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Study to Evaluate the Safety and Efficacy of Two Different Dosing Schedules of Pembrolizumab (MK-3475) Compared to Ipilimumab in Participants With Advanced Melanoma (MK-3475-006/KEYNOTE-006)

Primary Purpose

Melanoma

Status

Completed

Phase

Phase 3

Locations

Study Type

Interventional

Intervention

Pembrolizumab

Ipilimumab

About this trial

This is an interventional treatment trial for Melanoma focused on measuring Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Histologically-confirmed diagnosis of unresectable Stage III or metastatic melanoma not amenable to local therapy (excluding uveal or ocular melanoma)
At least one measurable lesion
No prior systemic treatment (excluding adjuvant or neoadjuvant therapy) for melanoma (first line) or one prior systemic treatment (excluding adjuvant or neoadjuvant therapy) for melanoma (second line)
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
Archived tissue sample or new biopsy sample
Female participants of childbearing potential must agree to use effective contraception from Visit 1 to 120 days after the last dose of study drug; male participants must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug

Exclusion criteria:

Prior treatment with ipilimumab or other anti-cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) agent or any anti-programmed cell death (PD-1 or PD-L2) agent
Chemotherapy, radioactive, or biological cancer therapy within four weeks prior to the first dose of study drug, or not recovered from adverse events caused by cancer therapeutics administered more than four weeks earlier
Currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study drug
Expected to require any other form of systemic or localized antineoplastic therapy while on study
On any systemic steroid therapy within one week before the planned date for first dose of randomized treatment or on any other form of immunosuppressive medication
History of a malignancy (other than the disease under treatment in the study) within 5 years prior to first study drug administration, excluding adequately treated Stage 1 or Stage 2 basal/squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other in situ cancers.
Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; participants with previously treated brain metastases are eligible
Severe hypersensitivity reaction to treatment with another monoclonal antibody
Active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents
Active infection requiring systemic therapy
Known history of Human Immunodeficiency Virus (HIV)
Known history of or positive for Hepatitis B or C
Known psychiatric or substance abuse disorder
Regular user (including recreational use) of illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol)
Pregnant or breastfeeding, or expecting to conceive, or father children within the projected duration of the study
Received a live vaccine within 30 days prior to first dose of study drug

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Arm Label

Ipilimumab

Pembrolizumab Q2W

Pembrolizumab Q3W

Arm Description

Participants receive ipilimumab, 3 mg/kg intravenously (IV), once every 3 weeks (Q3W) for a total of 4 doses (up to approximately 3 months).

Participants receive pembrolizumab, 10 mg/kg IV, once every 2 weeks (Q2W) for up to approximately 24 months.

Participants receive pembrolizumab, 10 mg/kg IV, Q3W for up to approximately 24 months.

Outcomes

Primary Outcome Measures

Progression-free Survival (PFS) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Independent Radiology Plus Oncology Review (IRO)

PFS was defined as the time from randomization to the first documented disease progression, based on blinded Independent Radiology plus Oncology review (IRO) using RECIST 1.1, or death due to any cause, whichever occurred first. Disease progression was defined as a 20% or greater increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of new lesions. The primary analysis of PFS was performed at the time of the first protocol pre-specified statistical analysis, with data cut-off of 03-Sep-2014.

Percentage of Participants With Overall Survival (OS) at 12 Months

OS was defined as the time from randomization to death due to any cause. The percentage of participants with OS (OS rate) at 12 months was reported for each arm. The reported percentage was estimated using a product-limit (Kaplan-Meier) method for censored data; data were censored at the date of cut-off. The primary analysis of OS was performed at the time of the second protocol pre-specified statistical analysis, with data cut-off of 03-Mar-2015.

Secondary Outcome Measures

Objective Response Rate (ORR) According to RECIST 1.1 as Assessed by IRO

ORR was defined as the percentage of the participants with a best tumor response of complete response (CR: disappearance of all target lesions with any pathological lymph nodes having a reduction in short axis to <10 mm) or partial response (PR: ≥30% decrease in the sum of diameters of target lesions), based on IRO using RECIST 1.1. The primary analysis of ORR was performed at the time of the first protocol pre-specified statistical analysis, with data cut-off of 03-Sep-2014.

