Clinical trial NCT01295827: 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)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2011-02-15
Enrollment: 1260
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: Per protocol, all participants who were receiving study intervention or in survival follow-up could enroll in the extension study, KEYNOTE-587 (NCT03486873), which would allow further study participation after the Primary Completion Date cut-off. Thus, all efficacy outcome measures except for survival (Overall Survival \[OS\]) were to be followed up to the Interim Database cut-off of 18-Sept-2018, and the primary safety analyses (except for the DLT analysis) and Overall Survival were to be followed up to the study Primary Completion Date (Final Database cut-off of 05-Nov-2018).

Five participants did not have end of study assessments completed by the Primary Completion Date cut-off and were subsequently followed up to the Study Completion Date (11-Dec-2018). End of treatment and end of study assessments are missing for these 5 and the status was noted as unknown as of the Primary Completion Date cut-off. Per protocol, any safety information after the Primary Completion Date cut-off (Final Database cut-off of 05-Nov-2018) would not be included in the safety analysis but reported by the Investigator to the Sponsor via the Sponsor Communication Form and filed in the electronic Trial Master File.

Eligibility criteria: Inclusion Criteria

* 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

Exclusion Criteria

* 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.
* Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.

Primary outcomes:
measure: 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)
timeFrame: Up to 28 days in Cycle 1
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018)
measure: 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)
timeFrame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
measure: ORR According to RECIST 1.1 as Assessed by Independent Review Committee (IRC): Non-Small Cell Lung Cancer (NSCLC) Participants (Parts C Plus F)
timeFrame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Secondary outcomes:
measure: ORR According to Immune-related Response Criteria (irRC) as Assessed by Investigator in Melanoma Participants (Parts B Plus D)
timeFrame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
measure: ORR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)
timeFrame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
measure: 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)
timeFrame: Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)
measure: Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Infinity (AUC 0-inf) in Solid Tumor Participants (Parts A and A1)
timeFrame: Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)
measure: Maximum Concentration (Cmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1)
timeFrame: Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)
measure: Time to Maximum Concentration (Tmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1)
timeFrame: Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)
measure: Terminal Half-Life (t ½) of Pembrolizumab in Solid Tumor Participants (Parts A and A1)
timeFrame: Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)
measure: Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 21 (AUC 0-21) in Solid Tumor Participants (Part A2)
timeFrame: Cycle 1: Day 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours; Day 5, Day 8: pre- and post-dose; Day 15 (Cycle = 21 days)
measure: Area Under the Concentration-Time Curve of Pembrolizumab From Day 21 to Day 42 (AUC21-42) in Solid Tumor Participants (Part A2)
timeFrame: Cycle 1: Day 21; Cycle 2: Day 1: Pre-dose, post-dose at 0.5 and 24 hours, Day 3, Day 8, Day 15 (Cycle = 21 days)
measure: Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2)
timeFrame: Parts A and A1: pre-dose at Cycles 2, 4, 6, 8, 10, 12, 14 (cycle=14 days); A2 Cohorts: pre-dose at Cycles 2, 3, 5, 7, 9, 11 (cycle=21 days)
measure: Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D)
timeFrame: Part B arms treated every 3 weeks: pre-dose at Cycles 2,5,9,13,17,25,33 (cycle=21 days); Part B treated every 2 weeks: pre-dose at Cycles 2,3,7,13,19,25,31,37 (cycle=14 days); Part D: pre-dose at Cycles 2,3,6,8,12,16,24,32 (cycle=21 days)
measure: Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F)
timeFrame: Part C: pre-dose at Cycles 2,5,9,13,17,21 (cycle=21 days); Part F treated every 3 weeks: pre-dose at Cycles 2,3,6,8,12,14,16,24,32 (cycle=21 days); Part F treated every 2 weeks: pre-dose at Cycles 2,3,6,7,8,9,12,16,18,24,32,36,40,48 (cycle=14 days)
measure: Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D)
timeFrame: Baseline, last available tumor assessment (up to approximately 53 months through Interim Database cut-off date of 18-Sep-2015)
measure: Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F)
timeFrame: Baseline, last available tumor assessment (up to approximately 53 months through Interim Database cut-off date of 18-Sep-2015)
measure: Disease Control Rate (DCR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D)
timeFrame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
measure: Duration of Response (DOR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D)
timeFrame: From time of first documented evidence of CR or PR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months)
measure: Progression Free Survival (PFS) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B Plus D)
timeFrame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
measure: Overall Survival (OS) in Melanoma Participants (Parts B Plus D)
timeFrame: Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018)
measure: DCR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D)
timeFrame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
measure: DOR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D)
timeFrame: From time of first documented evidence of iCR or iPR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months)
measure: PFS According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D)
timeFrame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
measure: DCR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F)
timeFrame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
measure: DOR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F)
timeFrame: From time of first documented evidence of CR or PR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months)
measure: PFS According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F)
timeFrame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
measure: OS in NSCLC Participants (Parts C Plus F)
timeFrame: Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018)
measure: DCR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)
timeFrame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
measure: DOR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)
timeFrame: From time of first documented evidence of iCR or iPR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months)
measure: PFS According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)
timeFrame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
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