Locally Advanced or Metastatic NRAS Mutant Melanoma
Conditions
Brief summary
In the phase Ib, the primary purpose is to establish the maximum tolerated dose (MTD)(s)/recommended phase ll dose (RP2D) and schedule of LEE011 and MEK162 orally administered combination. Once the MTD(s)/RP2D have been determined for each tested schedule, additional patients will be enrolled in the phase II portion of the study at the RP2D on the chosen schedule in order to assess the anti-tumor activity of the combination in addition to continued evaluation of safety.
Interventions
DRUGLEE011
LEE011 will be administered orally once daily
DRUGMEK162
MEK162 will be administered orally twice daily
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1. * Patients enrolled into phase Ib may be enrolled with evaluable disease only. Patients enrolled into the phase II expansion must have at least one measurable lesion as defined by RECIST 1.1 criteria for solid tumors. * Patients must have adequate organ function, as defined by the following parameter 1. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L. 2. Hemoglobin (Hgb) ≥ 9 g/dL. 3. Platelets ≥ 75 x 109/L without transfusions within 21 days before 1st treatment. 4. PT/INR and aPTT ≤ 1.5 ULN. 5. Serum creatinine ≤1.5 ULN. 6. Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN). 7. AST and ALT ≤ 3 x ULN, except in patients with tumor involvement of the liver who must have AST and ALT ≤ 5 x ULN.
Exclusion criteria
* Presence of any brain metastases detected by MRI or CT with i.v. contrast of the brain at screening. * Uncontrolled arterial hypertension despite medical treatment * Impaired cardiac function or clinically significant cardiac diseases, including any of the following: 1. Left ventricular ejection fraction (LVEF) \< 50% as determined by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO). 2. Congenital long QT syndrome or family history of unexpected sudden cardiac death. 3. QTcF corrected with Frederica's or Bazett's formula QTcB \>450 ms for males and \>470 ms for females on screening ECG. 4. Angina pectoris ≤ 3 months prior to starting study drug 5. Acute myocardial infarction ≤ 3 months prior to starting study drug 6. Clinically significant resting bradycardia 7. History or presence of ventricular tachyarrhythmia 8. Unstable atrial fibrillation (ventricular response \>100 bpm) 9. Complete left bundle branch block 10. Right bundle branch block and left anterior hemi block (bifascicular block) 11. Obligate use of a cardiac pacemaker or implantable cardioverter defibrillator 12. Any other clinically significant heart disease * Patients who are currently receiving treatment with agents that are known to cause QTc prolongation in humans. * Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) or elevated baseline CK levels (≥ Grade 2) * Patients who are currently receiving treatment with agents that are metabolized predominantly through CYP3A4 and that have a narrow therapeutic window. * Patients with concurrent severe and/or uncontrolled concurrent medical conditions that could compromise participation in the study (i.e. uncontrolled diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection). * History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes). Other protocol related inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Dose Limiting Toxicities (Phase Ib) | first 28 days of treatment | To estimate the maximum tolerate doses (MTDs) and/or identify the RP2D and schedule of LEE011 and MEK162 combination. A dose-limiting toxicity (DLT) was defined as an AE or clinically significant abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the first cycle of treatment with ribociclib and binimetinib. |
| Objective Response Rate (ORR) (Phase II) | Approximately 12 months after the FPFV | ORR is the proportion of patients with best overall response of complete response (CR) or partial response (PR) by month 2 assessed according to RECIST 1.1 criteria. ORR is done to describe the anti-tumor activity of LEE011 and MEK162 combination. The primary analysis of the ORR was based on the Investigator's assessment of overall lesion responses per RECIST 1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib) | Cycle 1 Day 1 | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib) | Cycle 1 Day 1 | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib) | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (Phase Ib) | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib) | For the 28-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 14 | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib) | For the 28-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 14 | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib) | Cycle 1 Day 1 | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib) | Cycle 1 Day 1 | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib) | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (Cmax,ss) of MEK162 (Phase Ib) | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib) | Cycle 1 Day 1 | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib) | Cycle 1 Day 1 | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib) | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (Tmax,ss) of MEK162 (Phase Ib) | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib) | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib) | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib) | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (T1/2,ss) of MEK162 (Phase Ib) | For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14 | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib) | Cycle 1 Day 1 | To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib). |
| Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib) | Cycle 1 Day 1 | To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib). |
| Number of Participants With Adverse Drug Reactions | Approximately 12 months after FPFV | Safety and tolerability will be characterized through the incidence and severity of adverse drug reactions, serious adverse drug reactions, changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, dose reduction and dose intensity. |
| Duration of Response (DoR) - Phase 2 | Approximately 12 months after the FPFV | To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer. Please note: As clinicaltrials.gov only allows numerical data entry, the value of 999 indicates not estimable for confidence interval. |
| Time to Progression (TTP) - Phase 2 | Approximately 12 months after the FPFV | To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer. |
| Progression Free Survival (PFS) - Phase 1b and Phase 2 | Approximately 12 months after the FPFV | To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer. In the Phase 1b part, patients were combined for purposes of PFS analyses based on schedule received, since too few patients received any individual dose level to allow for valid PFS estimates within the respective dose levels. This is how the data were analyses and presented for the clinical study report. |
| Overall Survival (OS) - Phase ll | Approximately 12 months after the FPFV | To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer. |
| Best Overall Response (BOR) - Phase II | Approximately 12 months after the FPFV | To assess clinical safety according to RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer. |
Countries
Australia, Germany, Italy, Netherlands, United States
Participant flow
Recruitment details
Upon study entry, all patients were required to provide either an archival tumor biopsy with the corresponding pathology report or a newly obtained tumor biopsy. Both parts of the study were limited to patients aged 18 or older with metastatic or locally advanced NRAS-mutant melanoma.
