Cancer, Melanoma
Conditions
Keywords
melanoma, dabrafenib, trametinib, malignant skin cancer, skin cancer, BRAF V600 Mutation-Positive Melanoma
Brief summary
This was a single-arm, open-label, multi-center, Phase II study to evaluate dabrafenib and trametinib combination therapy in subjects with BRAF V600 mutation-positive, unresectable or metastatic Acral lentiginous or cutaneous melanoma. This study evaluated the objective response rate (ORR), progression free survival (PFS), duration of response, overall survival (OS), safety and efficacy, to assess steady state (all subjects) exposure to dabrafenib, dabrafenib metabolites, and trametinib and characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of dabrafenib and trametinib. Enrolled subjects were administered dabrafenib 150 milligram (mg) orally twice daily and trametinib 2 mg orally once daily. Treatment continued until disease progression, death, unacceptable toxicity, or withdrawal of consent, or study closure. After treatment discontinuation, subjects were followed for survival and disease progression as applicable.
Detailed description
This was an open-label, single arm, Phase IIA, multi-center study to evaluate the Objective response rate (ORR) of dabrafenib and trametinib combination therapy in East Asian subjects that have BRAF V600 mutationpositive Stage IIIC (unresectable) or Stage IV (metastatic) acral lentiginous melanoma (ALM) or cutaneous melanoma. All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. A primary analysis presented the efficacy, safety and pharmacokinetics (PK) data up to the data cut-off date of 23-Feb-2018. Based on these results, dabrafenib and trametinib combination was approved in the People's Republic of China (PRC) for the treatment of BRAF-mutation positive unresectable or metastatic melanoma. Data from Mainland Chinese subjects from 01-Jul-2019 onwards are not included due to local regulations in China. Subjects continued study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study completion. After treatment discontinuation, subjects went into follow-up for survival and disease progression as applicable. Subjects could continue study treatment after disease progression if they achieved clinical response per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 or stable disease with tumour reduction; had no overt signs of toxicity; had Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 and did not require immediate surgical or radiological intervention.
Interventions
DRUGDabrafenib
Dabrafenib will be provided as 50 mg and 75 mg capsules. Each capsule will contain 50 mg or 75 mg of free base (present as the mesylate salt)
DRUGTrametinib
Trametinib study medication will be provided as 0.5 mg and 2.0 mg tablets. Each tablet will contain 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. * \>=18 years of age. * Histologically confirmed acral lentiginous or cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and BRAF V600 mutation-positive. The test was to have been conducted at a designated central laboratory. * Measurable disease (i.e., present with at least one measurable lesion) by RECIST version1.1. * Performance status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale. * All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values) must be \<=Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0) at the time of enrolment. * Able to swallow and retain oral medication and must not have had any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. * Women of child-bearing potential must have had a negative serum pregnancy test within 14 days of first dose of study treatment and agree to use effective contraception, from 14 days prior to enrolment, throughout the treatment period and for 4 months after the last dose of study treatment. * Adequate baseline organ function as defined below: Absolute Neutrophil Count:\>= 1.2 × 10\^9/liter (L); Hemoglobin: \>=9 grams (g)/deciliter (dL); Platelet count: \>=100 x 10\^9/L; Prothrombin Time/International Normalized Ratio (INR) (Subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to enrolment) and Partial Thromboplastin Time: \<=1.5 x Upper Limit of Normal (ULN); Albumin: \>=2.5 g/dL; Total bilirubin: \<=1.5 x ULN; Aspartate aminotransferase and Alanine aminotransferase: \<=2.5 x ULN; Calculated creatinine clearance (Calculate creatinine clearance using standard Cockcroft-Gault formula): \>=50 milliliter (mL)/ minute (min); Left Ventricular Ejection Fraction (LVEF) (ECHO scans must be used throughout the study) : \>= Lower limit of normal (LLN) by ECHO. * Subjects with East Asian origin.
