocol. * Uncontrolled diabetes or other medical condition that may interfere with assessment of toxicity.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | From study treatment start date till 30 days safety follow-up, assessed up to approximately 90 months | The distribution of adverse events was done via the analysis of frequencies for Adverse Events, Serious Adverse Events and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed. |
| Overall Response Rate (ORR) | From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months | Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) was used for efficacy based on radiological assessment of tumor burden: CR = Complete Response, disappearance of all target lesions; PR = Partial Response, \>=30% decrease in the sum of the longest diameter of target lesions; PD = progressive disease, \>=20% increase in sum of target lesions and/or presence of new lesions and/or substantial increase in non-target lesion; SD = stable disease, response not meeting CR or PR or PD; ORR = overall response rate, defined as CR+PR |
| Part 3: Progression Free Survival (PFS) | From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months | Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From study treatment start date until date of of death from any cause, assessed up to approximately 90 months | Overall Survival (OS) was defined as the time to death due to any cause. |
| Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Maximum observed concentration (Cmax) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics. |
| Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Time of occurrence of Cmax (tmax) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics. |
| Tmax of Trametinib in the Triple Combination (D+T+P) | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Time of occurrence of Cmax (tmax) of Trametinib was listed and summarized using descriptive statistics. |
| AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Day 1, Day 15, Week 8 (Dabrafenib derived metabolites), Week 12, Week 16, Week 20 | Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Area under the concentration-time curve from zero (pre-dose) 8 hours (AUC\[0-8\]) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics. |
| AUC[0-8] of Trametinib in the Triple Combination (D+T+P) | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Area under the concentration-time curve from zero (pre-dose) 8 hours (AUC\[0-8\]) of Trametinib was listed and summarized using descriptive statistics. |
| Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Day 15, Week 8, Week 12, Week 16, Week 20 | Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics. |
| Ctau of Trametinib in the Triple Combination (D+T+P) | Day 15, Week 8, Week 12, Week 16, Week 20 | Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Trametinib was listed and summarized using descriptive statistics. |
| Ctau of Panitumumab in the Triple Combination (D+T+P) | Day 15, Week 4, Week 8, Week 12, Week 16, Week 20 | Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Panitumumab was listed and summarized using descriptive statistics. |
| Apparent Base Clearance (CL0/F) and Apparent Maximum Inducible Clearance at Steady State (CLIND,SS/F) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The apparent base clearance (CL0/F) and apparent maximum inducible clearance at steady state (CLIND,SS/F) of Dabrafenib estimated with the PopPK model are summarized in this record. |
| Effect of Combination With Trametinib on Apparent Maximum Inducible Clearance at Steady State of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of combination with trametinib on apparent maximum inducible clearance at steady state (CLIND,SS/F) (CLCOMBO) of Dabrafenib estimated with the PopPK model is summarized in this record. The parameter in question is a covariate that describes the effect of Effect of combination with trametinib on apparent maximum inducible clearance: the number denoting the effect means that the including trametinib will decrease the apparent maximum inducible clearance as opposed to when dabrafenib is administered alone. |
| Oral Volume of Distribution (V/F) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The oral volume of distribution (V/F) of Dabrafenib of Dabrafenib estimated with the PopPK model is summarized in this record. |
| Absorption Rate Constant (Ka) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The absorption rate constant (Ka) of Dabrafenib estimated with the PopPK model is summarized in this record. |
| Cmax of Trametinib in the Double Combination (T+P) | Day 1, Day 15, Week 12, Week 20 | Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Maximum observed concentration (Cmax) of Trametinib was listed and summarized using descriptive statistics. |
| Tmax of Trametinib in the Double Combination (T+P) | Day 1, Day 15, Week 12, Week 20 | Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Time of occurrence of Cmax (tmax) of Trametinib was listed and summarized using descriptive statistics. |
| Cmax of Trametinib in the Triple Combination (D+T+P) | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Maximum observed concentration (Cmax) of Trametinib was listed and summarized using descriptive statistics. |
| Ctau of Trametinib in the Double Combination (T+P) | Day 15, Week 8, Week 12, Week 16, Week 20 | Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Trametinib was listed and summarized using descriptive statistics. |
| Ctau of Panitumumab in the Double Combination (T+P) | Day 15, Week 8, Week 12, Week 16, Week 20 | Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Panitumumab was listed and summarized using descriptive statistics. |
| Apparent Base Clearance (CL0/F) and Apparent Maximum Inducible Clearance at Steady State (CLIND,SS/F) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The apparent base clearance (CL0/F) and apparent maximum inducible clearance at steady state (CLIND,SS/F) dabrafenib estimated with the PopPK model are summarized in this record. |
| Oral Volume of Distribution (V/F) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The oral volume of distribution (V/F) of Dabrafenib estimated with the PopPK model is summarized in this record. |
| Absorption Rate Constant (Ka) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The absorption rate constant (Ka) of Dabrafenib estimated with the PopPK model is summarized in this record. |
| Apparent Clearance (CL/F) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The apparent clearance (CL/F) of Trametinib estimated with the PopPK model is summarized in this record. |
| Apparent Central Volume (V/F) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The apparent central volume (V/F) of Trametinib estimated with the PopPK model is summarized in this record. |
| Absorption Rate Constant 1 (Ka1) and Absorption Rate Constant 2 (Ka2) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The absorption rate constant 1 (Ka1) and absorption rate constant 2 (Ka2) of Trametinib estimated with the PopPK model are summarized in this record. |
| Time When Ka1 Transitions to Ka2 of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model | Day 1, Day 15, Week 8, Week 12, Week 16, Week 20 | The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The time when Ka1 transitions to Ka2 of Trametinib estimated with the PopPK model is summarized in this record. |
| Change in Levels of Proteins/Ribonucleic Acid (RNA) | Baseline, Day 15 | H-score or Histo-score measures cell membrane immunohistochemistry staining intensity in a fixed field. Membrane staining is categorized as 1+, 2+, or 3+. Minimum score is 0, maximum score is 300 (no subscale values are reported). H-score values themselves are not considered to be better or worse - measurements for levels of proteins/ribonucleic acid (RNA) are surrogate for MAPK pathway activity. Low values = low pathway activity. High values = high pathway activity. Changes in mean phosphorylated-ERK (pERK) and phosphorylated ribosomal protein S6 (pS6) H-score from baseline indicate changes in MAPK pathway activity that may be associated with treatment arms. A positive change from baseline suggests increased pathway activity. A negative change from baseline suggests decreased pathway activity. Total score is calculated as follows: \[1 x (% cells 1+) + 2 x (% cells 2+) + 3 x (% cells 3+)\]. |
| Part 3: Overall Response Rate (ORR) | From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months | Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) using RECIST 1.1 |
| Part 3: Duration of Response (DoR) | From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months | Duration of Response (DoR) was defined as the time from the first documented occurrence of response (PR or CR) until the date of the first documented progression based on RECIST v1.1 or death. |
| Part 3: Overall Survival (OS) | From study treatment start date until date of of death from any cause, assessed up to approximately 90 months | Overall Survival (OS) was defined as the time to death due to any cause. |
| Part 3: Number of Participants With Treatment Emergent Adverse Events | From study treatment start date till 30 days safety follow-up, assessed up to approximately 90 months | The distribution of adverse events (AE) will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. |
| AUC[0-t] of Trametinib in the Double Combination (T+P) | Day 1, Day 15, Week 12, Week 20 | Serial blood samples will be collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples will be collected every 4 weeks up to and including Week 20 on study. Area under the concentration-time curve from zero (pre-dose) the time of the last quantifiable concentration (AUC\[0-t\]) of Trametinib was listed and summarized using descriptive statistics. |
| Duration of Response (DoR) | From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months | Duration of Response (DoR) was defined as the time from the first documented occurrence of response (PR or CR) until the date of the first documented progression based on RECIST v1.1 or death. |
| Progression Free Survival (PFS) | From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months | Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm. |
Countries
Belgium, France, Italy, Japan, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted in 20 study centers across eight countries: Belgium (2), France (2), Italy (2), Japan (2), Netherlands (2), Spain (1), UK (1) and USA (8).
