Locally Advanced or Metastatic NRAS Mutant Melanoma Clinical Trial
Official title:
A Phase Ib/II, Multicenter, Open Label, Study of LEE011 in Combination With MEK162 in Adult Patients With NRAS Mutant Melanoma
| Verified date | November 2020 |
| Source | Pfizer |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Completed |
| Enrollment | 102 |
| Est. completion date | February 20, 2018 |
| Est. primary completion date | January 15, 2018 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | 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/exclusion criteria may apply. |
| Country | Name | City | State |
|---|---|---|---|
| Australia | Pfizer Investigator Site 1001 | East Melbourne | Victoria |
| Australia | Pfizer Investigative Site 1003 | North Sydney | New South Wales |
| Australia | Pfizer Investigative Site 1002 | Westmead | New South Wales |
| Germany | Pfizer Investigative Site 1050 | Essen | |
| Germany | Pfizer Investigative Site 1053 | Gera | |
| Germany | Pfizer Investigative Site 1052 | Hannover | |
| Germany | Pfizer Investigative Site 1051 | Muenchen | |
| Italy | Pfizer Investigative Site 1101 | Napoli | |
| Netherlands | Pfizer Investigative Site 1150 | Nijmegen | |
| Netherlands | Pfizer Investigative Site 1151 | Utrecht | The Netherlands |
| United States | Karmanos Cancer Institute Dept of Oncology | Detroit | Michigan |
| United States | University of Texas/MD Anderson Cancer Center Dept of Onc. | Houston | Texas |
| United States | Vanderbilt University Medical Center SC - Dept of Oncology . | Nashville | Tennessee |
| United States | Columbia University Medical Center- New York Presbyterian Onc Dept. | New York | New York |
| United States | Memorial Sloan Kettering Cancer Center Dept Oncology | New York | New York |
| United States | California Pacific Medical Center Onc Dept | San Francisco | California |
| United States | University of California, Dept of Oncology | San Francisco | California |
| Lead Sponsor | Collaborator |
|---|---|
| Pfizer |
United States, Australia, Germany, Italy, Netherlands,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| 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. | first 28 days of treatment | |
| 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. | Approximately 12 months after the FPFV | |
| 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). | Cycle 1 Day 1 | |
| 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). | Cycle 1 Day 1 | |
| 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). | 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 | |
| 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). | 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 | |
| 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). | 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 | |
| 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). | 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 | |
| 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). | Cycle 1 Day 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). | Cycle 1 Day 1 | |
| 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). | 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 | |
| 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). | 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 | |
| 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). | Cycle 1 Day 1 | |
| 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). | Cycle 1 Day 1 | |
| 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). | 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 | |
| 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). | 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 | |
| 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). | 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 | |
| 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). | 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 | |
| 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). | 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 | |
| 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). | 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 | |
| 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). | Cycle 1 Day 1 | |
| 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). | Cycle 1 Day 1 | |
| 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. | Approximately 12 months after FPFV | |
| 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. |
Approximately 12 months after the FPFV | |
| 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. | Approximately 12 months after the FPFV | |
| 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. |
Approximately 12 months after the FPFV | |
| 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. | Approximately 12 months after the FPFV | |
| 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. | Approximately 12 months after the FPFV |