Exclusion criteria
* Primary mucosal or ocular melanoma. * Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, LGX818, and XL281/BMS-908662) or a MEK inhibitor (including but not limited to trametinib, AZD6244, and RDEA119). * Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic anti-cancer therapy, or immuno anti-cancer therapy within 21 days prior to enrolment /or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to enrolment. (Note: Ipilimumab, pembrolizumab and nivolumab treatment must ended at least 8 weeks prior to enrollment). * Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to enrolment. (Note: in case ipilimuamb, pembrolizmab and nivolumab are investigational drug in the regions and countries, and in case of PD-L1 antibody, these investigational treatment must have ended at least 8 weeks prior to enrollment ). * Current use of a prohibited medication. * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO). * A history of Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and/or HCV will be permitted). * Leptomeningeal or brain metastases or metastases causing spinal cord compression that were: symptomatic or untreated or not stable for 3 months (must be documented by imaging) or requiring corticosteroids. Subjects that were on a stable dose of corticosteroids \>1 month or on replacement dose only, or have been off of corticosteroids for at least 2 weeks can be enrolled with approval of the medical monitor. Subjects must also have been off of enzyme-inducing anticonvulsants for \>4 weeks. * History of malignancy other than disease under study within 3 years of study enrolment with exceptions of subjects with a history of completely resected non-melanoma skin cancer, or subjects with indolent second malignancies were eligible only after the approval of the sponsor's medical monitor. * History of malignancy with confirmed activating RAS mutation at any time. Note: Prospective RAS testing was not required. However, if the results of previous RAS testing were known, they must have been used in assessing eligibility * Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could have interfered with the subject's safety, obtaining informed consent, or compliance with study procedures. * A history or evidence of cardiovascular risk including any of the following: Current LVEF \< Institutional LLN; A QTc interval corrected for heart rate \>=480 millisecond (msec) (using Bazett's formula); A history or evidence of current clinically significant uncontrolled arrhythmias. Clarification: Subjects with atrial fibrillation controlled for \>30 days prior to dosing are eligible; A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization; A history or evidence of current \>=Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines; Patients with intra-cardiac defibrillators; Treatment refractory hypertension defined as a blood pressure of systolic \>140 millimeters of mercury (mmHg) and/or diastolic \>90 mmHg which cannot be controlled by anti-hypertensive therapy; Known cardiac metastases; Abnormal cardiac valve morphology (\>=grade 2) documented by echocardiogram (subjects with grade 1 abnormalities \[i.e., mild regurgitation/stenosis\] can be entered on study). Subjects with moderate valvular thickening should not have been entered in study. * Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia determined by blood chemistry), long QT syndrome or taking medicinal products known to prolong the QT interval. * A history or current evidence of retinal vein occlusion (RVO) . * Pregnant or nursing females. * History of or current diagnosis of interstitial lung disease or pneumonitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to 35 months | To determine ORR of dabrafenib in combination with trametinib in subjects with BRAF V600 mutation-positive, unresectable or metastatic melanoma. ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 and as assessed by the investigator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to 36 months | PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China. |
| Duration of Response (DOR) - Estimate for Duration of Response - Median | Up to 36 months | Duration of response is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until the earliest date of documented radiological progression or death due to any cause among subjects who achieved a confirmed CR or PR. |
| Duration of Response (DOR) | Up to 36 months | Duration of response is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until the earliest date of documented radiological progression or death due to any cause among subjects who achieved a confirmed CR or PR. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China. |