Pre-assignment details
Screening details: Screening assessments were performed within 14 days prior to the first dose of ribociclib and binimetinib except for the pretreatment tumor biopsy, which was performed within 28 days before dosing. A total of 23 patients were screened but not enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg MEK162 45mg + LEE011 200mg | 16 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg MEK162 45mg+LEE011 250mg | 3 |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg MEK162 30mg+LEE011 300mg | 4 |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg MEK162 45mg+LEE011 300mg | 6 |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg MEK162 30mg+LEE011 200mg | 5 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg MEK162 45mg+LEE011 200mg | 6 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg MEK162 30mg+LEE011 300mg | 2 |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg MEK162 45mg+LEE011 300mg | 4 |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg MEK162 45mg+LEE011 450mg | 9 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg MEK162 45mg+LEE011 600mg | 6 |
| Phase 2: MEK162 45mg+LEE011 200mg MEK162 45mg+LEE011 200mg | 41 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| MEK162 30mg BID+LEE011 300mg | Adverse Event | 1 | 0 | 0 |
| MEK162 30mg BID+LEE011 300mg | Progressive Disease | 3 | 2 | 0 |
| MEK162 30mg LEE011 200mg | Progressive Disease | 0 | 5 | 0 |
| MEK162 45mg BID+LEE011 200mg | Adverse Event | 7 | 0 | 11 |
| MEK162 45mg BID+LEE011 200mg | Death | 0 | 0 | 1 |
| MEK162 45mg BID+LEE011 200mg | Physician Decision | 0 | 0 | 4 |
| MEK162 45mg BID+LEE011 200mg | Progressive disease | 8 | 6 | 23 |
| MEK162 45mg BID+LEE011 200mg | Withdrawal by Subject | 1 | 0 | 2 |
| MEK162 45mg BID+LEE011 250mg | Progressive Disease | 2 | 0 | 0 |
| MEK162 45mg BID+LEE011 250mg | Withdrawal by Subject | 1 | 0 | 0 |
| MEK162 45mg BID+LEE011 300mg | Adverse Event | 1 | 1 | 0 |
| MEK162 45mg BID+LEE011 300mg | Death | 1 | 0 | 0 |
| MEK162 45mg BID+LEE011 300mg | Progressive Disease | 4 | 3 | 0 |
| MEK162 45mg LEE011 450mg | Adverse Event | 0 | 1 | 0 |
| MEK162 45mg LEE011 450mg | Physician Decision | 0 | 2 | 0 |
| MEK162 45mg LEE011 450mg | Progressive Disease | 0 | 6 | 0 |
| MEK162 45mg LEE011 600mg | Adverse Event | 0 | 1 | 0 |
| MEK162 45mg LEE011 600mg | Progressive Disease | 0 | 5 | 0 |
Baseline characteristics
| Characteristic | Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Phase 2: MEK162 45mg+LEE011 200mg | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 2 Participants | 5 Participants | 1 Participants | 7 Participants | 22 Participants | 48 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 4 Participants | 3 Participants | 3 Participants | 1 Participants | 2 Participants | 4 Participants | 5 Participants | 9 Participants | 19 Participants | 54 Participants |
| Age, Continuous | 57 years STANDARD_DEVIATION 9.02 | 61.5 years STANDARD_DEVIATION 21.3 | 56 years STANDARD_DEVIATION 15.04 | 63.0 years STANDARD_DEVIATION 7.5 | 62.5 years STANDARD_DEVIATION 12.687 | 55.0 years STANDARD_DEVIATION 18.38 | 63.5 years STANDARD_DEVIATION 19.48 | 67.0 years STANDARD_DEVIATION 8.59 | 58.5 years STANDARD_DEVIATION 5.56 | 62 years STANDARD_DEVIATION 14.51 | 65 years STANDARD_DEVIATION 12.35 | 61 years STANDARD_DEVIATION 12.72 |
