Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

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).

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.

LEE011 will be administered orally once daily

LEE011

MEK162 will be administered orally twice daily

MEK162

Pfizer CT.gov Call Center

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.

A Phase Ib/II Study of LEE011 in Combination With MEK162 in Patients With NRAS Mutant Melanoma

A Phase Ib/II, Multicenter, Open Label, Study of LEE011 in Combination With MEK162 in Adult Patients With NRAS Mutant Melanoma

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.

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.

To Characterize the PK profiles of LEE011 as well as any other significant metabolites identified (Phase Ib).

To Characterize the PK profiles of MEK162 as well as any other significant metabolites identified (Phase Ib).

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.

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.

To assess clinical safety as per RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer.

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.

To assess clinical safety according to RECIST 1.1. Evaluation will occur continuously throughout the trial until progression, or death due to underlying cancer.

Pfizer

An AE is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after patient's signed informed consent has been obtained.

Phase 1b - 28 Day MEK162 45mg+LEE011 200mg

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

The dose-expansion phase was initiated with a newly recruited group of patients.

Binimetinib 45 mg BID + ribociclib 200 mg QD on 28-day schedule

Phase 2 - Dose Expansion Phase

Phase 1b 28-Day MEK162 45mg + LEE011 200mg

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 2: MEK162 45mg+LEE011 200mg

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race

Race/Ethnicity, Customized

Weight

Body mass index

ECOG performance status

The baseline analysis population consists of the Full Analysis Set (FAS), which includes all patients who received at least 1 dose of ribociclib or binimetinib.

Study Director

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.

Number of Dose Limiting Toxicities (Phase Ib)

binimetinib 45 mg BID + ribociclib 200 mg QD (MEK 45mg + LEE 200mg)

Phase 2: Dose Expansion

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.

Objective Response Rate (ORR) (Phase II)

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.

Plasma Concentration-time Profile (AUCtau) of LEE011 (Phase Ib)

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.

Plasma Concentration-time Profile (AUCtau) of MEK162 (Phase Ib)

Plasma Concentration-time Profile (AUCtau,ss) of LEE011 (Phase Ib)

Plasma Concentration-time Profile (AUCtau,ss) of MEK162 (Phase Ib)

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.

Plasma Concentration-time Profile (Cmin,ss) of LEE011 (Phase Ib)

Plasma Concentration-time Profile (Cmin,ss) of MEK162 (Phase Ib)

Plasma Concentration-time Profile (Cmax) of LEE011 (Phase Ib)

Plasma Concentration-time Profile (Cmax) of MEK162 (Phase Ib)

Plasma Concentration-time Profile (Cmax,ss) of LEE011 (Phase Ib)

Plasma Concentration-time Profile (Cmax,ss) of MEK162 (Phase Ib)

Plasma Concentration-time Profile (Tmax) of LEE011 (Phase Ib)

Plasma Concentration-time Profile (Tmax) of MEK162 (Phase Ib)

Plasma Concentration-time Profile (Tmax,ss) of LEE011 (Phase Ib)

Plasma Concentration-time Profile (Tmax,ss) of MEK162 (Phase Ib)

Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of LEE011 (Phase Ib)

Plasma Concentration-time Profile (Accumulation Ratio, Racc_AUC) of MEK162 (Phase Ib)

Plasma Concentration-time Profile (T1/2,ss) of LEE011 (Phase Ib)

Plasma Concentration-time Profile (T1/2,ss) of MEK162 (Phase Ib)

Plasma Concentration-time Profile (CL/F) of LEE011 (Phase Ib)

Plasma Concentration-time Profile (CL/F) of MEK162 (Phase Ib)

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.

Number of Participants With Adverse Drug Reactions

Duration of Response (DoR) - Phase 2

Time to Progression (TTP) - Phase 2

A combined total of 61 patients were treated in the 28-day (n=29) and 21-day (n=32) treatment cycles, and all patients discontinued treatment. The starting dose in the 28-day schedule was binimetinib 45 mg BID + ribociclib 200 mg QD.

28-Day Schedule: ribociclib was taken QD for 21 consecutive days followed by a 7-day planned break.

Binimetinib was taken BID on a continuous dosing schedule.

Phase 1b 28-Day Schedule

A combined total of 61 patients were treated in the 28-day (n=29) and 21-day (n=32) treatment cycles, and all patients discontinued treatment. The starting dose in the 21-day schedule was binimetinib 30 mg BID + ribociclib 200 mg QD.

21-Day Schedule: ribociclib QD and binimetinib BID were taken QD for 14 consecutive days followed by a 7-day planned break.

Phase 1b 21-Day Schedule

The dose-expansion phase was initiated with a newly recruited group of patients.

A total of 41 patients were treated, and all patients (100%) discontinued treatment. Based on the recommendations of the dose-escalation meetings between the Sponsor and the Investigators, the RP2D and schedule for the combination of binimetinib and ribociclib to be used for the dose-expansion phase of the study was binimetinib 45 mg BID + ribociclib 200 mg QD on the 28-day schedule.

Spots Global Cancer Trial Database for locally advanced or metastatic nras mutant melanoma