Study of Pembrolizumab (MK-3475) in Participants With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, or Non-small Cell Lung Carcinoma (P07990/MK-3475-001/KEYNOTE-001)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT01295827
First received: February 10, 2011
Last updated: July 10, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Cancer, Solid Tumor
Drug: Pembrolizumab 1 mg/kg
Drug: Pembrolizumab 3 mg/kg
Drug: Pembrolizumab 10 mg/kg
Drug: Pembrolizumab MEL
Drug: Pembrolizumab NSCLC
Drug: Pembrolizumab MEL Low Dose
Drug: Pembrolizumab MEL High Dose
Drug: Pembrolizumab NSCLC Low Dose
Drug: Pembrolizumab NSCLC High Dose
Drug: Pembrolizumab NSCLC Medium Dose
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of Single Agent MK-3475 in Patients With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Number of participants experiencing dose-limiting toxicities (DLTs) [ Time Frame: Cycle 1 (28 days) ] [ Designated as safety issue: Yes ]
  • Number of participants experiencing clinical and laboratory adverse events (AEs) [ Time Frame: First dose to 30 days post last dose ] [ Designated as safety issue: Yes ]
  • Number of all study participants who demonstrate a response rate (RR) [ Time Frame: Weeks 12 and 24 ] [ Designated as safety issue: No ]
  • Number of MEL participants who demonstrated a response rate (RR) and/or disease control rate (DCR) [ Time Frame: Weeks 12 and 24 ] [ Designated as safety issue: No ]
  • Number of NSCLC participants who demonstrated a response rate (RR) [ Time Frame: Week 9 and Week 18 ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]
  • Progression free survival (PFS) in MEL and NSCLC participants [ Time Frame: From first documented response up to 2 years ] [ Designated as safety issue: No ]
  • 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 2 years) ] [ Designated as safety issue: No ]
  • Duration of response (DR) in MEL and NSCLC participants [ Time Frame: From first documented response up to 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 1137
Study Start Date: March 2011
Estimated Study Completion Date: July 2016
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A: Pembrolizumab 1 mg/kg (Closed)
Participants receive pembrolizumab intravenous (IV) infusion over 30 minutes on Day 1 of each cycle, at dose of 1 mg/kg
Drug: Pembrolizumab 1 mg/kg
IV infusion over 30 minutes on Day 1 of each cycle, at dose of 1 mg/kg
Experimental: Part A: Pembrolizumab 3 mg/kg (Closed)
Participants receive pembrolizumab intravenous (IV) infusion over 30 minutes on Day 1 of each cycle, at dose of 3 mg/kg
Drug: Pembrolizumab 3 mg/kg
IV infusion over 30 minutes on Day 1 of each cycle, at dose of 3 mg/kg
Experimental: Part A: Pembrolizumab 10 mg/kg (Closed)
Participants receive pembrolizumab intravenous (IV) infusion over 30 minutes on Day 1 of each cycle, at dose of 1 mg/kg
Drug: 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: Part B: Pembrolizumab MEL (Closed)
Participants receive pembrolizumab IV infusion over 30 minutes on Day 1 of each cycle.
Drug: Pembrolizumab MEL
IV infusion over 30 minutes on Day 1 of each cycle
Experimental: Part C: Pembrolizumab NSCLC (Closed)
Participants receive pembrolizumab IV infusion over 30 minutes on Day 1 of each cycle
Drug: Pembrolizumab NSCLC
IV infusion over 30 minutes on Day 1 of each cycle
Experimental: Part D: Pembrolizumab MEL Low Dose (Closed)
participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
Drug: Pembrolizumab MEL Low Dose
IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
Experimental: Part D: Pembrolizumab MEL High Dose (Closed)
Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
Drug: Pembrolizumab MEL High Dose
IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
Experimental: Part E: Pembrolizumab NSCLC Low Dose (Closed)
Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
Drug: Pembrolizumab NSCLC Low Dose
IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
Experimental: Part E: Pembrolizumab NSCLC Med. Dose (Closed)
Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
Drug: Pembrolizumab NSCLC Medium Dose
IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
Experimental: Part E: Pembrolizumab NSCLC High Dose (Closed)
Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
Drug: Pembrolizumab NSCLC High Dose
IV infusion over 30 minutes every 2 or 3 weeks at dose determined during dose escalation
Experimental: Part F: Pembrolizumab NSCLC PD-L1 Low Dose
Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
Drug: Pembrolizumab NSCLC Low Dose
IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
Experimental: Part F: Pembrolizumab NSCLC PD-L1 High Dose
Participants receive pembrolizumab IV infusion over 30 minutes every 2 or 3 weeks at dose determined during dose escalation
Drug: Pembrolizumab NSCLC High Dose
IV infusion over 30 minutes every 2 or 3 weeks at dose determined during dose escalation

Detailed Description:

Part F (NSCLC) is the only part currently enrolling participants.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01295827

Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  More Information

No publications provided by Merck Sharp & Dohme Corp.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01295827     History of Changes
Other Study ID Numbers: P07990, MK-3475-001, 2011-002371-42
Study First Received: February 10, 2011
Last Updated: July 10, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Merck Sharp & Dohme Corp.:
Melanoma
Carcinoma
Cancer
Advanced cancer
Metastatic cancer
Metastatic melanoma
PD-1
PD1

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Melanoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Nevi and Melanomas

ClinicalTrials.gov processed this record on July 26, 2014