| Body mass index | 26.84 (kg)/m^2 STANDARD_DEVIATION 5.332 | 25.95 (kg)/m^2 STANDARD_DEVIATION 3.347 | 30.38 (kg)/m^2 STANDARD_DEVIATION 9.733 | 23.85 (kg)/m^2 STANDARD_DEVIATION 2.451 | 27.80 (kg)/m^2 STANDARD_DEVIATION 6.185 | 27.92 (kg)/m^2 STANDARD_DEVIATION 7.526 | 31.71 (kg)/m^2 STANDARD_DEVIATION 5.305 | 28.08 (kg)/m^2 STANDARD_DEVIATION 6.594 | 23.50 (kg)/m^2 STANDARD_DEVIATION 3.293 | 28.57 (kg)/m^2 STANDARD_DEVIATION 5.136 | 26.69 (kg)/m^2 STANDARD_DEVIATION 5.014 | 27.34 (kg)/m^2 STANDARD_DEVIATION 5.841 |
| ECOG performance status 0-Without restriction | 2 Participants | 1 Participants | 2 Participants | 3 Participants | 5 Participants | 2 Participants | 2 Participants | 5 Participants | 5 Participants | 10 Participants | 28 Participants | 65 Participants |
| ECOG performance status 1-Restricted in physically strenuous activity | 0 Participants | 3 Participants | 4 Participants | 2 Participants | 1 Participants | 0 Participants | 2 Participants | 4 Participants | 1 Participants | 5 Participants | 13 Participants | 35 Participants |
| ECOG performance status 2-Ambulatory and capable of all selfcare | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Caucasian | 3 Participants | 4 Participants | 6 Participants | 5 Participants | 6 Participants | 1 Participants | 4 Participants | 9 Participants | 6 Participants | 16 Participants | 40 Participants | 100 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 1 Participants | 2 Participants | 3 Participants | 1 Participants | 2 Participants | 1 Participants | 5 Participants | 8 Participants | 15 Participants | 41 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 5 Participants | 3 Participants | 3 Participants | 1 Participants | 2 Participants | 8 Participants | 1 Participants | 8 Participants | 26 Participants | 61 Participants |
| Weight | 91.47 kilograms STANDARD_DEVIATION 20.093 | 71.30 kilograms STANDARD_DEVIATION 12.631 | 97.48 kilograms STANDARD_DEVIATION 35.464 | 73.66 kilograms STANDARD_DEVIATION 8.104 | 85.20 kilograms STANDARD_DEVIATION 20.733 | 80.80 kilograms STANDARD_DEVIATION 15.274 | 97.20 kilograms STANDARD_DEVIATION 24.554 | 92.41 kilograms STANDARD_DEVIATION 20.709 | 62.95 kilograms STANDARD_DEVIATION 6.111 | 82.57 kilograms STANDARD_DEVIATION 15.014 | 79.63 kilograms STANDARD_DEVIATION 17.334 | 83.69 kilograms STANDARD_DEVIATION 20.621 |
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 | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 16 | 0 / 3 | 1 / 4 | 1 / 6 | 0 / 5 | 1 / 6 | 0 / 2 | 0 / 4 | 0 / 9 | 1 / 6 | 23 / 41 |
| other Total, other adverse events | 16 / 16 | 3 / 3 | 4 / 4 | 6 / 6 | 5 / 5 | 6 / 6 | 2 / 2 | 4 / 4 | 9 / 9 | 6 / 6 | 41 / 41 |
| serious Total, serious adverse events | 8 / 16 | 2 / 3 | 2 / 4 | 4 / 6 | 2 / 5 | 3 / 6 | 1 / 2 | 3 / 4 | 3 / 9 | 2 / 6 | 22 / 41 |
Outcome results
Primary
Number of Dose Limiting Toxicities (Phase Ib)
To estimate the maximum tolerate doses (MTDs) and/or identify the RP2D and schedule of LEE011 and MEK162 combination. A dose-limiting toxicity (DLT) was defined as an AE or clinically significant abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the first cycle of treatment with ribociclib and binimetinib.
