Overview

This trial is active, not recruiting.

Condition cancer, solid tumor
Treatments pembrolizumab 1 mg/kg, pembrolizumab 3 mg/kg, pembrolizumab 10 mg/kg, pembrolizumab mel, pembrolizumab nsclc, pembrolizumab mel low dose, pembrolizumab mel high dose, pembrolizumab nsclc low dose, pembrolizumab nsclc high dose, pembrolizumab nsclc medium dose, pembrolizumab nsclc 200 mg
Phase phase 1
Sponsor Merck Sharp & Dohme Corp.
Start date March 2011
End date January 2018
Trial size 1260 participants
Trial identifier NCT01295827, 2011-002371-42, MK-3475-001, P07990

Summary

This study will be done in 6 parts. In Part A the dose of intravenous (IV) pembrolizumab (MK-3475) will be escalated to find the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for participants with a histologically or cytologically confirmed diagnosis of any type of carcinoma or melanoma (MEL). Part B of the study will explore the safety, tolerability, and efficacy of the drug in participants with advanced or metastatic MEL and compare every 2 week to every 3 week dosing. Part C of the study will explore the safety, tolerability, and efficacy of the drug in participants with non-small cell lung carcinoma (NSCLC) that is locally advanced or metastatic. Part D of the study will explore the low and high doses of study drug identified in Parts A and B in participants with advanced or metastatic MEL. Part E (closed with Amendment 7) will explore low, medium, and high doses of study drug in combination with standard chemotherapy in participants with locally advanced or metastatic NSCLC. Part F will explore low and high doses of study drug in treatment-naive and previously-treated participants with NSCLC with programmed cell death 1 ligand (PD-L1) gene expression. In Parts D and F and some of Part B participants will be randomized to one dose level. The primary hypotheses are the following: that pembrolizumab has acceptable safety and tolerability; and that pembrolizumab shows a clinically meaningful response rate (RR) or disease-control rate (DCR) in participants with melanoma (ipilimumab-refractory or not), and a clinically meaningful RR in participants with NSCLC, especially a clinically meaningful RR in those participants with either cancer, whose tumors express PD-L1.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Participants receive pembrolizumab intravenous (IV) infusion over 30 minutes on Day 1 of each cycle, at dose of 1 mg/kg
pembrolizumab 1 mg/kg
IV infusion over 30 minutes on Day 1 of each cycle, at dose of 1 mg/kg
(Experimental)
Participants receive pembrolizumab intravenous (IV) infusion over 30 minutes on Day 1 of each cycle, at dose of 3 mg/kg
pembrolizumab 3 mg/kg
IV infusion over 30 minutes on Day 1 of each cycle, at dose of 3 mg/kg
(Experimental)
Participants receive pembrolizumab intravenous (IV) infusion over 30 minutes on Day 1 of each cycle, at dose of 1 mg/kg
pembrolizumab 10 mg/kg
IV infusion over 30 minutes on Day 1 of each cycle (every 2 or 3 weeks depending on study arm) at a dose of 10 mg/kg.
(Experimental)
Participants receive pembrolizumab IV infusion over 30 minutes on Day 1 of each cycle.
pembrolizumab mel
IV infusion over 30 minutes on Day 1 of each cycle
(Experimental)
Participants receive pembrolizumab IV infusion over 30 minutes on Day 1 of each cycle
pembrolizumab nsclc
IV infusion over 30 minutes on Day 1 of each cycle
(Experimental)
participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
pembrolizumab mel low dose
IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
(Experimental)
Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
pembrolizumab mel high dose
IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
(Experimental)
Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
pembrolizumab nsclc low dose
IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
(Experimental)
Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
pembrolizumab nsclc medium dose
IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
(Experimental)
Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
pembrolizumab nsclc high dose
IV infusion over 30 minutes every 2 or 3 weeks at dose determined during dose escalation
(Experimental)
Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation. All participants were changed over to a 200 mg fixed dose of pembrolizumab IV every 3 weeks based on analysis of safety and efficacy data.
pembrolizumab nsclc low dose
IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
pembrolizumab nsclc 200 mg KEYTRUDA®
IV infusion over 30 minutes every 3 weeks
(Experimental)
Participants receive pembrolizumab IV infusion over 30 minutes every 2 or 3 weeks at dose determined during dose escalation. All participants were changed over to a 200 mg fixed dose of pembrolizumab IV every 3 weeks based on analysis of safety and efficacy data.
pembrolizumab nsclc high dose
IV infusion over 30 minutes every 2 or 3 weeks at dose determined during dose escalation
pembrolizumab nsclc 200 mg KEYTRUDA®
IV infusion over 30 minutes every 3 weeks

Primary Outcomes

Measure
Number of participants experiencing dose-limiting toxicities (DLTs)
time frame: Up to 28 days in Cycle 1
Number of participants experiencing clinical and laboratory adverse events (AEs)
time frame: Up to 30 days post last dose
Number of all study participants who demonstrate a response rate (RR)
time frame: Weeks 9, 12, 18, and 24
Number of MEL participants who demonstrated a response rate (RR) and/or disease control rate (DCR)
time frame: Weeks 12 and 24
Number of NSCLC participants who demonstrated a response rate (RR)
time frame: Week 9 and Week 18
Change from Baseline in candidate biomarker expression levels in MELS and NSCLC participants
time frame: Week 12 and Week 24 (MEL), Week 9 and Week 18 (NSCLC)