Pre-assignment details
Since the tumor type enrolled in Part 1 and Part 2 was the same (metastatic colorectal cancer), the results were summarized by combination groups (and not by study parts) to allow a more meaningful interpretation of study results based on dose
Participants by arm
| Arm | Count |
|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W Part 1+2A+2B - Triple combination (Trametinib + Dabrafenib + Panitumumab): Dabrafenib 150 mg BID + Trametinib 1.5 mg QD + Panitumumab 4.8 mg/kg Q2W | 3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W Part 1+2A+2B - Triple combination (Trametinib + Dabrafenib + Panitumumab): Dabrafenib 150 mg BID + Trametinib 1.5 mg QD + Panitumumab 6.0 mg/kg Q2W | 4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W Part 1+2A+2B - Triple combination (Trametinib + Dabrafenib + Panitumumab): Dabrafenib 150 mg BID + Trametinib 2.0 mg QD + Panitumumab 4.8 mg/kg Q2W | 36 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W Part 1+2A+2B - Triple combination (Trametinib + Dabrafenib + Panitumumab): Dabrafenib 150 mg BID + Trametinib 2.0 mg QD + Panitumumab 6.0 mg/kg Q2W | 50 |
| Part 4A+4B - Double Combination (T+P) mBRAF: TRA 2MG QD, PAN 6MG/KG Q2W Part 4A+4B - Double combination (Trametinib + Panitumumab) mBRAF Patients: Trametinib 2.0 mg QD + Panitumumab 6.0 mg/kg Q2W | 11 |
| Part 4A+4B - Double Combination (T+P) mBRAF: TRA 1.5MG QD, PAN 6MG/KG Q2W Part 4A+4B - Double combination (Trametinib + Panitumumab) mBRAF Patients: Trametinib 1.5 mg QD + Panitumumab 6.0 mg/kg Q2W | 10 |
| Part 4A+4B - Double Combination (T+P) mBRAF: TRA 2MG QD, PAN 4.8MG/KG Q2W Part 4A+4B - Double combination (Trametinib + Panitumumab) mBRAF Patients: Trametinib 2.0 mg QD + Panitumumab 4.8 mg/kg Q2W | 10 |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 2MG QD, PAN 6MG/KG Q2W Part 4A+4B - Double combination (Trametinib + Panitumumab) anti-EGFR Patients: Trametinib 2.0 mg QD + Panitumumab 6.0 mg/kg Q2W | 2 |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 1.5MG QD, PAN 6MG/KG Q2W Part 4A+4B - Double combination (Trametinib + Panitumumab) anti-EGFR Patients: Trametinib 1.5 mg QD + Panitumumab 6.0 mg/kg Q2W | 10 |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 2MG QD, PAN 4.8MG/KG Q2W Part 4A+4B - Double combination (Trametinib + Panitumumab) anti-EGFR: Trametinib 2.0 mg QD + Panitumumab 4.8 mg/kg Q2W | 10 |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W Part 1+2A - Double combination (Dabrafenib + Panitumumab): Dabrafenib 150 mg BID + Panitumumab 6.0 mg/kg Q2W | 20 |
| Total | 166 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Last patient transitioned to a rollover protocol | 0 | 0 | 5 | 2 | 0 | 2 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 2 | 2 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 2 | 1 | 1 | 2 | 2 |
Baseline characteristics
| Characteristic | Total | Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Part 4A+4B - Double Combination (T+P) mBRAF: TRA 2MG QD, PAN 6MG/KG Q2W | Part 4A+4B - Double Combination (T+P) mBRAF: TRA 1.5MG QD, PAN 6MG/KG Q2W | Part 4A+4B - Double Combination (T+P) mBRAF: TRA 2MG QD, PAN 4.8MG/KG Q2W | Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 2MG QD, PAN 6MG/KG Q2W | Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 1.5MG QD, PAN 6MG/KG Q2W | Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 2MG QD, PAN 4.8MG/KG Q2W | Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 58 Participants | 1 Participants | 0 Participants | 16 Participants | 20 Participants | 3 Participants | 4 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 108 Participants | 2 Participants | 4 Participants | 20 Participants | 30 Participants | 8 Participants | 6 Participants | 9 Participants | 2 Participants | 9 Participants | 6 Participants | 12 Participants |
| ECOG Performance Status Grade 0 | 93 Participants | 2 Participants | 2 Participants | 17 Participants | 27 Participants | 6 Participants | 5 Participants | 6 Participants | 2 Participants | 5 Participants | 8 Participants | 13 Participants |
| ECOG Performance Status Grade 1 | 73 Participants | 1 Participants | 2 Participants | 19 Participants | 23 Participants | 5 Participants | 5 Participants | 4 Participants | 0 Participants | 5 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized Asian | 25 Participants | 0 Participants | 0 Participants | 7 Participants | 9 Participants | 1 Participants | 2 Participants | 3 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Missing | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 134 Participants | 3 Participants | 4 Participants | 28 Participants | 37 Participants | 10 Participants | 7 Participants | 7 Participants | 2 Participants | 8 Participants | 10 Participants | 18 Participants |
| Sex: Female, Male Female | 94 Participants | 3 Participants | 2 Participants | 21 Participants | 33 Participants | 5 Participants | 7 Participants | 6 Participants | 0 Participants | 3 Participants | 3 Participants | 11 Participants |
| Sex: Female, Male Male | 72 Participants | 0 Participants | 2 Participants | 15 Participants | 17 Participants | 6 Participants | 3 Participants | 4 Participants | 2 Participants | 7 Participants | 7 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 4 | 3 / 36 | 2 / 50 | 1 / 13 | 2 / 20 | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 36 / 36 | 50 / 50 | 13 / 13 | 20 / 20 | 20 / 20 | 20 / 20 |
| serious Total, serious adverse events | 2 / 3 | 2 / 4 | 21 / 36 | 28 / 50 | 6 / 13 | 10 / 20 | 9 / 20 | 6 / 20 |
Outcome results
Primary
Number of Participants With Adverse Events
The distribution of adverse events was done via the analysis of frequencies for Adverse Events, Serious Adverse Events and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.
Time frame: From study treatment start date till 30 days safety follow-up, assessed up to approximately 90 months
Population: All treated population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Any serious adverse event (SAE) | 2 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to permanent discontinuation of study treatment | 0 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Any Adverse Event (AE) | 3 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Deaths during treatment period | 0 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs related to study treatment | 0 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose interruption/delay | 2 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Deaths during follow-up period | 3 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose reduction | 2 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs | 0 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | SAEs related to study treatment | 1 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | AEs related to study treatment | 3 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs related to study treatment | 0 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose interruption/delay | 4 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Any serious adverse event (SAE) | 2 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Deaths during follow-up period | 4 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Deaths during treatment period | 0 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs related to study treatment | 4 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to permanent discontinuation of study treatment | 0 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Any Adverse Event (AE) | 4 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs | 0 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose reduction | 2 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | SAEs related to study treatment | 1 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs | 1 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Any serious adverse event (SAE) | 21 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Deaths during treatment period | 3 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Deaths during follow-up period | 25 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose interruption/delay | 32 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose reduction | 19 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs related to study treatment | 0 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | AEs related to study treatment | 36 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Any Adverse Event (AE) | 36 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to permanent discontinuation of study treatment | 9 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | SAEs related to study treatment | 12 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Deaths during treatment period | 2 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Any Adverse Event (AE) | 50 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs related to study treatment | 49 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to permanent discontinuation of study treatment | 12 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose reduction | 37 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose interruption/delay | 43 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Any serious adverse event (SAE) | 28 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | SAEs related to study treatment | 18 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs | 1 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs related to study treatment | 0 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Deaths during follow-up period | 42 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Any serious adverse event (SAE) | 6 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Deaths during treatment period | 1 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs related to study treatment | 0 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose interruption/delay | 9 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to permanent discontinuation of study treatment | 3 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs related to study treatment | 13 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs | 0 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Deaths during follow-up period | 11 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | SAEs related to study treatment | 5 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Any Adverse Event (AE) | 13 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose reduction | 7 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Deaths during treatment period | 2 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs related to study treatment | 19 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs related to study treatment | 0 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Any Adverse Event (AE) | 20 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | SAEs related to study treatment | 4 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose interruption/delay | 15 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to permanent discontinuation of study treatment | 4 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Deaths during follow-up period | 15 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs | 0 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Any serious adverse event (SAE) | 10 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose reduction | 14 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs related to study treatment | 0 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Any serious adverse event (SAE) | 9 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose reduction | 14 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | SAEs related to study treatment | 5 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to permanent discontinuation of study treatment | 2 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs | 0 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | AEs related to study treatment | 20 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Deaths during follow-up period | 17 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Any Adverse Event (AE) | 20 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | Deaths during treatment period | 0 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose interruption/delay | 18 Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Deaths during follow-up period | 16 Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs related to study treatment | 20 Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Any serious adverse event (SAE) | 6 Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Deaths during treatment period | 0 Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs | 0 Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to permanent discontinuation of study treatment | 1 Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose reduction | 5 Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | AEs leading to dose interruption/delay | 9 Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Any Adverse Event (AE) | 20 Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | SAEs related to study treatment | 5 Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Number of Participants With Adverse Events | Fatal SAEs related to study treatment | 0 Participants |
Primary
Overall Response Rate (ORR)
Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) was used for efficacy based on radiological assessment of tumor burden: CR = Complete Response, disappearance of all target lesions; PR = Partial Response, \>=30% decrease in the sum of the longest diameter of target lesions; PD = progressive disease, \>=20% increase in sum of target lesions and/or presence of new lesions and/or substantial increase in non-target lesion; SD = stable disease, response not meeting CR or PR or PD; ORR = overall response rate, defined as CR+PR
Time frame: From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
Population: All treated population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Overall Response Rate (ORR) | 67 Percentage of Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Overall Response Rate (ORR) | 0 Percentage of Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Overall Response Rate (ORR) | 28 Percentage of Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Overall Response Rate (ORR) | 20 Percentage of Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Overall Response Rate (ORR) | 0 Percentage of Participants |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Overall Response Rate (ORR) | 0 Percentage of Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Overall Response Rate (ORR) | 0 Percentage of Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Overall Response Rate (ORR) | 0 Percentage of Participants |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 1.5MG QD, PAN 6MG/KG Q2W | Overall Response Rate (ORR) | 0 Percentage of Participants |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 2MG QD, PAN 4.8MG/KG Q2W | Overall Response Rate (ORR) | 0 Percentage of Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Overall Response Rate (ORR) | 10 Percentage of Participants |
Primary
Part 3: Progression Free Survival (PFS)
Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.