Time frame: first 28 days of treatment
Population: Analysis is comprised of the dose-determining set, which is all patients from the safety set who either met the minimum exposure criterion below and had sufficient safety evaluations during Cycle 1 or discontinued earlier due to DLT during Cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Number of Dose Limiting Toxicities (Phase Ib) | 2 occurrence |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Number of Dose Limiting Toxicities (Phase Ib) | 0 occurrence |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Number of Dose Limiting Toxicities (Phase Ib) | 1 occurrence |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Number of Dose Limiting Toxicities (Phase Ib) | 3 occurrence |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Number of Dose Limiting Toxicities (Phase Ib) | 0 occurrence |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Number of Dose Limiting Toxicities (Phase Ib) | 1 occurrence |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Number of Dose Limiting Toxicities (Phase Ib) | 0 occurrence |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Number of Dose Limiting Toxicities (Phase Ib) | 1 occurrence |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Number of Dose Limiting Toxicities (Phase Ib) | 2 occurrence |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Number of Dose Limiting Toxicities (Phase Ib) | 0 occurrence |
Primary
Objective Response Rate (ORR) (Phase II)
ORR is the proportion of patients with best overall response of complete response (CR) or partial response (PR) by month 2 assessed according to RECIST 1.1 criteria. ORR is done to describe the anti-tumor activity of LEE011 and MEK162 combination. The primary analysis of the ORR was based on the Investigator's assessment of overall lesion responses per RECIST 1.1.
Time frame: Approximately 12 months after the FPFV
Population: Analysis population consist of the Full Analysis Set, which included all patients who received at least one dose of binimetinib or ribociclib and was used for the analysis of all endpoints unless noted otherwise.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Objective Response Rate (ORR) (Phase II) | 8 Participants |
Secondary
Best Overall Response (BOR) - Phase II
To assess clinical safety according to RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer.
Time frame: Approximately 12 months after the FPFV
Population: Analysis population consist of the Full Analysis Set, which included all patients who received at least one dose of binimetinib or ribociclib and was used for the analysis of all endpoints unless noted otherwise.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Best Overall Response (BOR) - Phase II | Complete Response | 0 Participants |
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Best Overall Response (BOR) - Phase II | Partial Response | 8 Participants |
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Best Overall Response (BOR) - Phase II | Stable Disease | 21 Participants |
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Best Overall Response (BOR) - Phase II | Progressive Disease | 6 Participants |
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Best Overall Response (BOR) - Phase II | Non-CR/Non-PD | 0 Participants |
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Best Overall Response (BOR) - Phase II | Unknown | 6 Participants |
Secondary
Duration of Response (DoR) - Phase 2
To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer. Please note: As clinicaltrials.gov only allows numerical data entry, the value of 999 indicates not estimable for confidence interval.
Time frame: Approximately 12 months after the FPFV
Population: Analysis population consist of the Full Analysis Set, which included all patients who received at least one dose of binimetinib or ribociclib and was used for the analysis of all endpoints unless noted otherwise.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Duration of Response (DoR) - Phase 2 | 10.3 months |
Secondary
Number of Participants With Adverse Drug Reactions
Safety and tolerability will be characterized through the incidence and severity of adverse drug reactions, serious adverse drug reactions, changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, dose reduction and dose intensity.
Time frame: Approximately 12 months after FPFV
Population: Analysis group consists of the safety set, which included all patients who received at least 1 dose of ribociclib or binimetinib and had at least 1 postbaseline safety assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Number of Participants With Adverse Drug Reactions | 16 Participants |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Number of Participants With Adverse Drug Reactions | 3 Participants |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Number of Participants With Adverse Drug Reactions | 4 Participants |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Number of Participants With Adverse Drug Reactions | 6 Participants |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Number of Participants With Adverse Drug Reactions | 5 Participants |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Number of Participants With Adverse Drug Reactions | 6 Participants |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Number of Participants With Adverse Drug Reactions | 2 Participants |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Number of Participants With Adverse Drug Reactions | 4 Participants |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Number of Participants With Adverse Drug Reactions | 9 Participants |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Number of Participants With Adverse Drug Reactions | 6 Participants |
| Phase 2: MEK162 45mg+LEE011 200mg | Number of Participants With Adverse Drug Reactions | 41 Participants |
Secondary
Overall Survival (OS) - Phase ll
To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer.