Secondary Outcomes

Measure
The area under the curve (AUC) of plasma concentration of drug against time after administration of pembrolizumab (Part A)
time frame: Pre-dose, 30 minutes, 6, 24, and 48 hours post-dose, and on Days 8, 15, 22, and 29 of Cycle 1; pre- and post-dose on Day 1 of every other subsequent 14-day cycle up to 12 months
Maximum concentration (Cmax) after first dose interval of pembrolizumab
time frame: Part A, Cycle 1 + Day 1 of Cycle 2 and then every 14-day cycle for up to 12 months; Part B Q2W, Cycles 1 and 3; Part B Q3W, Cycles 1 and 2; Part C, Cycles 1 and 2; Part D, Cycles 1 and 6; Part E, Cycles 1 and 6; Part F, Cycles 1 and 6.
Time at which maximum concentration (Tmax) occurs for pembrolizumab (Part A)
time frame: Pre-dose, 30 minutes, 6, 24, and 48 hours post-dose, and on Days 8, 15, 22, and 29 of Cycle 1; pre- and post-dose on Day 1 of every other subsequent 14-day cycle up to 12 months
Lowest plasma concentration (C[trough]) of pembrolizumab
time frame: Part A, Cycle 1+ Day 1 Cycle 2, and each 14-day cycle for up to 12 mo.; Part B Q2W, Cycles 1,3,7 + every 4 cycles for 12 mo.; Parts B/C Q3W, Cycles 1, 2, 5 + every 4 cycles for 12 mo.; Parts D/E/F, Cycles 1, 2, 3, 6, 8 + every 4 cycles for up to 2 yrs.
Terminal half-life (t1/2) of pembrolizumab (Parts B, C, D, E and F)
time frame: Pre-dose, 30 minutes, 6, 24, and 48 hours post-dose, and on Days 8, 15, 22, and 29 of Cycle 1; pre- and post-dose on Day 1 of every other subsequent 14-day cycle starting with Cycle 2 for up to 12 months.
Progression free survival (PFS) in MEL and NSCLC participants
time frame: From first documented response up to 5 years
Overall survival (OS) in MEL and NSCLC participants
time frame: From first dose of study drug until death or lost to follow-up (up to 5 years)
Duration of response (DR) in MEL and NSCLC participants
time frame: From first documented response up to 5 years

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion criteria (Part F is the only part currently enrolling participants). - In Part A: Histological or cytological diagnosis of MEL or any type of carcinoma, progressive metastatic disease, or progressive locally advanced disease not amenable to local therapy. In Parts B and D of the study, histological or cytological diagnoses of metastatic MEL with progressive locally advanced or metastatic disease. In Parts C and F, histological or cytological diagnosis of NSCLC. In Part F, participants with Stage IV NSCLC without prior systemic therapy may be eligible. - Failure of established standard medical anti-cancer therapies for a given tumor type or intolerance to such therapy. - In Parts B, C, D, or F of the study, MEL or NSCLC must be measurable by imaging. - In Part F of the study, NSCLC with PD-L1 gene expression. - Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. - Adequate organ function. - Female participants of childbearing potential should have a negative urine or serum pregnancy test prior to receiving study medication - Female participants of childbearing potential must be willing to use adequate contraception from study start, through the course of the study, and for 120 days after the last dose of study medication - Male participants of childbearing potential must agree to use adequate contraception from the first dose of study medication through 120 days after the last dose of study medication Exclusion criteria (Part F is the only part currently enrolling participants) - Chemotherapy, radioactive, or biological cancer therapy within 4 weeks prior to the first dose of study therapy, or not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from the adverse events caused by therapy administered more than 4 weeks prior to first dose. - Participation in a study of an investigational agent or using an investigational device within 30 days of administration of pembrolizumab, with the exception of participants in the follow-up phase. - Other form(s) of antineoplastic therapy anticipated during the period of the study. - History of pneumonitis requiring treatment with steroids, or has a history of interstitial lung disease. - Medical condition that requires chronic systemic steroid therapy, or on any other form of immunosuppressive medication, excepting use of inhaled steroids. - History of acute diverticulitis, intra-abdominal abscess, GI obstruction, abdominal carcinomatosis. - History of a hematologic malignancy, malignant primary brain tumor, malignant sarcoma, or another malignant primary solid tumor, unless no evidence of that disease for 5 years. - Active central nervous system (CNS) metastases and/or carcinomatous meningitis. - Previous severe hypersensitivity reaction to another monoclonal antibody (mAb). - Active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents, except vitiligo or resolved childhood asthma/atopy. - Prior therapy with another anti-programmed cell death (PD)-1 agent or previously enrolled in any pembrolizumab trial. - Active infection requiring therapy. - Positive for Human Immunodeficiency Virus (HIV), Hepatitis B (Hepatitis B Surface Antigen [HBsAg] reactive), or Hepatitis C virus (Hepatitis C Virus Ribonucleic Acid [HCV RNA] (qualitative) is detected). - Regular use of illicit drugs or a recent history (within the last year) of substance abuse (including alcohol). - Symptomatic ascites or pleural effusion. - Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.

Additional Information

Official title Phase I Study of Single Agent Pembrolizumab (MK-3475) in Patients With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma (KEYNOTE 001)
Trial information was received from ClinicalTrials.gov and was last updated in September 2016.
Information provided to ClinicalTrials.gov by Merck Sharp & Dohme Corp..