| Overall Survival (OS) - Median | Approximately 5 years | OS is defined as the interval from first dose of study treatment to the date of death, irrespective of the cause of death; subjects still alive will be censored at the date of the last contact |
| Overall Survival (OS) | Approximately 5 years | OS is defined as the interval from first dose of study treatment to the date of death, irrespective of the cause of death; subjects still alive will be censored at the date of the last contact. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China. |
| Number of Participants With Adverse Events | Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 51 months (for both dabrafenib and also Rametinib). | An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. |
| Population Pharmacokinetics of Dabrafenib - Cmax | Day 1 and Day 15 | Cmax is the maximum peak concentration. |
| Population Pharmacokinetics of Dabrafenib - Tmax | Day 1 and Day 15 | Tmax is Time to Cmax (maximum peak concentration). |
| Population Pharmacokinetics of Dabrafenib - AUC(0-12) | Day 1 and Day 15 | AUC is the area under the concentration-time curve. |
| Population Pharmacokinetics of Dabrafenib - Ctrough | Day 1 and Day 15 | Ctrough is trough concentration. |
| Population Pharmacokinetics of Dabrafenib - Racc | Day 1 and Day 15 | Racc is the accumulation ratio. |
| Population Pharmacokinetics of Hydroxydabrafenib - Cmax | Day 1 and Day 15 | Cmax is the maximum peak concentration. |
| Population Pharmacokinetics of Hydroxydabrafenib - Tmax | Day 1 and Day 15 | Tmax is Time to Cmax (maximum peak concentration). |
| Population Pharmacokinetics of Hydroxydabrafenib - AUC(0-12) | Day 1 and Day 15 | AUC is the area under the concentration-time curve. |
| Population Pharmacokinetics of Hydroxydabrafenib - Rm/p | Day 1 and Day 15 | Rm/p is the metabolite-to-parent ratio. |
| Population Pharmacokinetics of Hydroxydabrafenib - Ctrough | Day 1 and Day 15 | Ctrough is trough concentration. |
| Population Pharmacokinetics of Hydroxydabrafenib - Racc | Day 1 and Day 15 | Racc is the accumulation ratio. |
| Progression-free Survival (PFS) - Median | Up to 36 months | PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause |
| Population Pharmacokinetics of Desmethyl-dabrafenib - Tmax | Day 1 and Day 15 | Tmax is Time to Cmax (maximum peak concentration). |
| Population Pharmacokinetics of Desmethyl-dabrafenib - AUC(0-12) | Day 1 and Day 15 | AUC is the area under the concentration-time curve. AUC0-12 and Rm/p could not be calculated on Day 1 because all desmethyl-dabrafenib PK profiles on Day 1 were still ascending. Therefore, the Racc on Day 15 could not be calculated for desmethyldabrafenib. |
| Population Pharmacokinetics of Desmethyl-dabrafenib - Rm/p | Day 1 and Day 15 | Rm/p is the metabolite-to-parent ratio. AUC0-12 and Rm/p could not be calculated on Day 1 because all desmethyl-dabrafenib PK profiles on Day 1 were still ascending. Therefore, the Racc on Day 15 could not be calculated for desmethyldabrafenib. |
| Population Pharmacokinetics of Desmethyl-dabrafenib - Ctrough | Day 1 and Day 15 | Ctrough is trough concentration. |
| Population Pharmacokinetics of Carboxydabrafenib - Cmax | Day 1 and Day 15 | Cmax is the maximum peak concentration. |
| Population Pharmacokinetics of Carboxydabrafenib - Tmax | Day 1 and Day 15 | Tmax is Time to Cmax (maximum peak concentration). |
| Population Pharmacokinetics of Carboxydabrafenib - AUC(0-12) | Day 1 and Day 15 | AUC is the area under the concentration-time curve. |
| Population Pharmacokinetics of Carboxydabrafenib - Rm/p | Day 1 and Day 15 | Rm/p is the metabolite-to-parent ratio. |
| Population Pharmacokinetics of Carboxydabrafenib - Ctrough | Day 1 and Day 15 | Ctrough is trough concentration. |
| Population Pharmacokinetics of Carboxydabrafenib - Racc | Day 1 and Day 15 | Racc is the accumulation ratio. |
| Population Pharmacokinetics of Trametinib - Cmax | Day 1 and Day 15 | Cmax is the maximum peak concentration. |
| Population Pharmacokinetics of Trametinib - Tmax | Day 1 and Day 15 | Tmax is Time to Cmax (maximum peak concentration). |
| Population Pharmacokinetics of Trametinib - AUC(0-t) | Day 1 and Day 15 | Area under the concentration-time curve from time zero (predose) to last time of quantifiable concentration within a subject across all treatments |
| Population Pharmacokinetics of Trametinib - AUC(0-24) | Day 1 and Day 15 | AUC is the area under the concentration-time curve. |