Time frame: Approximately 12 months after the FPFV
Population: Analysis population consist of the Full Analysis Set, which included all patients who received at least one dose of binimetinib or ribociclib and was used for the analysis of all endpoints unless noted otherwise.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Overall Survival (OS) - Phase ll | 11.3 months |
Secondary
Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib)
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Time frame: For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Population: Analysis population consist of the pharmacokinetic analysis set (PAS), which consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib) | 1.51 (hr*ng/mL) / (hr*ng/mL) | Geometric Coefficient of Variation 53.9 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib) | 2.52 (hr*ng/mL) / (hr*ng/mL) | — |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib) | 2.25 (hr*ng/mL) / (hr*ng/mL) | — |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib) | 2.29 (hr*ng/mL) / (hr*ng/mL) | Geometric Coefficient of Variation 38.4 |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib) | 2.89 (hr*ng/mL) / (hr*ng/mL) | Geometric Coefficient of Variation 32.8 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib) | 2.28 (hr*ng/mL) / (hr*ng/mL) | Geometric Coefficient of Variation 54.6 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib) | 3.29 (hr*ng/mL) / (hr*ng/mL) | Geometric Coefficient of Variation 165 |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib) | 3.50 (hr*ng/mL) / (hr*ng/mL) | Geometric Coefficient of Variation 8.68 |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib) | 1.97 (hr*ng/mL) / (hr*ng/mL) | Geometric Coefficient of Variation 45.4 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib) | 3.95 (hr*ng/mL) / (hr*ng/mL) | Geometric Coefficient of Variation 58.6 |
Secondary
Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib)
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Time frame: For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Population: Analysis population consist of the pharmacokinetic analysis set (PAS), which consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib) | 2.53 (hr*ng/mL) / (hr*ng/mL | Geometric Coefficient of Variation 45.8 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib) | 7.59 (hr*ng/mL) / (hr*ng/mL | — |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib) | 1.74 (hr*ng/mL) / (hr*ng/mL | — |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib) | 3.39 (hr*ng/mL) / (hr*ng/mL | Geometric Coefficient of Variation 15.2 |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib) | 4.47 (hr*ng/mL) / (hr*ng/mL | Geometric Coefficient of Variation 21.5 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib) | 2.26 (hr*ng/mL) / (hr*ng/mL | Geometric Coefficient of Variation 27.3 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib) | 3.14 (hr*ng/mL) / (hr*ng/mL | Geometric Coefficient of Variation 161 |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib) | 3.48 (hr*ng/mL) / (hr*ng/mL | Geometric Coefficient of Variation 53 |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib) | 2.09 (hr*ng/mL) / (hr*ng/mL | Geometric Coefficient of Variation 53.5 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib) | 3.06 (hr*ng/mL) / (hr*ng/mL | Geometric Coefficient of Variation 26 |
Secondary
Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib)
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Time frame: Cycle 1 Day 1
Population: Analysis population consist of the pharmacokinetic analysis set (PAS) which consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib) | 2120 h*ng/ml | Geometric Coefficient of Variation 66.2 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib) | 3020 h*ng/ml | Geometric Coefficient of Variation 99.4 |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib) | 5280 h*ng/ml | Geometric Coefficient of Variation 27.8 |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib) | 3860 h*ng/ml | Geometric Coefficient of Variation 42.3 |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib) | 2340 h*ng/ml | Geometric Coefficient of Variation 113 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib) | 2230 h*ng/ml | Geometric Coefficient of Variation 74.5 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib) | 5020 h*ng/ml | — |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib) | 2960 h*ng/ml | Geometric Coefficient of Variation 46.4 |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib) | 5550 h*ng/ml | Geometric Coefficient of Variation 50.3 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib) | 9840 h*ng/ml | Geometric Coefficient of Variation 65.7 |
Secondary
Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib)
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Time frame: Cycle 1 Day 1
Population: The analysis group is comprised of the pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib) | 1310 h*ng/ml | Geometric Coefficient of Variation 36.8 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib) | 1070 h*ng/ml | — |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib) | 1640 h*ng/ml | — |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib) | 1240 h*ng/ml | — |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib) | 1610 h*ng/ml | Geometric Coefficient of Variation 76 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib) | 1820 h*ng/ml | Geometric Coefficient of Variation 82.1 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib) | 747 h*ng/ml | Geometric Coefficient of Variation 31.8 |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib) | 2740 h*ng/ml | — |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib) | 2110 h*ng/ml | Geometric Coefficient of Variation 44.2 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib) | 4060 h*ng/ml | — |
Secondary
Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib)
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Time frame: For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Population: The analysis group is comprised of the pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib) | 3080 h*ng/mL | Geometric Coefficient of Variation 63.2 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib) | 15000 h*ng/mL | — |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib) | 8650 h*ng/mL | — |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib) | 7050 h*ng/mL | Geometric Coefficient of Variation 41.3 |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib) | 4700 h*ng/mL | Geometric Coefficient of Variation 28.9 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib) | 4370 h*ng/mL | Geometric Coefficient of Variation 60.3 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib) | 7480 h*ng/mL | Geometric Coefficient of Variation 2.89 |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib) | 9570 h*ng/mL | Geometric Coefficient of Variation 50.5 |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib) | 11100 h*ng/mL | Geometric Coefficient of Variation 29.1 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib) | 30700 h*ng/mL | Geometric Coefficient of Variation 46.4 |
Secondary
Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (Phase Ib)
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Time frame: For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Population: The analysis group is comprised of the pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (Phase Ib) | 2250 h*ng/mL | Geometric Coefficient of Variation 37.7 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (Phase Ib) | 2450 h*ng/mL | — |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (Phase Ib) | 1540 h*ng/mL | Geometric Coefficient of Variation 30 |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (Phase Ib) | 2180 h*ng/mL | Geometric Coefficient of Variation 12.1 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (Phase Ib) | 2980 h*ng/mL | Geometric Coefficient of Variation 58.9 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (Phase Ib) | 1990 h*ng/mL | Geometric Coefficient of Variation 22.2 |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (Phase Ib) | 3680 h*ng/mL | Geometric Coefficient of Variation 40.9 |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (Phase Ib) | 2840 h*ng/mL | Geometric Coefficient of Variation 57.5 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (Phase Ib) | 3340 h*ng/mL | Geometric Coefficient of Variation 86.5 |