Full Information

NCT ID

NCT01866319

First Posted

May 28, 2013

Last Updated

May 22, 2020

Sponsor

Merck Sharp & Dohme LLC

1. Study Identification

Unique Protocol Identification Number

NCT01866319

Brief Title

Study to Evaluate the Safety and Efficacy of Two Different Dosing Schedules of Pembrolizumab (MK-3475) Compared to Ipilimumab in Participants With Advanced Melanoma (MK-3475-006/KEYNOTE-006)

Official Title

A Multicenter, Randomized, Controlled, Three-Arm, Phase III Study to Evaluate the Safety and Efficacy of Two Dosing Schedules of Pembrolizumab (MK-3475) Compared to Ipilimumab in Patients With Advanced Melanoma

Study Type

Interventional

2. Study Status

Record Verification Date

May 2020

Overall Recruitment Status

Completed

Study Start Date

August 28, 2013 (Actual)

Primary Completion Date

March 3, 2015 (Actual)

Study Completion Date

June 3, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This study will evaluate the safety and efficacy of 2 different dosing schedules of pembrolizumab (MK-3475), every 2 weeks (Q2W) and every 3 weeks (Q3W), and compare the 2 schedules to treatment with ipilimumab in ipilimumab-naïve participants with unresectable or metastatic melanoma. The primary hypotheses are that pembrolizumab is superior to ipilimumab with respect to progression-free survival (PFS) and overall survival (OS).

Detailed Description

Participants assigned to a primary course of pembrolizumab can receive up to 24 months of treatment. Participants with Stable Disease (SD) or better will then proceed to Post Treatment Follow-up. All efficacy and safety analyses will be based on the primary pembrolizumab course. Participants who experience disease progression during the Post Treatment Follow-up will be eligible for a Second Course of pembrolizumab treatment for up to 1 additional year. With Amendment 05, all Second Course participants will be treated with a fixed dose of pembrolizumab 200 mg Q3W. With Amendment 06, after the study has achieved its key objectives or the study has ended, participants will be discontinued from this study and enrolled in an extension study to continue protocol-defined assessments and treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Melanoma

Keywords

Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

834 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ipilimumab

Arm Type

Experimental

Arm Description

Participants receive ipilimumab, 3 mg/kg intravenously (IV), once every 3 weeks (Q3W) for a total of 4 doses (up to approximately 3 months).

Arm Title

Pembrolizumab Q2W

Arm Type

Experimental

Arm Description

Participants receive pembrolizumab, 10 mg/kg IV, once every 2 weeks (Q2W) for up to approximately 24 months.

Arm Title

Pembrolizumab Q3W

Arm Type

Active Comparator

Arm Description

Participants receive pembrolizumab, 10 mg/kg IV, Q3W for up to approximately 24 months.

Intervention Type

Biological

Intervention Name(s)

Pembrolizumab

Other Intervention Name(s)

MK-3475

Intervention Description

10 mg/kg IV, administered Q2W or Q3W based upon randomization.

Intervention Type

Biological

Intervention Name(s)

Ipilimumab

Intervention Description

3 mg/kg IV Q3W.

Primary Outcome Measure Information:

Title

Progression-free Survival (PFS) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Independent Radiology Plus Oncology Review (IRO)

Description

Time Frame

Up to approximately 12 months (through first pre-specified statistical analysis cut-off date of 03-Sep-2014)

Title

Percentage of Participants With Overall Survival (OS) at 12 Months

Description

Time Frame

Month 12

Secondary Outcome Measure Information:

Title

Objective Response Rate (ORR) According to RECIST 1.1 as Assessed by IRO

Description

Time Frame

Up to approximately 12 months (through first pre-specified statistical analysis cut-off date of 03-Sep-2014)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Histologically-confirmed diagnosis of unresectable Stage III or metastatic melanoma not amenable to local therapy (excluding uveal or ocular melanoma) At least one measurable lesion No prior systemic treatment (excluding adjuvant or neoadjuvant therapy) for melanoma (first line) or one prior systemic treatment (excluding adjuvant or neoadjuvant therapy) for melanoma (second line) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Archived tissue sample or new biopsy sample Female participants of childbearing potential must agree to use effective contraception from Visit 1 to 120 days after the last dose of study drug; male participants must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug Exclusion criteria: Prior treatment with ipilimumab or other anti-cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) agent or any anti-programmed cell death (PD-1 or PD-L2) agent Chemotherapy, radioactive, or biological cancer therapy within four weeks prior to the first dose of study drug, or not recovered from adverse events caused by cancer therapeutics administered more than four weeks earlier Currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study drug Expected to require any other form of systemic or localized antineoplastic therapy while on study On any systemic steroid therapy within one week before the planned date for first dose of randomized treatment or on any other form of immunosuppressive medication History of a malignancy (other than the disease under treatment in the study) within 5 years prior to first study drug administration, excluding adequately treated Stage 1 or Stage 2 basal/squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other in situ cancers. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; participants with previously treated brain metastases are eligible Severe hypersensitivity reaction to treatment with another monoclonal antibody Active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents Active infection requiring systemic therapy Known history of Human Immunodeficiency Virus (HIV) Known history of or positive for Hepatitis B or C Known psychiatric or substance abuse disorder Regular user (including recreational use) of illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol) Pregnant or breastfeeding, or expecting to conceive, or father children within the projected duration of the study Received a live vaccine within 30 days prior to first dose of study drug

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director

Organizational Affiliation

Merck Sharp & Dohme LLC

Official's Role

Study Director

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

IPD Sharing URL

http://engagezone.msd.com/ds_documentation.php

Citations:

Citation

Robert C,Schachter J,Long GV,Arance A,Grob JJ,Mortier L,Daud A,Carlino MS,McNeil C,Lotem M,Larkin J,Lorigan P,Neyns B,Blank CU,Hamid O,Mateus C,Shapira-Frommer R,Kosh M,Zhou H,Ibrahim N,Ebbinghaus S,Ribas A,KEYNOTE-006 investigators . Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015 Apr 19; PMID: 25891173

Results Reference

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PubMed Identifier

28822576

Citation

Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. doi: 10.1016/S0140-6736(17)31601-X. Epub 2017 Aug 16.

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Citation

Hamid O, Robert C, Daud A, Carlino MS, Mitchell TC, Hersey P, Schachter J, Long GV, Hodi FS, Wolchok JD, Arance A, Grob JJ, Joshua AM, Weber JS, Mortier L, Jensen E, Diede SJ, Moreno BH, Ribas A. Long-term outcomes in patients with advanced melanoma who had initial stable disease with pembrolizumab in KEYNOTE-001 and KEYNOTE-006. Eur J Cancer. 2021 Nov;157:391-402. doi: 10.1016/j.ejca.2021.08.013. Epub 2021 Sep 25.

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PubMed Identifier

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Citation

Robert C, Hwu WJ, Hamid O, Ribas A, Weber JS, Daud AI, Hodi FS, Wolchok JD, Mitchell TC, Hersey P, Dronca R, Joseph RW, Boutros C, Min L, Long GV, Schachter J, Puzanov I, Dummer R, Lin J, Ibrahim N, Diede SJ, Carlino MS, Joshua AM. Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma. Eur J Cancer. 2021 Feb;144:182-191. doi: 10.1016/j.ejca.2020.11.010. Epub 2020 Dec 24.

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Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. doi: 10.1016/S1470-2045(19)30388-2. Epub 2019 Jul 22.

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Hamid O, Robert C, Ribas A, Hodi FS, Walpole E, Daud A, Arance AS, Brown E, Hoeller C, Mortier L, Schachter J, Long J, Ebbinghaus S, Ibrahim N, Butler M. Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006. Br J Cancer. 2018 Sep;119(6):670-674. doi: 10.1038/s41416-018-0207-6. Epub 2018 Sep 11.

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25891173

Citation

Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. doi: 10.1056/NEJMoa1503093. Epub 2015 Apr 19.

Results Reference

derived

Links:

URL

http://merckoncologyclinicaltrials.com

Description

Merck Oncology Clinical Trials Information

Available IPD and Supporting Information:

Available IPD/Information Type

CSR Synopsis

Available IPD/Information URL

http://www.merck.com/clinical-trials/study.html?id=3475-006&kw=3475-006&tab=access

Learn more about this trial

Study to Evaluate the Safety and Efficacy of Two Different Dosing Schedules of Pembrolizumab (MK-3475) Compared to Ipilimumab in Participants With Advanced Melanoma (MK-3475-006/KEYNOTE-006)

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