| Population Pharmacokinetics of Trametinib - Ctrough | Day 1 and Day 15 | Ctrough is trough concentration. |
| Population Pharmacokinetics of Trametinib - Racc | Day 1 and Day 15 | Racc is the accumulation ratio. |
| Population Pharmacokinetics of Desmethyl-dabrafenib - Cmax | Day 1 and Day 15 | Cmax is the maximum peak concentration. |
Countries
China, Hong Kong, South Korea, Taiwan, Thailand
Participant flow
Pre-assignment details
77 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure | 77 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Disease progression | 46 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Study closed/terminated | 5 |
| Overall Study | Withdrawal by Subject | 9 |
Baseline characteristics
| Characteristic | Arm 1 |
|---|---|
| Age, Continuous | 50.6 years STANDARD_DEVIATION 13.08 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 77 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 42 Participants |
| Sex: Female, Male Male | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 16 / 77 |
| other Total, other adverse events | 75 / 77 |
| serious Total, serious adverse events | 18 / 77 |
Outcome results
Primary
Objective Response Rate (ORR)
To determine ORR of dabrafenib in combination with trametinib in subjects with BRAF V600 mutation-positive, unresectable or metastatic melanoma. ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 and as assessed by the investigator.
Time frame: Up to 35 months
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 | Objective Response Rate (ORR) | 61 Percentage of Participants |
Secondary
Duration of Response (DOR)
Duration of response is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until the earliest date of documented radiological progression or death due to any cause among subjects who achieved a confirmed CR or PR. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China.
Time frame: Up to 36 months
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1 | Duration of Response (DOR) | PFS - Disease Progression | 27 Participants |
| Arm 1 | Duration of Response (DOR) | PFS - Death | 2 Participants |
| Arm 1 | Duration of Response (DOR) | PFS - Censored, follow-up ended | 9 Participants |
| Arm 1 | Duration of Response (DOR) | PFS - Censored, follow-up ongoing | 10 Participants |
Secondary
Duration of Response (DOR) - Estimate for Duration of Response - Median
Duration of response is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until the earliest date of documented radiological progression or death due to any cause among subjects who achieved a confirmed CR or PR.
Time frame: Up to 36 months
Population: Full analysis set, for participants who achieved CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 | Duration of Response (DOR) - Estimate for Duration of Response - Median | 12.65 Months |
Secondary
Number of Participants With Adverse Events
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Time frame: Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 51 months (for both dabrafenib and also Rametinib).
Population: Safety set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1 | Number of Participants With Adverse Events | AEs leading to discontinuation - all grades | 6 Participants |
| Arm 1 | Number of Participants With Adverse Events | Adverse events - all grades | 76 Participants |
| Arm 1 | Number of Participants With Adverse Events | Adverse events - Treatment-related - all grades | 69 Participants |
| Arm 1 | Number of Participants With Adverse Events | SAEs - all grades | 18 Participants |
| Arm 1 | Number of Participants With Adverse Events | SAEs - Treatment-related - all grades | 9 Participants |
| Arm 1 | Number of Participants With Adverse Events | Fatal SAEs - all grades | 4 Participants |
| Arm 1 | Number of Participants With Adverse Events | Fatal SAEs - Treatment-related - all grades | 1 Participants |
| Arm 1 | Number of Participants With Adverse Events | AEs leading to discontinuation - Treatment-related - all grades | 3 Participants |
| Arm 1 | Number of Participants With Adverse Events | AEs leading to dose adjustment/interruption - all grades | 39 Participants |
| Arm 1 | Number of Participants With Adverse Events | AEs leading to dose reduction - all grades | 23 Participants |
Secondary
Overall Survival (OS)
OS is defined as the interval from first dose of study treatment to the date of death, irrespective of the cause of death; subjects still alive will be censored at the date of the last contact. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China.