Secondary
Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib)
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Time frame: Cycle 1 Day 1
Population: Analysis population consist of the pharmacokinetic analysis set (PAS), which consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib) | 72.7 L/h | Geometric Coefficient of Variation 75.4 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib) | 41.2 L/h | — |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib) | 39.2 L/h | Geometric Coefficient of Variation 26.7 |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib) | 67.6 L/h | Geometric Coefficient of Variation 35.9 |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib) | 34.3 L/h | Geometric Coefficient of Variation 81.7 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib) | 57.2 L/h | Geometric Coefficient of Variation 52.7 |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib) | 93.9 L/h | Geometric Coefficient of Variation 36.1 |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib) | 78.4 L/h | Geometric Coefficient of Variation 16 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib) | 48.7 L/h | Geometric Coefficient of Variation 68.8 |
Secondary
Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib)
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Time frame: Cycle 1 Day 1
Population: Analysis population consist of the pharmacokinetic analysis set (PAS), which consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib) | 32.5 L/h | Geometric Coefficient of Variation 36.3 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib) | 35.9 L/h | — |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib) | 17.8 L/h | — |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib) | 35.5 L/h | — |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib) | 17.9 L/h | Geometric Coefficient of Variation 80.7 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib) | 23.9 L/h | Geometric Coefficient of Variation 83.6 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib) | 37.2 L/h | Geometric Coefficient of Variation 23 |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib) | 15.9 L/h | — |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib) | 20.8 L/h | Geometric Coefficient of Variation 45.8 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib) | 10.2 L/h | — |
Secondary
Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib)
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Time frame: Cycle 1 Day 1
Population: The analysis group is comprised of the pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib) | 217 ng/mL | Geometric Coefficient of Variation 90.5 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib) | 271 ng/mL | Geometric Coefficient of Variation 87.4 |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib) | 555 ng/mL | Geometric Coefficient of Variation 44.4 |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib) | 374 ng/mL | Geometric Coefficient of Variation 47.9 |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib) | 236 ng/mL | Geometric Coefficient of Variation 143 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib) | 229 ng/mL | Geometric Coefficient of Variation 86 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib) | 368 ng/mL | — |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib) | 307 ng/mL | Geometric Coefficient of Variation 33 |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib) | 506 ng/mL | Geometric Coefficient of Variation 65.6 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib) | 1030 ng/mL | Geometric Coefficient of Variation 54.1 |
Secondary
Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib)
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Time frame: Cycle 1 Day 1
Population: The analysis group is comprised of the pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib) | 315 ng/mL | Geometric Coefficient of Variation 55.7 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib) | 296 ng/mL | Geometric Coefficient of Variation 48.4 |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib) | 247 ng/mL | Geometric Coefficient of Variation 59.7 |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib) | 231 ng/mL | Geometric Coefficient of Variation 47.3 |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib) | 234 ng/mL | Geometric Coefficient of Variation 73.9 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib) | 453 ng/mL | Geometric Coefficient of Variation 67.1 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib) | 163 ng/mL | Geometric Coefficient of Variation 47.8 |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib) | 396 ng/mL | Geometric Coefficient of Variation 52.7 |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib) | 385 ng/mL | Geometric Coefficient of Variation 50.3 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib) | 402 ng/mL | Geometric Coefficient of Variation 69.8 |
Secondary
Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib)
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Time frame: For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Population: The analysis group is comprised of the pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib) | 220 ng/mL | Geometric Coefficient of Variation 76.5 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib) | 343 ng/mL | Geometric Coefficient of Variation 150 |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib) | 220 ng/mL | — |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib) | 530 ng/mL | Geometric Coefficient of Variation 30.6 |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib) | 373 ng/mL | Geometric Coefficient of Variation 62.4 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib) | 341 ng/mL | Geometric Coefficient of Variation 69 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib) | 543 ng/mL | Geometric Coefficient of Variation 11.9 |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib) | 747 ng/mL | Geometric Coefficient of Variation 33 |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib) | 727 ng/mL | Geometric Coefficient of Variation 34.7 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib) | 1910 ng/mL | Geometric Coefficient of Variation 38.5 |
Secondary
Plasma Concentration-time Profile (Cmax,ss) of MEK162 (Phase Ib)
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Time frame: For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Population: The analysis group is comprised of the pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (Cmax,ss) of MEK162 (Phase Ib) | 441 ng/mL | Geometric Coefficient of Variation 52.6 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (Cmax,ss) of MEK162 (Phase Ib) | 309 ng/mL | Geometric Coefficient of Variation 1.6 |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Cmax,ss) of MEK162 (Phase Ib) | 284 ng/mL | Geometric Coefficient of Variation 14.5 |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (Cmax,ss) of MEK162 (Phase Ib) | 376 ng/mL | Geometric Coefficient of Variation 18 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (Cmax,ss) of MEK162 (Phase Ib) | 444 ng/mL | Geometric Coefficient of Variation 36.6 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Cmax,ss) of MEK162 (Phase Ib) | 367 ng/mL | Geometric Coefficient of Variation 31.5 |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Cmax,ss) of MEK162 (Phase Ib) | 590 ng/mL | Geometric Coefficient of Variation 12.3 |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (Cmax,ss) of MEK162 (Phase Ib) | 452 ng/mL | Geometric Coefficient of Variation 59.2 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (Cmax,ss) of MEK162 (Phase Ib) | 471 ng/mL | Geometric Coefficient of Variation 75.6 |