Time frame: From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
Population: All treated population. The original intention of the study was to include a randomized phase 2 portion of the study as a Part 3; however, a preliminary analysis did not meet predetermined criteria for efficacy. As a result, Part 3 of the study was not initiated.
Secondary
Absorption Rate Constant 1 (Ka1) and Absorption Rate Constant 2 (Ka2) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The absorption rate constant 1 (Ka1) and absorption rate constant 2 (Ka2) of Trametinib estimated with the PopPK model are summarized in this record.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: All subjects who received at least one dose of dabrafenib in Part 4A and 4B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Absorption Rate Constant 1 (Ka1) and Absorption Rate Constant 2 (Ka2) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model | Absorption rate constant 1 (Ka1) | 0.134 1/h |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Absorption Rate Constant 1 (Ka1) and Absorption Rate Constant 2 (Ka2) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model | Absorption rate constant 2 (Ka2) | 1.55 1/h |
Secondary
Absorption Rate Constant (Ka) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The absorption rate constant (Ka) of Dabrafenib estimated with the PopPK model is summarized in this record.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: All subjects who received at least one dose of dabrafenib in Part 4A and 4B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Absorption Rate Constant (Ka) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model | 1.22 1/h |
Secondary
Absorption Rate Constant (Ka) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The absorption rate constant (Ka) of Dabrafenib estimated with the PopPK model is summarized in this record.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: All subjects who received at least one dose of dabrafenib in Part 1, 2A and 2B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Absorption Rate Constant (Ka) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model | 1.22 1/h |
Secondary
Apparent Base Clearance (CL0/F) and Apparent Maximum Inducible Clearance at Steady State (CLIND,SS/F) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The apparent base clearance (CL0/F) and apparent maximum inducible clearance at steady state (CLIND,SS/F) dabrafenib estimated with the PopPK model are summarized in this record.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: All subjects who received at least one dose of dabrafenib in Part 4A and 4B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Apparent Base Clearance (CL0/F) and Apparent Maximum Inducible Clearance at Steady State (CLIND,SS/F) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model | Apparent base clearance (CL0/F) | 16.7 L/h |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Apparent Base Clearance (CL0/F) and Apparent Maximum Inducible Clearance at Steady State (CLIND,SS/F) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model | Apparent maximum inducible clearance at steady state (CLIND,SS/F) | 18.6 L/h |
Secondary
Apparent Base Clearance (CL0/F) and Apparent Maximum Inducible Clearance at Steady State (CLIND,SS/F) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The apparent base clearance (CL0/F) and apparent maximum inducible clearance at steady state (CLIND,SS/F) of Dabrafenib estimated with the PopPK model are summarized in this record.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: All subjects who received at least one dose of dabrafenib in Part 1, 2A and 2B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Apparent Base Clearance (CL0/F) and Apparent Maximum Inducible Clearance at Steady State (CLIND,SS/F) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model | Apparent base clearance (CL0/F) | 16.7 L/h |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Apparent Base Clearance (CL0/F) and Apparent Maximum Inducible Clearance at Steady State (CLIND,SS/F) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model | Apparent maximum inducible clearance at steady state (CLIND,SS/F) | 18.6 L/h |
Secondary
Apparent Central Volume (V/F) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The apparent central volume (V/F) of Trametinib estimated with the PopPK model is summarized in this record.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: All subjects who received at least one dose of dabrafenib in Part 4A and 4B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Apparent Central Volume (V/F) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model | 184 Liter (L) |
Secondary
Apparent Clearance (CL/F) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The apparent clearance (CL/F) of Trametinib estimated with the PopPK model is summarized in this record.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: All subjects who received at least one dose of dabrafenib in Part 4A and 4B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Apparent Clearance (CL/F) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model | 5.07 L/h |
Secondary
AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Area under the concentration-time curve from zero (pre-dose) 8 hours (AUC\[0-8\]) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.
Time frame: Day 1, Day 15, Week 8 (Dabrafenib derived metabolites), Week 12, Week 16, Week 20
Population: Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D1 (n=3,3,6,18) | 302 h*ng/mL | Geometric Coefficient of Variation 26.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=1,3,4,15) | 7300 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk12 (n=1,2,0,1) | 42.1 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk8 (n=1,2,0,1) | 506 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk16 (n=2,2,0,1) | 94.2 h*ng/mL | Geometric Coefficient of Variation 170.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D1 (n=3,3,7,18) | 6610 h*ng/mL | Geometric Coefficient of Variation 49.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk12 (n=1,2,0,1) | 260 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=1,3,4,14) | 4470 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk8 (n=1,2,0,1) | 61.6 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk16 (n=2,2,0,1) | 331 h*ng/mL | Geometric Coefficient of Variation 14.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=1,3,4,14) | 1720 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D1 (n=3,4,8,19) | 8750 h*ng/mL | Geometric Coefficient of Variation 70.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk8 (n=1,2,0,1) | 624 h*ng/mL | Geometric Coefficient of Variation 92.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk8 (n=1,2,0,1) | 443 h*ng/mL | Geometric Coefficient of Variation 6273.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk12 (n=1,2,0,1) | 250 h*ng/mL | Geometric Coefficient of Variation 22.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk16 (n=2,2,0,1) | 308 h*ng/mL | Geometric Coefficient of Variation 128.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk12 (n=1,2,0,1) | 41.1 h*ng/mL | Geometric Coefficient of Variation 1.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=1,3,4,14) | 3510 h*ng/mL | Geometric Coefficient of Variation 48.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D1 (n=3,3,7,18) | 6730 h*ng/mL | Geometric Coefficient of Variation 99.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=1,3,4,15) | 7220 h*ng/mL | Geometric Coefficient of Variation 93.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D1 (n=3,4,8,19) | 8250 h*ng/mL | Geometric Coefficient of Variation 134.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk16 (n=2,2,0,1) | 96.6 h*ng/mL | Geometric Coefficient of Variation 100.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk16 (n=0,1,0,0) | 593 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk20 (n=0,1,0,0) | 1090 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D1 (n=3,3,6,18) | 75.4 h*ng/mL | Geometric Coefficient of Variation 174.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk20 (n=0,2,0,1) | 104 h*ng/mL | Geometric Coefficient of Variation 1.48 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk20 (n=0,2,0,1) | 603 h*ng/mL | Geometric Coefficient of Variation 163.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=1,3,4,14) | 1960 h*ng/mL | Geometric Coefficient of Variation 54.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=1,3,4,14) | 2130 h*ng/mL | Geometric Coefficient of Variation 178.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D1 (n=3,4,8,19) | 6880 h*ng/mL | Geometric Coefficient of Variation 54.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=1,3,4,15) | 3390 h*ng/mL | Geometric Coefficient of Variation 223 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D1 (n=3,3,6,18) | 93.4 h*ng/mL | Geometric Coefficient of Variation 70.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=1,3,4,14) | 1900 h*ng/mL | Geometric Coefficient of Variation 87.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D1 (n=3,3,7,18) | 4440 h*ng/mL | Geometric Coefficient of Variation 30.7 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D1 (n=3,3,7,18) | 3090 h*ng/mL | Geometric Coefficient of Variation 89.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk20 (n=0,2,0,1) | 460 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk16 (n=2,2,0,1) | 538 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=1,3,4,14) | 1970 h*ng/mL | Geometric Coefficient of Variation 126.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk12 (n=1,2,0,1) | 480 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk8 (n=1,2,0,1) | 343 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk8 (n=1,2,0,1) | 156 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=1,3,4,14) | 1490 h*ng/mL | Geometric Coefficient of Variation 117.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D1 (n=3,3,6,18) | 52.6 h*ng/mL | Geometric Coefficient of Variation 137.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk12 (n=1,2,0,1) | 255 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk12 (n=0,0,0,1) | 372 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=1,3,4,15) | 5060 h*ng/mL | Geometric Coefficient of Variation 57.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk16 (n=2,2,0,1) | 83.2 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D1 (n=3,4,8,19) | 5200 h*ng/mL | Geometric Coefficient of Variation 77.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk20 (n=0,2,0,1) | 154 h*ng/mL | — |
Secondary
AUC[0-8] of Trametinib in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Area under the concentration-time curve from zero (pre-dose) 8 hours (AUC\[0-8\]) of Trametinib was listed and summarized using descriptive statistics.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Trametinib in the Triple Combination (D+T+P) | Day 1 (n=3,3,8,19) | 21.3 h*ng/mL | Geometric Coefficient of Variation 12.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=1,3,3,16) | 141 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Trametinib in the Triple Combination (D+T+P) | Week 8 (n=2,0,0,0) | 73.6 h*ng/mL | Geometric Coefficient of Variation 54.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Trametinib in the Triple Combination (D+T+P) | Week 12 (n=2,0,0,1) | 49.6 h*ng/mL | Geometric Coefficient of Variation 67.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Trametinib in the Triple Combination (D+T+P) | Week 16 (n=1,1,0,0) | 99.2 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Trametinib in the Triple Combination (D+T+P) | Week 20 (n=1,0,0,0) | 90.4 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Trametinib in the Triple Combination (D+T+P) | Day 1 (n=3,3,8,19) | 22.3 h*ng/mL | Geometric Coefficient of Variation 59.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=1,3,3,16) | 134 h*ng/mL | Geometric Coefficient of Variation 24.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Trametinib in the Triple Combination (D+T+P) | Week 16 (n=1,1,0,0) | 89.6 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Trametinib in the Triple Combination (D+T+P) | Day 1 (n=3,3,8,19) | 32.9 h*ng/mL | Geometric Coefficient of Variation 42.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | AUC[0-8] of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=1,3,3,16) | 152 h*ng/mL | Geometric Coefficient of Variation 24.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Trametinib in the Triple Combination (D+T+P) | Day 1 (n=3,3,8,19) | 16.4 h*ng/mL | Geometric Coefficient of Variation 108.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Trametinib in the Triple Combination (D+T+P) | Week 12 (n=2,0,0,1) | 74.6 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | AUC[0-8] of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=1,3,3,16) | 111 h*ng/mL | Geometric Coefficient of Variation 35.5 |
Secondary
AUC[0-t] of Trametinib in the Double Combination (T+P)
Serial blood samples will be collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples will be collected every 4 weeks up to and including Week 20 on study. Area under the concentration-time curve from zero (pre-dose) the time of the last quantifiable concentration (AUC\[0-t\]) of Trametinib was listed and summarized using descriptive statistics.
