A Phase Ib/II, Multicenter, Open Label, Study of LEE011 in Combination With MEK162 in Adult Patients With NRAS Mutant Melanoma
Overview
- Phase
- Phase 1
- Intervention
- LEE011
- Conditions
- Locally Advanced or Metastatic NRAS Mutant Melanoma
- Sponsor
- Pfizer
- Enrollment
- 102
- Locations
- 17
- Primary Endpoint
- Number of Dose Limiting Toxicities (Phase Ib)
- Status
- Completed
- Last Updated
- 5 years ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 -
- •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
- •Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L.
- •Hemoglobin (Hgb) ≥ 9 g/dL.
- •Platelets ≥ 75 x 109/L without transfusions within 21 days before 1st treatment.
- •PT/INR and aPTT ≤ 1.5 ULN.
- •Serum creatinine ≤1.5 ULN.
- •Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN).
- •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:
- •Left ventricular ejection fraction (LVEF) \< 50% as determined by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO).
- •Congenital long QT syndrome or family history of unexpected sudden cardiac death.
- •QTcF corrected with Frederica's or Bazett's formula QTcB \>450 ms for males and \>470 ms for females on screening ECG.
- •Angina pectoris ≤ 3 months prior to starting study drug
- •Acute myocardial infarction ≤ 3 months prior to starting study drug
- •Clinically significant resting bradycardia
- •History or presence of ventricular tachyarrhythmia
Arms & Interventions
Phase Ib
The phase Ib is the dose escalation part where successive cohorts of 3-6 newly enrolled patients receiving various dose pairs considering the recommendation from an adaptive BLRM incorporating the EWOC principle until MTD(s)/RP2D is defined. If multiple alternate dosing schedules are explored in parallel, the allocation of patients will proceed in an alternating fashion. Approximately 40 patients are expected to be treated during the phase Ib part of the study. Dosing Schedule 1: MEK162 administered orally twice daily on a continuous dosing schedule. LEE011 administered orally once daily for 21 days followed by a 1 week break (28-day cycle). Dosing Schedule 2: MEK162 administered orally twice daily and LEE011 administered orally once daily for 3 weeks followed by a 1 week break (28-day cycle). Dosing Schedule 3: MEK162 administered orally twice daily and LEE011 administered once daily for 2 weeks followed by a 1 week break (21-day cycle).
Intervention: LEE011
Phase Ib
The phase Ib is the dose escalation part where successive cohorts of 3-6 newly enrolled patients receiving various dose pairs considering the recommendation from an adaptive BLRM incorporating the EWOC principle until MTD(s)/RP2D is defined. If multiple alternate dosing schedules are explored in parallel, the allocation of patients will proceed in an alternating fashion. Approximately 40 patients are expected to be treated during the phase Ib part of the study. Dosing Schedule 1: MEK162 administered orally twice daily on a continuous dosing schedule. LEE011 administered orally once daily for 21 days followed by a 1 week break (28-day cycle). Dosing Schedule 2: MEK162 administered orally twice daily and LEE011 administered orally once daily for 3 weeks followed by a 1 week break (28-day cycle). Dosing Schedule 3: MEK162 administered orally twice daily and LEE011 administered once daily for 2 weeks followed by a 1 week break (21-day cycle).
Intervention: MEK162
Phase II
The Phase II part will begin once the MTD(s)/RP2D have been determined in the Phase Ib in order to assess antitumor activity of the LEE011and MEK162 combination. Patients enrolled in the Phase II part of the study are required to have measurable disease. Approximately 40 patients will be treated in this part. Phase II part will begin at the RP2D on the chosen schedule in order to assess antitumor activity of the LEE011 and MEK162 combination.
Intervention: LEE011
Phase II
The Phase II part will begin once the MTD(s)/RP2D have been determined in the Phase Ib in order to assess antitumor activity of the LEE011and MEK162 combination. Patients enrolled in the Phase II part of the study are required to have measurable disease. Approximately 40 patients will be treated in this part. Phase II part will begin at the RP2D on the chosen schedule in order to assess antitumor activity of the LEE011 and MEK162 combination.
Intervention: MEK162
Outcomes
Primary Outcomes
Number of Dose Limiting Toxicities (Phase Ib)
Time Frame: 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)
Time Frame: 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 Outcomes
- Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib)(Cycle 1 Day 1)
- 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)
- Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib)(Cycle 1 Day 1)
- 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)
- 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)
- Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib)(Cycle 1 Day 1)
- Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib)(Cycle 1 Day 1)
- 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)
- 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)
- Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib)(Cycle 1 Day 1)
- Best Overall Response (BOR) - Phase II(Approximately 12 months after the FPFV)
- 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)
- 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)
- 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)
- Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib)(Cycle 1 Day 1)
- 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)
- 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)
- 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)
- 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)
- Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib)(Cycle 1 Day 1)
- Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib)(Cycle 1 Day 1)
- Number of Participants With Adverse Drug Reactions(Approximately 12 months after FPFV)
- Duration of Response (DoR) - Phase 2(Approximately 12 months after the FPFV)
- Time to Progression (TTP) - Phase 2(Approximately 12 months after the FPFV)
- Progression Free Survival (PFS) - Phase 1b and Phase 2(Approximately 12 months after the FPFV)
- Overall Survival (OS) - Phase ll(Approximately 12 months after the FPFV)