Secondary
Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib)
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Time frame: For the 28-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 14
Population: Analysis population consist of the pharmacokinetic analysis set (PAS), which consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib) | 88.1 ng/mL | Geometric Coefficient of Variation 56.3 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib) | 256 ng/mL | Geometric Coefficient of Variation 79.8 |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib) | 220 ng/mL | — |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib) | 113 ng/mL | Geometric Coefficient of Variation 56.4 |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib) | 117 ng/mL | Geometric Coefficient of Variation 39.8 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib) | 97.6 ng/mL | Geometric Coefficient of Variation 77.8 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib) | 140 ng/mL | Geometric Coefficient of Variation 25.6 |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib) | 216 ng/mL | Geometric Coefficient of Variation 7.88 |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib) | 264 ng/mL | Geometric Coefficient of Variation 44.9 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib) | 570 ng/mL | Geometric Coefficient of Variation 91.3 |
Secondary
Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib)
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Time frame: For the 28-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was predose on Cycle 1 Day 14
Population: Analysis population consist of the pharmacokinetic analysis set (PAS), which consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib) | 73.2 ng/mL | Geometric Coefficient of Variation 75.4 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib) | 188 ng/mL | Geometric Coefficient of Variation 73.9 |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib) | 84.2 ng/mL | — |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib) | 43.9 ng/mL | Geometric Coefficient of Variation 60.7 |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib) | 103 ng/mL | Geometric Coefficient of Variation 31.4 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib) | 90.4 ng/mL | Geometric Coefficient of Variation 20 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib) | 123 ng/mL | — |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib) | 178 ng/mL | Geometric Coefficient of Variation 38.1 |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib) | 63.9 ng/mL | Geometric Coefficient of Variation 94.3 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib) | 179 ng/mL | Geometric Coefficient of Variation 98.3 |
Secondary
Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib)
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Time frame: For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Population: Analysis population consist of the pharmacokinetic analysis set (PAS), which consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib) | 16.7 h | Geometric Coefficient of Variation 83.6 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib) | 32.9 h | — |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib) | 28.2 h | — |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib) | 28.0 h | Geometric Coefficient of Variation 54.7 |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib) | 38.5 h | Geometric Coefficient of Variation 44.4 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib) | 26.9 h | Geometric Coefficient of Variation 82 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib) | 275 h | Geometric Coefficient of Variation 64.5 |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib) | 49.5 h | Geometric Coefficient of Variation 10.3 |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib) | 30.3 h | Geometric Coefficient of Variation 17.6 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib) | 55.3 h | Geometric Coefficient of Variation 73.1 |
Secondary
Plasma Concentration-time Profile (T1/2,ss) of MEK162 (Phase Ib)
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Time frame: For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Population: Analysis population consist of the pharmacokinetic analysis set (PAS), which consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (T1/2,ss) of MEK162 (Phase Ib) | 8.17 h | Geometric Coefficient of Variation 30.6 |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (T1/2,ss) of MEK162 (Phase Ib) | 7.38 h | Geometric Coefficient of Variation 92.6 |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (T1/2,ss) of MEK162 (Phase Ib) | 6.33 h | Geometric Coefficient of Variation 81.1 |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (T1/2,ss) of MEK162 (Phase Ib) | 15.0 h | Geometric Coefficient of Variation 54.8 |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (T1/2,ss) of MEK162 (Phase Ib) | 5.21 h | Geometric Coefficient of Variation 73.2 |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (T1/2,ss) of MEK162 (Phase Ib) | 15.4 h | Geometric Coefficient of Variation 11.4 |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (T1/2,ss) of MEK162 (Phase Ib) | 8.95 h | Geometric Coefficient of Variation 23.9 |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (T1/2,ss) of MEK162 (Phase Ib) | 8.73 h | Geometric Coefficient of Variation 19.3 |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (T1/2,ss) of MEK162 (Phase Ib) | 12.0 h | Geometric Coefficient of Variation 31.2 |
Secondary
Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib)
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Time frame: Cycle 1 Day 1
Population: Analysis population consist of the pharmacokinetic analysis set (PAS), which consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib) | 2.12 h |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib) | 3.75 h |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib) | 2.98 h |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib) | 1.50 h |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib) | 2.98 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib) | 1.12 h |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib) | 4.22 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib) | 1.50 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib) | 2.13 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib) | 2.03 h |
Secondary
Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib)
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Time frame: Cycle 1 Day 1
Population: Analysis population consist of the pharmacokinetic analysis set (PAS), which consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib) | 1.08 h |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib) | 2.05 h |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib) | 1.02 h |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib) | 2.00 h |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib) | 1.98 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib) | 1.11 h |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib) | 0.76 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib) | 2.00 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib) | 2.17 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib) | 1.17 h |
Secondary
Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib)
To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).