Time frame: Day 1, Day 15, Week 12, Week 20
Population: Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-t] of Trametinib in the Double Combination (T+P) | Day 15 (n=1,2,0) | 81 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-t] of Trametinib in the Double Combination (T+P) | Week 12 (n=1,0,0) | 78.6 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | AUC[0-t] of Trametinib in the Double Combination (T+P) | Week 20 (n=1,0,0) | 171 h*ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-t] of Trametinib in the Double Combination (T+P) | Day 1 (n=0,2,0) | 2.78 h*ng/mL | Geometric Coefficient of Variation 718.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | AUC[0-t] of Trametinib in the Double Combination (T+P) | Day 15 (n=1,2,0) | 38.4 h*ng/mL | Geometric Coefficient of Variation 56.5 |
Secondary
Change in Levels of Proteins/Ribonucleic Acid (RNA)
H-score or Histo-score measures cell membrane immunohistochemistry staining intensity in a fixed field. Membrane staining is categorized as 1+, 2+, or 3+. Minimum score is 0, maximum score is 300 (no subscale values are reported). H-score values themselves are not considered to be better or worse - measurements for levels of proteins/ribonucleic acid (RNA) are surrogate for MAPK pathway activity. Low values = low pathway activity. High values = high pathway activity. Changes in mean phosphorylated-ERK (pERK) and phosphorylated ribosomal protein S6 (pS6) H-score from baseline indicate changes in MAPK pathway activity that may be associated with treatment arms. A positive change from baseline suggests increased pathway activity. A negative change from baseline suggests decreased pathway activity. Total score is calculated as follows: \[1 x (% cells 1+) + 2 x (% cells 2+) + 3 x (% cells 3+)\].
Time frame: Baseline, Day 15
Population: All treated population. Parameter information at baseline of patients with two different baseline were excluded. Day 15 included post-baseline information between study day 13 - 18.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score @ change from BL @ D15 (n=1,2,10,13,4,4,5,1,4,4,10) | 150.0 H-Score | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 210.0 H-Score | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score @ change from BL @ D15 (n=1,2,10,13,4,4,6,1,4,4,9) | 85.0 H-Score | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: Baseline (BL) (n=1,3,13,15,4,4,5,1,4,4,11) | 60.0 H-Score | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 260.0 H-Score | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: Baseline (BL) (n=1,3,13,15,4,4,6,1,4,4,10) | 175.0 H-Score | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score @ change from BL @ D15 (n=1,2,10,13,4,4,5,1,4,4,10) | -158.0 H-Score | Standard Deviation 18.38 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: Baseline (BL) (n=1,3,13,15,4,4,5,1,4,4,11) | 195.7 H-Score | Standard Deviation 14.01 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: Baseline (BL) (n=1,3,13,15,4,4,6,1,4,4,10) | 209.3 H-Score | Standard Deviation 77.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score @ change from BL @ D15 (n=1,2,10,13,4,4,6,1,4,4,9) | -107.5 H-Score | Standard Deviation 31.82 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 30.5 H-Score | Standard Deviation 27.58 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 60.0 H-Score | Standard Deviation 70.71 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: Baseline (BL) (n=1,3,13,15,4,4,6,1,4,4,10) | 143.7 H-Score | Standard Deviation 80.48 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: Baseline (BL) (n=1,3,13,15,4,4,5,1,4,4,11) | 140.7 H-Score | Standard Deviation 96.51 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 59.7 H-Score | Standard Deviation 78.21 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score @ change from BL @ D15 (n=1,2,10,13,4,4,5,1,4,4,10) | -62.9 H-Score | Standard Deviation 71.41 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score @ change from BL @ D15 (n=1,2,10,13,4,4,6,1,4,4,9) | -68.1 H-Score | Standard Deviation 61.49 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 73.8 H-Score | Standard Deviation 59.93 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score @ change from BL @ D15 (n=1,2,10,13,4,4,6,1,4,4,9) | -27.2 H-Score | Standard Deviation 66.65 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 82.6 H-Score | Standard Deviation 78.16 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: Baseline (BL) (n=1,3,13,15,4,4,6,1,4,4,10) | 102.3 H-Score | Standard Deviation 75.55 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: Baseline (BL) (n=1,3,13,15,4,4,5,1,4,4,11) | 148.7 H-Score | Standard Deviation 83.46 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 68.0 H-Score | Standard Deviation 76.64 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score @ change from BL @ D15 (n=1,2,10,13,4,4,5,1,4,4,10) | -66.0 H-Score | Standard Deviation 56.12 |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: Baseline (BL) (n=1,3,13,15,4,4,6,1,4,4,10) | 194.0 H-Score | Standard Deviation 132.7 |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: Baseline (BL) (n=1,3,13,15,4,4,5,1,4,4,11) | 114.3 H-Score | Standard Deviation 60.31 |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score @ change from BL @ D15 (n=1,2,10,13,4,4,6,1,4,4,9) | -126.3 H-Score | Standard Deviation 101.27 |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 40.0 H-Score | Standard Deviation 39.16 |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 67.8 H-Score | Standard Deviation 76.81 |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score @ change from BL @ D15 (n=1,2,10,13,4,4,5,1,4,4,10) | -74.3 H-Score | Standard Deviation 44.92 |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 98.5 H-Score | Standard Deviation 110.15 |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: Baseline (BL) (n=1,3,13,15,4,4,5,1,4,4,11) | 255.3 H-Score | Standard Deviation 33.72 |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 52.5 H-Score | Standard Deviation 65.89 |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score @ change from BL @ D15 (n=1,2,10,13,4,4,5,1,4,4,10) | -202.8 H-Score | Standard Deviation 74.41 |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: Baseline (BL) (n=1,3,13,15,4,4,6,1,4,4,10) | 193.8 H-Score | Standard Deviation 83.4 |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score @ change from BL @ D15 (n=1,2,10,13,4,4,6,1,4,4,9) | -95.3 H-Score | Standard Deviation 88.35 |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score @ change from BL @ D15 (n=1,2,10,13,4,4,6,1,4,4,9) | -116.5 H-Score | Standard Deviation 103.16 |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: Baseline (BL) (n=1,3,13,15,4,4,5,1,4,4,11) | 209.2 H-Score | Standard Deviation 89.95 |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score @ change from BL @ D15 (n=1,2,10,13,4,4,5,1,4,4,10) | -77.2 H-Score | Standard Deviation 97.77 |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: Baseline (BL) (n=1,3,13,15,4,4,6,1,4,4,10) | 180.8 H-Score | Standard Deviation 75.59 |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 131.3 H-Score | Standard Deviation 36.04 |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 64.3 H-Score | Standard Deviation 73.21 |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score @ change from BL @ D15 (n=1,2,10,13,4,4,6,1,4,4,9) | -50.0 H-Score | — |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: Baseline (BL) (n=1,3,13,15,4,4,6,1,4,4,10) | 40.0 H-Score | — |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score @ change from BL @ D15 (n=1,2,10,13,4,4,5,1,4,4,10) | -45.0 H-Score | — |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: Baseline (BL) (n=1,3,13,15,4,4,5,1,4,4,11) | 145.0 H-Score | — |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 40.0 H-Score | — |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 100.0 H-Score | — |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score @ change from BL @ D15 (n=1,2,10,13,4,4,5,1,4,4,10) | 8.8 H-Score | Standard Deviation 110.78 |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: Baseline (BL) (n=1,3,13,15,4,4,6,1,4,4,10) | 51.0 H-Score | Standard Deviation 51.48 |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 155.0 H-Score | Standard Deviation 54.47 |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 44.8 H-Score | Standard Deviation 53.92 |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: Baseline (BL) (n=1,3,13,15,4,4,5,1,4,4,11) | 146.3 H-Score | Standard Deviation 71.81 |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 1.5MG QD, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score @ change from BL @ D15 (n=1,2,10,13,4,4,6,1,4,4,9) | -6.3 H-Score | Standard Deviation 15.28 |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: Baseline (BL) (n=1,3,13,15,4,4,5,1,4,4,11) | 188.8 H-Score | Standard Deviation 33.26 |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: Baseline (BL) (n=1,3,13,15,4,4,6,1,4,4,10) | 65.5 H-Score | Standard Deviation 50.71 |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score @ change from BL @ D15 (n=1,2,10,13,4,4,6,1,4,4,9) | 7.3 H-Score | Standard Deviation 101.26 |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 171.0 H-Score | Standard Deviation 76.18 |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score @ change from BL @ D15 (n=1,2,10,13,4,4,5,1,4,4,10) | -17.8 H-Score | Standard Deviation 102.67 |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 2MG QD, PAN 4.8MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 72.8 H-Score | Standard Deviation 88.31 |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score @ change from BL @ D15 (n=1,2,10,13,4,4,6,1,4,4,9) | -70.4 H-Score | Standard Deviation 67.19 |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: Baseline (BL) (n=1,3,13,15,4,4,5,1,4,4,11) | 163.9 H-Score | Standard Deviation 80.84 |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score @ change from BL @ D15 (n=1,2,10,13,4,4,5,1,4,4,10) | -14.7 H-Score | Standard Deviation 77.91 |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pERK H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 149.2 H-Score | Standard Deviation 81.68 |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: Baseline (BL) (n=1,3,13,15,4,4,6,1,4,4,10) | 202.8 H-Score | Standard Deviation 86.14 |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Change in Levels of Proteins/Ribonucleic Acid (RNA) | pS6 H score: D15 (n=1,2,10,14,4,4,6,1,4,4,11) | 130.1 H-Score | Standard Deviation 75.7 |
