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)

NCT01295827 | Completed Phase 1 Results FDA Drug

• 4 other identifiers: P07990MK-3475-0012011-002371-42KEYNOTE-001
• Study Type: interventional
• Target: 1,260
• Locations: 0 countries
• Sites: N/A

Brief Summary

The present study has 5 parts. In Parts A and A1, the dose of intravenous (IV) pembrolizumab (MK-3475) will be escalated from 1 to 10 mg/kg to determine 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) by evaluating the Dose Limiting Toxicities (DLTs). Following completion of the dose escalation, additional patients will be enrolled in Part A2 to further define pharmacokinetic characteristics. Part B of the study will investigate the safety, tolerability, and efficacy of pembrolizumab (2 mg/kg and 10 mg/kg) in participants with advanced or metastatic MEL and compare every 2 week dosing (Q2W) to every 3 week dosing (Q3W). Part C of the study will investigate the safety, tolerability, and efficacy of pembrolizumab administered at 10 mg/kg Q3W in participants with non-small cell lung carcinoma (NSCLC) that is locally advanced or metastatic. Part D of the study will investigate the low and high doses of study drug identified in Parts A and B (2 mg/kg and 10 mg/kg) administered Q3W in participants with advanced or metastatic MEL. Part E (closed with Amendment 7) was planned to investigate low, medium, and high doses of pembrolizumab in combination with standard chemotherapy in participants with locally advanced or metastatic NSCLC. Part F will investigate low and high doses of pembrolizumab (2 mg/kg and 10 mg/kg) administered Q2W or Q3W in treatment-naive and previously-treated participants with NSCLC with programmed cell death 1 ligand (PD-L1) gene expression. The primary hypotheses are the following: that pembrolizumab will have acceptable safety and tolerability; that pembrolizumab will show a clinically meaningful response rate (RR) or disease-control rate (DCR) in participants with melanoma (ipilimumab-refractory or not) and NSCLC, and that pembrolizumab will show a more clinically meaningful RR in participants with either cancer whose tumors express PD-L1.

Conditions

Cancer, Solid Tumor

Keywords

Melanoma; Carcinoma; Cancer; Advanced cancer; Metastatic cancer; Metastatic melanoma; Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1)

Outcome Measures

Primary Outcomes (4)

• Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0) in Participants With Solid Tumors (Parts A and A1)

  DLTs were assessed according to NCI-CTCAE v.4.0 during the first cycle (28 days) and were defined as occurrence of any of the following toxicities if judged by the investigator to be possibly, probably or definitely related to study drug administration: Grade (Gr) 4 nonhematologic toxicity; Gr 4 hematologic toxicity lasting ≥14 days; Gr 3 nonhematologic toxicity lasting \>3 days despite optimal supportive care; any Grade 3 non-hematologic laboratory value if medical intervention was required to treat the participant, the abnormality led to hospitalization, or the abnormality persisted for \>1 week; Gr 3 or 4 febrile neutropenia; thrombocytopenia \<25,000 cells/mm\^3 (if associated with a bleeding event requiring an elective platelet transfusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to an Intensive Care Unit); or Gr 5 toxicity. The number of participants in Part A and Part A1 with a DLT were reported by pembrolizumab dose received.

  Up to 28 days in Cycle 1

• Number of Participants Who Experienced an Adverse Event (AE)

  An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of the Sponsor's product was also an AE. The number of participants who experienced an AE was reported for each arm.

  Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018)

• Overall Response Rate (ORR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Integrated Radiology and Oncology (IRO): Melanoma Participants (Parts B Plus D)

  ORR was defined as the percentage of participants in the analysis population who had a confirmed Complete Response (CR: disappearance of all lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters \[SOD\] of target lesions, taking as reference the baseline SOD) according to RECIST 1.1, which was modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experienced a confirmed CR or PR according to RECIST 1.1 as assessed by IRO was reported as the ORR for each melanoma dose arm (Parts B plus D).

  Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)

• ORR According to RECIST 1.1 as Assessed by Independent Review Committee (IRC): Non-Small Cell Lung Cancer (NSCLC) Participants (Parts C Plus F)

  ORR was defined as the percentage of participants in the analysis population who had a confirmed CR (disappearance of all lesions) or PR (at least a 30% decrease in the sum of diameters \[SOD\] of target lesions, taking as reference the baseline SOD) according to RECIST 1.1, which was modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experienced a confirmed CR or PR according to RECIST 1.1 as assessed by IRC was reported as the ORR for each NSCLC dose arm (Parts C plus F).

  Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)

Secondary Outcomes (28)

• ORR According to Immune-related Response Criteria (irRC) as Assessed by Investigator in Melanoma Participants (Parts B Plus D)

  Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)

• ORR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)

  Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)

• Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 28 (AUC 0-28) in Solid Tumor Participants (Parts A and A1)

  Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)

• Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Infinity (AUC 0-inf) in Solid Tumor Participants (Parts A and A1)

  Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)

• Maximum Concentration (Cmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1)

  Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)

Study Arms (15)

Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A)

EXPERIMENTAL

During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab intravenous (IV) infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg every 2 weeks (Q2W) starting with Cycle 2.

Biological: Pembrolizumab

Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A)

EXPERIMENTAL

During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.

Biological: Pembrolizumab

Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1)

EXPERIMENTAL

During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.

Biological: Pembrolizumab

Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2)

EXPERIMENTAL

During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.

Biological: Pembrolizumab

Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2)

EXPERIMENTAL

During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.

Biological: Pembrolizumab

Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2)

EXPERIMENTAL

During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.

Biological: Pembrolizumab

MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D)

EXPERIMENTAL

Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.

Biological: Pembrolizumab

MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D)

EXPERIMENTAL

Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.

Biological: Pembrolizumab

MEL: Pembrolizumab 10 mg/kg Q2W (Part B)

EXPERIMENTAL

Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.

Biological: Pembrolizumab

NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F)

EXPERIMENTAL

Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.

Biological: Pembrolizumab

NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F)

EXPERIMENTAL

Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.

Biological: Pembrolizumab

NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)

EXPERIMENTAL

Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.

Biological: Pembrolizumab

NSCLC: Pembrolizumab 2 mg/kg Q3W (Part E-Not Enrolled)

EXPERIMENTAL

Participants were to receive pembrolizumab IV at a dose of 2 mg/kg Q3W. No participants were enrolled in this arm.

Biological: Pembrolizumab

NSCLC: Pembrolizumab 5 mg/kg Q3W (Part E-Not Enrolled)

EXPERIMENTAL

Participants were to receive pembrolizumab IV at a dose of 5 mg/kg Q3W. No participants were enrolled in this arm.

Biological: Pembrolizumab

NSCLC: Pembrolizumab 10 mg/kg Q3W (Part E-Not Enrolled)

EXPERIMENTAL

Participants were to receive pembrolizumab IV at a dose of 10 mg/kg Q3W. No participants were enrolled in this arm.

Biological: Pembrolizumab

Interventions

Pembrolizumab BIOLOGICAL

IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.

Also known as: MK-3475, KEYTRUDA®

MEL: Pembrolizumab 10 mg/kg Q2W (Part B); MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D); MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D); NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F); NSCLC: Pembrolizumab 10 mg/kg Q3W (Part E-Not Enrolled); NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F); NSCLC: Pembrolizumab 2 mg/kg Q3W (Part E-Not Enrolled); NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F); NSCLC: Pembrolizumab 5 mg/kg Q3W (Part E-Not Enrolled); Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A); Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1); Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A); Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2); Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2); Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 F1, 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

You may not qualify if:

• 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 non-infectious 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.
• Risk factors for bowel obstruction or bowel perforation (including a history of acute diverticulitis, intra-abdominal abscess, 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.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

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  PMID: 23724846 DERIVED

MeSH Terms

Conditions

Neoplasms; Melanoma; Carcinoma; Neoplasm Metastasis; Parkinson Disease 4, Autosomal Dominant Lewy Body

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Neoplasms, Glandular and Epithelial; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 10, 2011
• First Posted: February 15, 2011
• Study Start: March 4, 2011
• Primary Completion: November 5, 2018
• Study Completion: December 11, 2018
• Last Updated: December 13, 2019
• Results First Posted: December 13, 2019

Record last verified: 2019-11

Data Sharing

• IPD Sharing: Will share