Time frame: Approximately 5 years
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1 | Overall Survival (OS) | Censored, follow-up ongoing | 21 Participants |
| Arm 1 | Overall Survival (OS) | Died (Event) | 43 Participants |
| Arm 1 | Overall Survival (OS) | Censored, follow-up ended | 13 Participants |
Secondary
Overall Survival (OS) - Median
OS is defined as the interval from first dose of study treatment to the date of death, irrespective of the cause of death; subjects still alive will be censored at the date of the last contact
Time frame: Approximately 5 years
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 | Overall Survival (OS) - Median | 22.90 Months |
Secondary
Population Pharmacokinetics of Carboxydabrafenib - AUC(0-12)
AUC is the area under the concentration-time curve.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Carboxydabrafenib - AUC(0-12) | Day 1 (n=1) | 34400 h.ng/mL | — |
| Arm 1 | Population Pharmacokinetics of Carboxydabrafenib - AUC(0-12) | Day 15 | 86500 h.ng/mL | Geometric Coefficient of Variation 34.1 |
Secondary
Population Pharmacokinetics of Carboxydabrafenib - Cmax
Cmax is the maximum peak concentration.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Carboxydabrafenib - Cmax | Day 1 | 3760 ng/mL | Geometric Coefficient of Variation 75.7 |
| Arm 1 | Population Pharmacokinetics of Carboxydabrafenib - Cmax | Day 15 (n=18) | 9750 ng/mL | Geometric Coefficient of Variation 32.8 |
Secondary
Population Pharmacokinetics of Carboxydabrafenib - Ctrough
Ctrough is trough concentration.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Carboxydabrafenib - Ctrough | 5160 ng/mL | Geometric Coefficient of Variation 46 |
Secondary
Population Pharmacokinetics of Carboxydabrafenib - Racc
Racc is the accumulation ratio.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Arm 1 | Population Pharmacokinetics of Carboxydabrafenib - Racc | 1.51 ratio |
Secondary
Population Pharmacokinetics of Carboxydabrafenib - Rm/p
Rm/p is the metabolite-to-parent ratio.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Carboxydabrafenib - Rm/p | Day 1 (n=1) | 3.34 ratio | — |
| Arm 1 | Population Pharmacokinetics of Carboxydabrafenib - Rm/p | Day 15 | 12.4 ratio | Geometric Coefficient of Variation 55.8 |
Secondary
Population Pharmacokinetics of Carboxydabrafenib - Tmax
Tmax is Time to Cmax (maximum peak concentration).
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Carboxydabrafenib - Tmax | Day 1 | 8.94 hr |
| Arm 1 | Population Pharmacokinetics of Carboxydabrafenib - Tmax | Day 15 (n=18) | 3.5 hr |
Secondary
Population Pharmacokinetics of Dabrafenib - AUC(0-12)
AUC is the area under the concentration-time curve.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Dabrafenib - AUC(0-12) | Day 1 | 11400 h.ng/mL | Geometric Coefficient of Variation 46.1 |
| Arm 1 | Population Pharmacokinetics of Dabrafenib - AUC(0-12) | Day 15 | 6600 h.ng/mL | Geometric Coefficient of Variation 55.6 |
Secondary
Population Pharmacokinetics of Dabrafenib - Cmax
Cmax is the maximum peak concentration.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Dabrafenib - Cmax | Day 1 | 2950 ng/mL | Geometric Coefficient of Variation 72.8 |
| Arm 1 | Population Pharmacokinetics of Dabrafenib - Cmax | Day 15 (n=18) | 2300 ng/mL | Geometric Coefficient of Variation 70.6 |
Secondary
Population Pharmacokinetics of Dabrafenib - Ctrough
Ctrough is trough concentration.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Dabrafenib - Ctrough | 77 ng/mL | Geometric Coefficient of Variation 84.3 |
Secondary
Population Pharmacokinetics of Dabrafenib - Racc
Racc is the accumulation ratio.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Dabrafenib - Racc | 0.624 ratio | Geometric Coefficient of Variation 42.7 |
Secondary
Population Pharmacokinetics of Dabrafenib - Tmax
Tmax is Time to Cmax (maximum peak concentration).