Secondary
Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Maximum observed concentration (Cmax) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D1 (n=3,4,8,22) | 1430 ng/mL | Geometric Coefficient of Variation 51.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=1,3,5,18) | 2410 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk8 (n=1,2,0,3) | 32.4 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=1,3,5,19) | 311 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk12 (n=1,2,0,3) | 21.4 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk16 (n=2,2,0,2) | 209 ng/mL | Geometric Coefficient of Variation 65.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk16 (n=2,2,0,2) | 59.4 ng/mL | Geometric Coefficient of Variation 358.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk8 (n=1,2,0,3) | 266 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D1 (n=3,4,8,22) | 2440 ng/mL | Geometric Coefficient of Variation 91.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=1,3,5,19) | 1050 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk12 (n=1,2,0,3) | 132 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D1 (n=3,4,7,21) | 120 ng/mL | Geometric Coefficient of Variation 43.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=1,3,5,18) | 1800 ng/mL | Geometric Coefficient of Variation 161.7 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=1,3,5,19) | 718 ng/mL | Geometric Coefficient of Variation 69.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk8 (n=1,2,0,3) | 312 ng/mL | Geometric Coefficient of Variation 88.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D1 (n=3,4,8,22) | 1010 ng/mL | Geometric Coefficient of Variation 92.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk12 (n=1,2,0,3) | 130 ng/mL | Geometric Coefficient of Variation 23.7 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk16 (n=2,2,0,2) | 135 ng/mL | Geometric Coefficient of Variation 79.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk20 (n=0,2,1,2) | 269 ng/mL | Geometric Coefficient of Variation 110.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D1 (n=3,4,8,22) | 2400 ng/mL | Geometric Coefficient of Variation 162.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk16 (n=2,2,0,2) | 42.5 ng/mL | Geometric Coefficient of Variation 59 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk12 (n=1,2,0,3) | 21.3 ng/mL | Geometric Coefficient of Variation 2.7 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk16 (n=0,1,0,1) | 74.1 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk20 (n=0,1,1,1) | 136 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk20 (n=0,2,1,2) | 46.4 ng/mL | Geometric Coefficient of Variation 189.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk8 (n=1,2,0,3) | 221 ng/mL | Geometric Coefficient of Variation 6687 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D1 (n=3,4,7,21) | 21.2 ng/mL | Geometric Coefficient of Variation 109 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=1,3,5,19) | 360 ng/mL | Geometric Coefficient of Variation 77 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk20 (n=0,2,1,2) | 82.1 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D1 (n=3,4,8,22) | 2180 ng/mL | Geometric Coefficient of Variation 83.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=1,3,5,18) | 1100 ng/mL | Geometric Coefficient of Variation 331.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk20 (n=0,1,1,1) | 7.92 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D1 (n=3,4,7,21) | 34.8 ng/mL | Geometric Coefficient of Variation 76.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=1,3,5,19) | 347 ng/mL | Geometric Coefficient of Variation 94.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D1 (n=3,4,8,22) | 1060 ng/mL | Geometric Coefficient of Variation 56.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=1,3,5,19) | 477 ng/mL | Geometric Coefficient of Variation 202.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk20 (n=0,2,1,2) | 12 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D1 (n=3,4,8,22) | 1550 ng/mL | Geometric Coefficient of Variation 87.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D1 (n=3,4,8,22) | 674 ng/mL | Geometric Coefficient of Variation 71 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk8 (n=1,2,0,3) | 197 ng/mL | Geometric Coefficient of Variation 47.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=1,3,5,19) | 328 ng/mL | Geometric Coefficient of Variation 70.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk20 (n=0,2,1,2) | 284 ng/mL | Geometric Coefficient of Variation 812.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=1,3,5,19) | 656 ng/mL | Geometric Coefficient of Variation 86 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D1 (n=3,4,7,21) | 23.3 ng/mL | Geometric Coefficient of Variation 97.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk20 (n=0,1,1,1) | 5700 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk8 (n=1,2,0,3) | 238 ng/mL | Geometric Coefficient of Variation 310.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk16 (n=0,1,0,1) | 2150 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk12 (n=0,0,0,3) | 848 ng/mL | Geometric Coefficient of Variation 3137.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk12 (n=1,2,0,3) | 518 ng/mL | Geometric Coefficient of Variation 362.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk8 (n=0,0,0,2) | 699 ng/mL | Geometric Coefficient of Variation 237.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=1,3,5,18) | 1580 ng/mL | Geometric Coefficient of Variation 84.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk16 (n=2,2,0,2) | 200 ng/mL | Geometric Coefficient of Variation 2064.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk20 (n=0,2,1,2) | 404 ng/mL | Geometric Coefficient of Variation 131.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk16 (n=2,2,0,2) | 421 ng/mL | Geometric Coefficient of Variation 106.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk12 (n=1,2,0,3) | 385 ng/mL | Geometric Coefficient of Variation 86 |
Secondary
Cmax of Trametinib in the Double Combination (T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Maximum observed concentration (Cmax) of Trametinib was listed and summarized using descriptive statistics.
Time frame: Day 1, Day 15, Week 12, Week 20
Population: Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Trametinib in the Double Combination (T+P) | Day 15 (n=1,2,0) | 22.9 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Trametinib in the Double Combination (T+P) | Week 12 (n=1,0,0) | 19.3 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Trametinib in the Double Combination (T+P) | Week 20 (n=1,0,0) | 29.9 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Trametinib in the Double Combination (T+P) | Day 1 (n=0,2,0) | 1.53 ng/mL | Geometric Coefficient of Variation 164.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Trametinib in the Double Combination (T+P) | Day 15 (n=1,2,0) | 12 ng/mL | Geometric Coefficient of Variation 47.1 |
Secondary
Cmax of Trametinib in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Maximum observed concentration (Cmax) of Trametinib was listed and summarized using descriptive statistics.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Week 16 (n=1,1,0,1) | 12.4 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Week 20 (n=1,0,1,1) | 11.3 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Day 1 (n=3,4,8,22) | 5.31 ng/mL | Geometric Coefficient of Variation 28.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Week 8 (n=2,0,0,2) | 9.2 ng/mL | Geometric Coefficient of Variation 54.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Week 12 (n=2,0,0,3) | 6.2 ng/mL | Geometric Coefficient of Variation 67.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=1,3,4,18) | 24 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Week 16 (n=1,1,0,1) | 11.2 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=1,3,4,18) | 20 ng/mL | Geometric Coefficient of Variation 33.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Day 1 (n=3,4,8,22) | 5.08 ng/mL | Geometric Coefficient of Variation 82.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=1,3,4,18) | 22.2 ng/mL | Geometric Coefficient of Variation 42.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Day 1 (n=3,4,8,22) | 10.3 ng/mL | Geometric Coefficient of Variation 58.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Week 20 (n=1,0,1,1) | 6.89 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Week 20 (n=1,0,1,1) | 38.1 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Day 1 (n=3,4,8,22) | 4.65 ng/mL | Geometric Coefficient of Variation 112.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=1,3,4,18) | 19.5 ng/mL | Geometric Coefficient of Variation 47.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Week 8 (n=2,0,0,2) | 30.1 ng/mL | Geometric Coefficient of Variation 18.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Week 12 (n=2,0,0,3) | 19.7 ng/mL | Geometric Coefficient of Variation 73.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Cmax of Trametinib in the Triple Combination (D+T+P) | Week 16 (n=1,1,0,1) | 29.5 ng/mL | — |
Secondary
Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.