Time frame: For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Population: Analysis population consist of the pharmacokinetic analysis set (PAS), which consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib) | 2.25 h |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib) | 5.90 h |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib) | 23.93 h |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib) | 2.99 h |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib) | 4.00 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib) | 1.87 h |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib) | 2.03 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib) | 4.05 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib) | 3.92 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib) | 1.93 h |
Secondary
Plasma Concentration-time Profile (Tmax,ss) of MEK162 (Phase Ib)
To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).
Time frame: For the 28-day schedule the steady-state parameter time frame was Cycle 1 Day 21, and for the 21-day schedule the steady-state parameter time frame was Cycle 1 Day 14
Population: Analysis population consist of the pharmacokinetic analysis set (PAS), which consisted of all patients who had at least one blood sample providing evaluable PK data and received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Plasma Concentration-time Profile (Tmax,ss) of MEK162 (Phase Ib) | 1.00 h |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Plasma Concentration-time Profile (Tmax,ss) of MEK162 (Phase Ib) | 3.03 h |
| Phase 1b 28-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Tmax,ss) of MEK162 (Phase Ib) | 2.31 h |
| Phase 1b 21-Day MEK162 30mg+LEE011 200mg | Plasma Concentration-time Profile (Tmax,ss) of MEK162 (Phase Ib) | 1.00 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 200mg | Plasma Concentration-time Profile (Tmax,ss) of MEK162 (Phase Ib) | 1.96 h |
| Phase 1b 21-Day MEK162 30mg+LEE011 300mg | Plasma Concentration-time Profile (Tmax,ss) of MEK162 (Phase Ib) | 1.49 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 300mg | Plasma Concentration-time Profile (Tmax,ss) of MEK162 (Phase Ib) | 2.02 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 450mg | Plasma Concentration-time Profile (Tmax,ss) of MEK162 (Phase Ib) | 1.92 h |
| Phase 1b 21-Day MEK162 45mg+LEE011 600mg | Plasma Concentration-time Profile (Tmax,ss) of MEK162 (Phase Ib) | 1.49 h |
Secondary
Progression Free Survival (PFS) - Phase 1b and Phase 2
To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer. In the Phase 1b part, patients were combined for purposes of PFS analyses based on schedule received, since too few patients received any individual dose level to allow for valid PFS estimates within the respective dose levels. This is how the data were analyses and presented for the clinical study report.
Time frame: Approximately 12 months after the FPFV
Population: Analysis population consist of the Full Analysis Set, which included all patients who received at least one dose of binimetinib or ribociclib and was used for the analysis of all endpoints unless noted otherwise.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Progression Free Survival (PFS) - Phase 1b and Phase 2 | 6.7 months |
| Phase 1b 28-Day MEK162 45mg+LEE011 250mg | Progression Free Survival (PFS) - Phase 1b and Phase 2 | 4.1 months |
| Phase 1b 28-Day MEK162 30mg+LEE011 300mg | Progression Free Survival (PFS) - Phase 1b and Phase 2 | 3.7 months |
Secondary
Time to Progression (TTP) - Phase 2
To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer.
Time frame: Approximately 12 months after the FPFV
Population: Analysis population consist of the Full Analysis Set, which included all patients who received at least one dose of binimetinib or ribociclib and was used for the analysis of all endpoints unless noted otherwise.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b 28-Day MEK162 45mg + LEE011 200mg | Time to Progression (TTP) - Phase 2 | 3.7 months |