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Dabrafenib - Tmax | Day 1 | 1.95 hr |
| Arm 1 | Population Pharmacokinetics of Dabrafenib - Tmax | Day 15 (n=18) | 1.5 hr |
Secondary
Population Pharmacokinetics of Desmethyl-dabrafenib - AUC(0-12)
AUC is the area under the concentration-time curve. AUC0-12 and Rm/p could not be calculated on Day 1 because all desmethyl-dabrafenib PK profiles on Day 1 were still ascending. Therefore, the Racc on Day 15 could not be calculated for desmethyldabrafenib.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Desmethyl-dabrafenib - AUC(0-12) | 3960 h.ng/mL | Geometric Coefficient of Variation 52.9 |
Secondary
Population Pharmacokinetics of Desmethyl-dabrafenib - Cmax
Cmax is the maximum peak concentration.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Desmethyl-dabrafenib - Cmax | Day 1 | 48.9 ng/mL | Geometric Coefficient of Variation 93.5 |
| Arm 1 | Population Pharmacokinetics of Desmethyl-dabrafenib - Cmax | Day 15 (n=18) | 466 ng/mL | Geometric Coefficient of Variation 51.6 |
Secondary
Population Pharmacokinetics of Desmethyl-dabrafenib - Ctrough
Ctrough is trough concentration.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Desmethyl-dabrafenib - Ctrough | 365 ng/mL | Geometric Coefficient of Variation 63.7 |
Secondary
Population Pharmacokinetics of Desmethyl-dabrafenib - Rm/p
Rm/p is the metabolite-to-parent ratio. AUC0-12 and Rm/p could not be calculated on Day 1 because all desmethyl-dabrafenib PK profiles on Day 1 were still ascending. Therefore, the Racc on Day 15 could not be calculated for desmethyldabrafenib.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Desmethyl-dabrafenib - Rm/p | 0.616 ratio | Geometric Coefficient of Variation 51.4 |
Secondary
Population Pharmacokinetics of Desmethyl-dabrafenib - Tmax
Tmax is Time to Cmax (maximum peak concentration).
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Desmethyl-dabrafenib - Tmax | Day 1 | 9.9 hr |
| Arm 1 | Population Pharmacokinetics of Desmethyl-dabrafenib - Tmax | Day 15 (n=18) | 2.48 hr |
Secondary
Population Pharmacokinetics of Hydroxydabrafenib - AUC(0-12)
AUC is the area under the concentration-time curve.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Hydroxydabrafenib - AUC(0-12) | Day 1 (n=17) | 7930 h.ng/mL | Geometric Coefficient of Variation 43 |
| Arm 1 | Population Pharmacokinetics of Hydroxydabrafenib - AUC(0-12) | Day 15 | 4440 h.ng/mL | Geometric Coefficient of Variation 43.4 |
Secondary
Population Pharmacokinetics of Hydroxydabrafenib - Cmax
Cmax is the maximum peak concentration.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Hydroxydabrafenib - Cmax | Day 1 | 1230 ng/mL | Geometric Coefficient of Variation 44.1 |
| Arm 1 | Population Pharmacokinetics of Hydroxydabrafenib - Cmax | Day 15 (n=18) | 1200 ng/mL | Geometric Coefficient of Variation 58.7 |
Secondary
Population Pharmacokinetics of Hydroxydabrafenib - Ctrough
Ctrough is trough concentration.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Hydroxydabrafenib - Ctrough | 94 ng/mL | Geometric Coefficient of Variation 61.9 |
Secondary
Population Pharmacokinetics of Hydroxydabrafenib - Racc
Racc is the accumulation ratio.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Hydroxydabrafenib - Racc | 0.56 ratio | Geometric Coefficient of Variation 35.5 |
Secondary
Population Pharmacokinetics of Hydroxydabrafenib - Rm/p
Rm/p is the metabolite-to-parent ratio.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Hydroxydabrafenib - Rm/p | Day 1 (n=17) | 0.68 ratio | Geometric Coefficient of Variation 17 |
| Arm 1 | Population Pharmacokinetics of Hydroxydabrafenib - Rm/p | Day 15 | 0.653 ratio | Geometric Coefficient of Variation 21.4 |
Secondary
Population Pharmacokinetics of Hydroxydabrafenib - Tmax
Tmax is Time to Cmax (maximum peak concentration).