Time frame: Day 15, Week 8, Week 12, Week 16, Week 20
Population: Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=2,4,27,38) | 36.7 ng/mL | Geometric Coefficient of Variation 73.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk8 (n=3,2,2,4) | 95.9 ng/mL | Geometric Coefficient of Variation 119.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk16 (n=3,2,2,4) | 138 ng/mL | Geometric Coefficient of Variation 99 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk12 (n=3,4,1,4) | 169 ng/mL | Geometric Coefficient of Variation 65 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk20 (n=2,2,2,4) | 267 ng/mL | Geometric Coefficient of Variation 21.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=2,4,27,38) | 62.7 ng/mL | Geometric Coefficient of Variation 53.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk16 (n=3,2,2,4) | 65.3 ng/mL | Geometric Coefficient of Variation 190.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk8 (n=3,2,2,4) | 76.1 ng/mL | Geometric Coefficient of Variation 132.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk16 (n=3,2,2,4) | 76.6 ng/mL | Geometric Coefficient of Variation 187.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk20 (n=2,2,2,4) | 116 ng/mL | Geometric Coefficient of Variation 203.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=2,4,27,38) | 202 ng/mL | Geometric Coefficient of Variation 44.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk12 (n=3,4,1,4) | 93.3 ng/mL | Geometric Coefficient of Variation 205.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk8 (n=3,2,2,4) | 553 ng/mL | Geometric Coefficient of Variation 72.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk20 (n=2,2,2,4) | 162 ng/mL | Geometric Coefficient of Variation 156 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk12 (n=3,4,1,4) | 171 ng/mL | Geometric Coefficient of Variation 48.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk12 (n=3,4,1,4) | 146 ng/mL | Geometric Coefficient of Variation 21 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk8 (n=3,2,2,4) | 221 ng/mL | Geometric Coefficient of Variation 6687 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk20 (n=2,2,2,4) | 38 ng/mL | Geometric Coefficient of Variation 499.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk16 (n=3,2,2,4) | 135 ng/mL | Geometric Coefficient of Variation 79.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk8 (n=3,2,2,4) | 343 ng/mL | Geometric Coefficient of Variation 10622.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=2,4,27,38) | 69.5 ng/mL | Geometric Coefficient of Variation 226.7 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk12 (n=3,4,1,4) | 49.6 ng/mL | Geometric Coefficient of Variation 126.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk20 (n=2,2,2,4) | 269 ng/mL | Geometric Coefficient of Variation 110.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk12 (n=3,4,1,4) | 40.2 ng/mL | Geometric Coefficient of Variation 132.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk8 (n=3,2,2,4) | 312 ng/mL | Geometric Coefficient of Variation 88.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk20 (n=2,2,2,4) | 46.4 ng/mL | Geometric Coefficient of Variation 189.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk16 (n=3,2,2,4) | 42.5 ng/mL | Geometric Coefficient of Variation 59 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=2,4,27,38) | 249 ng/mL | Geometric Coefficient of Variation 26.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk16 (n=3,2,2,4) | 36.7 ng/mL | Geometric Coefficient of Variation 129.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=2,4,27,38) | 59.7 ng/mL | Geometric Coefficient of Variation 691.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk12 (n=3,4,1,4) | 134 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=2,4,27,38) | 65.8 ng/mL | Geometric Coefficient of Variation 180 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk8 (n=3,2,2,4) | 65.8 ng/mL | Geometric Coefficient of Variation 85.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk12 (n=3,4,1,4) | 361 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk16 (n=3,2,2,4) | 23.5 ng/mL | Geometric Coefficient of Variation 621.7 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk20 (n=2,2,2,4) | 45.5 ng/mL | Geometric Coefficient of Variation 2117.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=2,4,27,38) | 237 ng/mL | Geometric Coefficient of Variation 123.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk8 (n=3,2,2,4) | 154 ng/mL | Geometric Coefficient of Variation 5.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk16 (n=3,2,2,4) | 100 ng/mL | Geometric Coefficient of Variation 74.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk20 (n=2,2,2,4) | 87.8 ng/mL | Geometric Coefficient of Variation 9.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=2,4,27,38) | 52.3 ng/mL | Geometric Coefficient of Variation 135.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk8 (n=3,2,2,4) | 76 ng/mL | Geometric Coefficient of Variation 83.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk12 (n=3,4,1,4) | 275 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk16 (n=3,2,2,4) | 32.7 ng/mL | Geometric Coefficient of Variation 287.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk20 (n=2,2,2,4) | 58.9 ng/mL | Geometric Coefficient of Variation 1252 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk8 (n=3,2,2,4) | 129 ng/mL | Geometric Coefficient of Variation 114.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk8 (n=3,2,2,4) | 110 ng/mL | Geometric Coefficient of Variation 1636.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk8 (n=3,2,2,4) | 88 ng/mL | Geometric Coefficient of Variation 1592.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=2,4,27,38) | 276 ng/mL | Geometric Coefficient of Variation 90.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk20 (n=2,2,2,4) | 234 ng/mL | Geometric Coefficient of Variation 4585.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=2,4,27,38) | 63.3 ng/mL | Geometric Coefficient of Variation 138.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk12 (n=3,4,1,4) | 264 ng/mL | Geometric Coefficient of Variation 593.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk16 (n=3,2,2,4) | 187 ng/mL | Geometric Coefficient of Variation 2138.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk12 (n=3,4,1,4) | 381 ng/mL | Geometric Coefficient of Variation 3566.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk20 (n=2,2,2,4) | 170 ng/mL | Geometric Coefficient of Variation 411.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk20 (n=2,2,2,4) | 254 ng/mL | Geometric Coefficient of Variation 146.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk16 (n=3,2,2,4) | 381 ng/mL | Geometric Coefficient of Variation 63.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk16 (n=3,2,2,4) | 157 ng/mL | Geometric Coefficient of Variation 666.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=2,4,27,38) | 54.2 ng/mL | Geometric Coefficient of Variation 136.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk12 (n=3,4,1,4) | 378 ng/mL | Geometric Coefficient of Variation 67 |
Secondary
Ctau of Panitumumab in the Double Combination (T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Panitumumab was listed and summarized using descriptive statistics.
Time frame: Day 15, Week 8, Week 12, Week 16, Week 20
Population: Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Double Combination (T+P) | Day 15 (n=9,11,11) | 16000 ng/mL | Geometric Coefficient of Variation 47.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Double Combination (T+P) | Week 8 (n=4,5,6) | 25300 ng/mL | Geometric Coefficient of Variation 18.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Double Combination (T+P) | Week 12 (n=5,2,4) | 13600 ng/mL | Geometric Coefficient of Variation 80.7 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Double Combination (T+P) | Week 16 (n=3,0,0) | 3510 ng/mL | Geometric Coefficient of Variation 3526 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Double Combination (T+P) | Week 20 (n=2,1,0) | 11800 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Panitumumab in the Double Combination (T+P) | Day 15 (n=9,11,11) | 17400 ng/mL | Geometric Coefficient of Variation 44 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Panitumumab in the Double Combination (T+P) | Week 20 (n=2,1,0) | NA ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Panitumumab in the Double Combination (T+P) | Week 12 (n=5,2,4) | 31700 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Panitumumab in the Double Combination (T+P) | Week 8 (n=4,5,6) | 10000 ng/mL | Geometric Coefficient of Variation 233.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Double Combination (T+P) | Day 15 (n=9,11,11) | 8160 ng/mL | Geometric Coefficient of Variation 65.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Double Combination (T+P) | Week 12 (n=5,2,4) | 5210 ng/mL | Geometric Coefficient of Variation 24.7 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Double Combination (T+P) | Week 8 (n=4,5,6) | 9570 ng/mL | Geometric Coefficient of Variation 40.8 |
Secondary
Ctau of Panitumumab in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Panitumumab was listed and summarized using descriptive statistics.
Time frame: Day 15, Week 4, Week 8, Week 12, Week 16, Week 20
Population: Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Day 15 (n=3,3,24,34) | 11100 ng/mL | Geometric Coefficient of Variation 52.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 8 (n=3,2,1,4) | 46300 ng/mL | Geometric Coefficient of Variation 37.7 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 12 (n=3,4,0,3) | 34700 ng/mL | Geometric Coefficient of Variation 53.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 16 (n=3,2,1,3) | 14000 ng/mL | Geometric Coefficient of Variation 326.7 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 20 (n=2,2,2,3) | 24400 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 20 (n=2,2,2,3) | 35400 ng/mL | Geometric Coefficient of Variation 4.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 12 (n=3,4,0,3) | 36100 ng/mL | Geometric Coefficient of Variation 51.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 8 (n=3,2,1,4) | 29900 ng/mL | Geometric Coefficient of Variation 66.7 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Day 15 (n=3,3,24,34) | 25600 ng/mL | Geometric Coefficient of Variation 53.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 16 (n=3,2,1,3) | 56400 ng/mL | Geometric Coefficient of Variation 4.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 4 (n=0,0,20,26) | 18100 ng/mL | Geometric Coefficient of Variation 73.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 8 (n=3,2,1,4) | 19300 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 20 (n=2,2,2,3) | 23800 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 16 (n=3,2,1,3) | 29400 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Day 15 (n=3,3,24,34) | 9860 ng/mL | Geometric Coefficient of Variation 99 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Day 15 (n=3,3,24,34) | 21300 ng/mL | Geometric Coefficient of Variation 64.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 16 (n=3,2,1,3) | 25200 ng/mL | Geometric Coefficient of Variation 85.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 20 (n=2,2,2,3) | 40700 ng/mL | Geometric Coefficient of Variation 46.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 12 (n=3,4,0,3) | 31700 ng/mL | Geometric Coefficient of Variation 85.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 4 (n=0,0,20,26) | 37000 ng/mL | Geometric Coefficient of Variation 52.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Panitumumab in the Triple Combination (D+T+P) | Week 8 (n=3,2,1,4) | 27900 ng/mL | Geometric Coefficient of Variation 57.7 |
Secondary
Ctau of Trametinib in the Double Combination (T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Trametinib was listed and summarized using descriptive statistics.
Time frame: Day 15, Week 8, Week 12, Week 16, Week 20
Population: Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Double Combination (T+P) | Week 16 (n=1,2,1) | 8.37 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Double Combination (T+P) | Week 12 (n=4,5,6) | 4.54 ng/mL | Geometric Coefficient of Variation 368.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Double Combination (T+P) | Day 15 (n=9,15,14) | 11 ng/mL | Geometric Coefficient of Variation 19.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Double Combination (T+P) | Week 8 (n=4,6,7) | 4.71 ng/mL | Geometric Coefficient of Variation 251.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Double Combination (T+P) | Week 20 (n=2,1,1) | 13.1 ng/mL | Geometric Coefficient of Variation 170.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Trametinib in the Double Combination (T+P) | Week 12 (n=4,5,6) | 7.28 ng/mL | Geometric Coefficient of Variation 62.7 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Trametinib in the Double Combination (T+P) | Day 15 (n=9,15,14) | 9.44 ng/mL | Geometric Coefficient of Variation 34 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Trametinib in the Double Combination (T+P) | Week 8 (n=4,6,7) | 3.36 ng/mL | Geometric Coefficient of Variation 154.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Trametinib in the Double Combination (T+P) | Week 16 (n=1,2,1) | 5.07 ng/mL | Geometric Coefficient of Variation 16.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Trametinib in the Double Combination (T+P) | Week 20 (n=2,1,1) | 5.48 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Double Combination (T+P) | Week 20 (n=2,1,1) | 10.7 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Double Combination (T+P) | Week 16 (n=1,2,1) | 1.49 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Double Combination (T+P) | Day 15 (n=9,15,14) | 11.2 ng/mL | Geometric Coefficient of Variation 38.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Double Combination (T+P) | Week 12 (n=4,5,6) | 4.26 ng/mL | Geometric Coefficient of Variation 98.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Double Combination (T+P) | Week 8 (n=4,6,7) | 7.66 ng/mL | Geometric Coefficient of Variation 116.3 |
Secondary
Ctau of Trametinib in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Trametinib was listed and summarized using descriptive statistics.
Time frame: Day 15, Week 8, Week 12, Week 16, Week 20
Population: Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 16 (n=3,2,2,4) | 4.55 ng/mL | Geometric Coefficient of Variation 114.3 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 8 (n=3,2,2,4) | 7.37 ng/mL | Geometric Coefficient of Variation 56.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 20 (n=2,2,2,4) | 6.91 ng/mL | Geometric Coefficient of Variation 78.8 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 12 (n=3,4,1,4) | 6.6 ng/mL | Geometric Coefficient of Variation 46.7 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=2,4,27,38) | 8.35 ng/mL | Geometric Coefficient of Variation 23.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 12 (n=3,4,1,4) | 8.39 ng/mL | Geometric Coefficient of Variation 158.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 16 (n=3,2,2,4) | 8.92 ng/mL | Geometric Coefficient of Variation 33.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 20 (n=2,2,2,4) | 8.67 ng/mL | Geometric Coefficient of Variation 16.4 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 8 (n=3,2,2,4) | 10.4 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=2,4,27,38) | 11.8 ng/mL | Geometric Coefficient of Variation 9.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 12 (n=3,4,1,4) | 7.51 ng/mL | — |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=2,4,27,38) | 10.8 ng/mL | Geometric Coefficient of Variation 36.9 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 8 (n=3,2,2,4) | 9.58 ng/mL | Geometric Coefficient of Variation 27.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 16 (n=3,2,2,4) | 6.66 ng/mL | Geometric Coefficient of Variation 8.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 20 (n=2,2,2,4) | 6.81 ng/mL | Geometric Coefficient of Variation 1.6 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 16 (n=3,2,2,4) | 19.4 ng/mL | Geometric Coefficient of Variation 68.1 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 8 (n=3,2,2,4) | 11.6 ng/mL | Geometric Coefficient of Variation 224.2 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=2,4,27,38) | 9.98 ng/mL | Geometric Coefficient of Variation 40.5 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 12 (n=3,4,1,4) | 15.8 ng/mL | Geometric Coefficient of Variation 78.7 |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Ctau of Trametinib in the Triple Combination (D+T+P) | Week 20 (n=2,2,2,4) | 7.28 ng/mL | Geometric Coefficient of Variation 317.3 |
Secondary
Duration of Response (DoR)
Duration of Response (DoR) was defined as the time from the first documented occurrence of response (PR or CR) until the date of the first documented progression based on RECIST v1.1 or death.
Time frame: From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
Population: All treated population. Only participants with an evaluable DoR events were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Duration of Response (DoR) | 2.9 Months |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Duration of Response (DoR) | 8.9 Months |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Duration of Response (DoR) | 6.9 Months |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Duration of Response (DoR) | 6.9 Months |
Secondary
Effect of Combination With Trametinib on Apparent Maximum Inducible Clearance at Steady State of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of combination with trametinib on apparent maximum inducible clearance at steady state (CLIND,SS/F) (CLCOMBO) of Dabrafenib estimated with the PopPK model is summarized in this record. The parameter in question is a covariate that describes the effect of Effect of combination with trametinib on apparent maximum inducible clearance: the number denoting the effect means that the including trametinib will decrease the apparent maximum inducible clearance as opposed to when dabrafenib is administered alone.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: All subjects who received at least one dose of dabrafenib in Part 1, 2A and 2B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Effect of Combination With Trametinib on Apparent Maximum Inducible Clearance at Steady State of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model | 0.625 no unit of measure |
Secondary
Oral Volume of Distribution (V/F) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The oral volume of distribution (V/F) of Dabrafenib estimated with the PopPK model is summarized in this record.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: All subjects who received at least one dose of dabrafenib in Part 4A and 4B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Oral Volume of Distribution (V/F) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model | 58.5 Liter (L) |
Secondary
Oral Volume of Distribution (V/F) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The oral volume of distribution (V/F) of Dabrafenib of Dabrafenib estimated with the PopPK model is summarized in this record.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: All subjects who received at least one dose of dabrafenib in Part 1, 2A and 2B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Oral Volume of Distribution (V/F) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model | 58.5 Liter (L) |
Secondary
Overall Survival (OS)
Overall Survival (OS) was defined as the time to death due to any cause.
Time frame: From study treatment start date until date of of death from any cause, assessed up to approximately 90 months
Population: All treated population. Only participants with an evaluable OS events were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Overall Survival (OS) | 20.7 Months |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Overall Survival (OS) | 14.7 Months |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Overall Survival (OS) | 18.8 Months |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Overall Survival (OS) | 8.3 Months |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Overall Survival (OS) | 8.2 Months |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Overall Survival (OS) | 5.8 Months |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Overall Survival (OS) | 8.6 Months |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Overall Survival (OS) | 11.2 Months |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 1.5MG QD, PAN 6MG/KG Q2W | Overall Survival (OS) | 11.5 Months |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 2MG QD, PAN 4.8MG/KG Q2W | Overall Survival (OS) | 19.9 Months |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Overall Survival (OS) | 13.9 Months |
Secondary
Part 3: Duration of Response (DoR)
Duration of Response (DoR) was defined as the time from the first documented occurrence of response (PR or CR) until the date of the first documented progression based on RECIST v1.1 or death.
Time frame: From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
Population: All treated population. The original intention of the study was to include a randomized phase 2 portion of the study as a Part 3; however, a preliminary analysis did not meet predetermined criteria for efficacy. As a result, Part 3 of the study was not initiated.