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Hydroxydabrafenib - Tmax | Day 15 (n=18) | 1.96 hr |
| Arm 1 | Population Pharmacokinetics of Hydroxydabrafenib - Tmax | Day 1 | 3.08 hr |
Secondary
Population Pharmacokinetics of Trametinib - AUC(0-24)
AUC is the area under the concentration-time curve.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Trametinib - AUC(0-24) | Day 1 | 72.7 h.ng/mL | Geometric Coefficient of Variation 27.2 |
| Arm 1 | Population Pharmacokinetics of Trametinib - AUC(0-24) | Day 15 (n=18) | 357 h.ng/mL | Geometric Coefficient of Variation 22.7 |
Secondary
Population Pharmacokinetics of Trametinib - AUC(0-t)
Area under the concentration-time curve from time zero (predose) to last time of quantifiable concentration within a subject across all treatments
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Trametinib - AUC(0-t) | Day 1 | 72.6 h.ng/mL | Geometric Coefficient of Variation 27.3 |
| Arm 1 | Population Pharmacokinetics of Trametinib - AUC(0-t) | Day 15 (n=18) | 346 h.ng/mL | Geometric Coefficient of Variation 24 |
Secondary
Population Pharmacokinetics of Trametinib - Cmax
Cmax is the maximum peak concentration.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Trametinib - Cmax | Day 1 | 9.87 ng/mL | Geometric Coefficient of Variation 58.1 |
| Arm 1 | Population Pharmacokinetics of Trametinib - Cmax | Day 15 (n=18) | 25.9 ng/mL | Geometric Coefficient of Variation 33.3 |
Secondary
Population Pharmacokinetics of Trametinib - Ctrough
Ctrough is trough concentration.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Trametinib - Ctrough | 11.2 ng/mL | Geometric Coefficient of Variation 25.2 |
Secondary
Population Pharmacokinetics of Trametinib - Racc
Racc is the accumulation ratio.
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Trametinib - Racc | 5.16 ratio | Geometric Coefficient of Variation 15.1 |
Secondary
Population Pharmacokinetics of Trametinib - Tmax
Tmax is Time to Cmax (maximum peak concentration).
Time frame: Day 1 and Day 15
Population: PK analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 | Population Pharmacokinetics of Trametinib - Tmax | Day 1 | 1.5 hr |
| Arm 1 | Population Pharmacokinetics of Trametinib - Tmax | Day 15 (n=18) | 11.3 hr |
Secondary
Progression-free Survival (PFS)
PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China.
Time frame: Up to 36 months
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1 | Progression-free Survival (PFS) | Progressive Disease (PD) (event) | 52 Participants |
| Arm 1 | Progression-free Survival (PFS) | Died (event) | 4 Participants |
| Arm 1 | Progression-free Survival (PFS) | Censored, follow-up ended | 10 Participants |
| Arm 1 | Progression-free Survival (PFS) | Censored, follow-up ongoing | 11 Participants |
Secondary
Progression-free Survival (PFS) - Median
PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause
Time frame: Up to 36 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 | Progression-free Survival (PFS) - Median | 9.17 months |
Post Hoc
All Collected Deaths
Deaths are reported in the following categories: On-treatment deaths are defined as deaths that occurred after treatment start up to 30 days after study drug discontinuation. Post-treatment deaths are defined as deaths that occurred more than 30 days after study drug discontinuation until end of post-treatment follow up. Total deaths are the combination of on-treatment deaths and post-treatment deaths.
Time frame: The collection period for mortality data occurred from start of treatment until the end of the post-treatment period, up to a maximum timeframe of 4.25 years.
Population: Safety Set (on-treatment deaths) and Full Analysis Set (total deaths)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 | All Collected Deaths | Total Deaths | 43 Participants |
| Arm 1 | All Collected Deaths | On-treatment Deaths | 16 Participants |
| Arm 1 | All Collected Deaths | Post-treatment Deaths | 27 Participants |