Secondary
Part 3: Number of Participants With Treatment Emergent Adverse Events
The distribution of adverse events (AE) will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
Time frame: From study treatment start date till 30 days safety follow-up, assessed up to approximately 90 months
Population: All treated population. The original intention of the study was to include a randomized phase 2 portion of the study as a Part 3; however, a preliminary analysis did not meet predetermined criteria for efficacy. As a result, Part 3 of the study was not initiated.
Secondary
Part 3: Overall Response Rate (ORR)
Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) using RECIST 1.1
Time frame: From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
Population: All treated population. The original intention of the study was to include a randomized phase 2 portion of the study as a Part 3; however, a preliminary analysis did not meet predetermined criteria for efficacy. As a result, Part 3 of the study was not initiated.
Secondary
Part 3: Overall Survival (OS)
Overall Survival (OS) was defined as the time to death due to any cause.
Time frame: From study treatment start date until date of of death from any cause, assessed up to approximately 90 months
Population: All treated population. The original intention of the study was to include a randomized phase 2 portion of the study as a Part 3; however, a preliminary analysis did not meet predetermined criteria for efficacy. As a result, Part 3 of the study was not initiated.
Secondary
Progression Free Survival (PFS)
Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.
Time frame: From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
Population: All treated population. Only participants with an evaluable PFS events were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Progression Free Survival (PFS) | 8.3 Months |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Progression Free Survival (PFS) | 4.0 Months |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Progression Free Survival (PFS) | 7.4 Months |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Progression Free Survival (PFS) | 4.2 Months |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | Progression Free Survival (PFS) | 2.9 Months |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | Progression Free Survival (PFS) | 1.6 Months |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | Progression Free Survival (PFS) | 2.7 Months |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Progression Free Survival (PFS) | 3.0 Months |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 1.5MG QD, PAN 6MG/KG Q2W | Progression Free Survival (PFS) | 2.8 Months |
| Part 4A+4B - Double Combination (T+P) Anti-EGFR: TRA 2MG QD, PAN 4.8MG/KG Q2W | Progression Free Survival (PFS) | 2.9 Months |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | Progression Free Survival (PFS) | 3.5 Months |
Secondary
Time When Ka1 Transitions to Ka2 of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The time when Ka1 transitions to Ka2 of Trametinib estimated with the PopPK model is summarized in this record.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: All subjects who received at least one dose of dabrafenib in Part 4A and 4B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Time When Ka1 Transitions to Ka2 of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model | 0.404 hour (h) |
Secondary
Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Time of occurrence of Cmax (tmax) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D1 (n=3,4,3,22) | 4 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=1,3,5,18) | 2.05 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk8 (n=1,2,0,3) | 16.8 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=1,3,5,19) | 6.03 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk12 (n=1,2,0,3) | 16.3 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk16 (n=2,2,0,2) | 21.3 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk16 (n=2,2,0,2) | 21.3 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk8 (n=1,2,0,3) | 16.8 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D1 (n=3,4,8,22) | 2 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=1,3,5,19) | 4 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk12 (n=1,2,0,3) | 16.3 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D1 (n=3,4,7,21) | 8 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=1,3,5,18) | 2 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=1,3,5,19) | 2 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk8 (n=1,2,0,3) | 16 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D1 (n=3,4,3,22) | 3 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk12 (n=1,2,0,3) | 16.6 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk16 (n=2,2,0,2) | 14.4 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk20 (n=0,2,1,2) | 14.5 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D1 (n=3,4,8,22) | 1.5 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk16 (n=2,2,0,2) | 14.4 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk12 (n=1,2,0,3) | 16.6 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk16 (n=0,1,0,1) | 11.5 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk20 (n=0,1,1,1) | 12 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk20 (n=0,2,1,2) | 14.5 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk8 (n=1,2,0,3) | 16 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D1 (n=3,4,7,21) | 7 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=1,3,5,19) | 1 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk20 (n=0,2,1,2) | 0.42 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D1 (n=3,4,8,22) | 2 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=1,3,5,18) | 1 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk20 (n=0,1,1,1) | 0.42 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D1 (n=3,4,7,21) | 8 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=1,3,5,19) | 2 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D1 (n=3,4,3,22) | 3 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=1,3,5,19) | 1 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk20 (n=0,2,1,2) | 0.42 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D1 (n=3,4,8,22) | 2 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D1 (n=3,4,3,22) | 4 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk8 (n=1,2,0,3) | 7.58 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D15 (n=1,3,5,19) | 2 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk20 (n=0,2,1,2) | 7.35 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ D15 (n=1,3,5,19) | 2.02 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ D1 (n=3,4,7,21) | 8 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk20 (n=0,1,1,1) | 0.87 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk8 (n=1,2,0,3) | 7.58 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk16 (n=0,1,0,1) | 2.23 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk12 (n=0,0,0,3) | 4.88 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk12 (n=1,2,0,3) | 4.88 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ Wk8 (n=0,0,0,2) | 4.75 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | Dabrafenib @ D15 (n=1,3,5,18) | 2 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2285403 @ Wk16 (n=2,2,0,2) | 7.87 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk20 (n=0,2,1,2) | 7.35 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk16 (n=2,2,0,2) | 7.87 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P) | GSK2167542 @ Wk12 (n=1,2,0,3) | 4.88 Hour (hr) |
Secondary
Tmax of Trametinib in the Double Combination (T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Time of occurrence of Cmax (tmax) of Trametinib was listed and summarized using descriptive statistics.
Time frame: Day 1, Day 15, Week 12, Week 20
Population: Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Trametinib in the Double Combination (T+P) | Day 15 (n=1,2,0) | 4 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Trametinib in the Double Combination (T+P) | Week 12 (n=1,0,0) | 4.07 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Trametinib in the Double Combination (T+P) | Week 20 (n=1,0,0) | 5.72 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Trametinib in the Double Combination (T+P) | Day 1 (n=0,2,0) | 2.5 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Trametinib in the Double Combination (T+P) | Day 15 (n=1,2,0) | 3 Hour (hr) |
Secondary
Tmax of Trametinib in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Time of occurrence of Cmax (tmax) of Trametinib was listed and summarized using descriptive statistics.
Time frame: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Population: Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Week 16 (n=1,1,0,1) | 11.8 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Week 20 (n=1,0,1,1) | 11.5 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=1,3,4,18) | 1 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Week 8 (n=2,0,0,2) | 10.5 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Week 12 (n=2,0,0,3) | 18.8 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Day 1 (n=3,4,8,22) | 1 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Week 16 (n=1,1,0,1) | 23 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=1,3,4,18) | 2 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Day 1 (n=3,4,8,22) | 1.5 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=1,3,4,18) | 1.04 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Week 20 (n=1,0,1,1) | 0.42 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Day 1 (n=3,4,8,22) | 2 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Week 20 (n=1,0,1,1) | 0.87 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Day 1 (n=3,4,8,22) | 2 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Day 15 (n=1,3,4,18) | 2 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Week 8 (n=2,0,0,2) | 4.75 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Week 12 (n=2,0,0,3) | 4.88 Hour (hr) |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | Tmax of Trametinib in the Triple Combination (D+T+P) | Week 16 (n=1,1,0,1) | 2.23 Hour (hr) |
Post Hoc
All Collected Deaths
On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 2454 days (treatment duration ranged from 1 to 2424 days). Deaths post treatment survival follow up were collected after the on- treatment period, up to approximately 7 years. Patients who didn't die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.
Time frame: up to 2454 days (on-treatment), up to approximately 7 years (study duration)
Population: Clinical database population; all treated patients.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | All Collected Deaths | On-treatment deaths | 0 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | All Collected Deaths | All deaths | 3 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W | All Collected Deaths | Post-treatment deaths | 3 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | All Collected Deaths | All deaths | 4 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | All Collected Deaths | Post-treatment deaths | 4 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W | All Collected Deaths | On-treatment deaths | 0 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | All Collected Deaths | All deaths | 28 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | All Collected Deaths | On-treatment deaths | 3 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W | All Collected Deaths | Post-treatment deaths | 25 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | All Collected Deaths | On-treatment deaths | 2 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | All Collected Deaths | Post-treatment deaths | 42 Participants |
| Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W | All Collected Deaths | All deaths | 44 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | All Collected Deaths | Post-treatment deaths | 11 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | All Collected Deaths | On-treatment deaths | 1 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W | All Collected Deaths | All deaths | 12 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | All Collected Deaths | Post-treatment deaths | 15 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | All Collected Deaths | On-treatment deaths | 2 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 1.5MG QD, PAN 6MG/KG Q2W | All Collected Deaths | All deaths | 17 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | All Collected Deaths | Post-treatment deaths | 17 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | All Collected Deaths | On-treatment deaths | 0 Participants |
| Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W | All Collected Deaths | All deaths | 17 Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | All Collected Deaths | On-treatment deaths | 0 Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | All Collected Deaths | Post-treatment deaths | 16 Participants |
| Part 1+2A - Double Combination (D+P): DAB 150MG BID, PAN 6MG/KG Q2W | All Collected Deaths | All deaths | 16 Participants |