Malignant MelanomaPhase 2NCT01704287

Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Participants With Advanced Melanoma (MK-3475-002/P08719/KEYNOTE-002)

A Phase 2 study testing Pembrolizumab, Carboplatin and Paclitaxel in people with Malignant Melanoma, run by Merck Sharp & Dohme LLC.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

This study was conducted to compare survival using pembrolizumab (SCH 900475, MK-3475) or standard chemotherapy in participants with advanced melanoma (MEL) who had progressed after prior therapy. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Malignant Melanoma
What is being tested?: Pembrolizumab, Carboplatin and Paclitaxel
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 540 participants
Where: No sites listed yet
Study dates: 20 Nov 2012to 31 Jan 2019
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Histologically or cytologically confirmed diagnosis of unresectable Stage III or metastatic MEL not amenable to local therapy
Participants must be refractory to ipilimumab
Participants with BRAF gene mutant melanoma must have had a prior treatment regimen that included vemurafenib, dabrafenib, or an approved BRAF gene and/or mitogen-activated protein kinase (MEK) protein inhibitor
Must consent to allow correlative studies; must provide a newly obtained tissue/biopsy specimen (or specimen obtained within 60 days of consenting)
Radiographically measurable disease
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Who cannot join

Chemotherapy, radiation therapy, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or not recovered from the AEs due to cancer therapies administered more than 4 weeks earlier
Disease progression within 24 weeks of last dose of ipilimumab
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
Chronic systemic steroid therapy within 2 weeks before the planned date for first dose randomized treatment or on any other form of immunosuppressive medication
Known history of any other than the current malignancy excepting adequately treated basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, breast cancer, or other in situ cancers

Show all 14Show fewer

Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
Active autoimmune disease or a history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents
Prior treatment with any other anti-programmed cell death (PD) agent
Active infection requiring systemic therapy
Known history of Human Immunodeficiency Virus (HIV)
Active Hepatitis B or Hepatitis C
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 through 120 days after last dose of study drug

About this study

Official title: Randomized, Phase II Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Patients With Advanced Melanoma (KEYNOTE 002)

This study was conducted to compare survival using pembrolizumab (SCH 900475, MK-3475) or standard chemotherapy in participants with advanced melanoma (MEL) who had progressed after prior therapy.

Initial Treatment Period:

Participants were initially randomized to receive either low-dose (2 mg/kg) pembrolizumab, higher dose (10 mg/kg) pembrolizumab or Investigator-choice chemotherapy (ICC). The four standard chemotherapy choices were: carboplatin + paclitaxel, paclitaxel alone, dacarbazine, or temozolomide. The randomization to either pembrolizumab or ICC was conducted in an open-label fashion.

The starting pembrolizumab dose was initially blinded to Investigators and participants until Amendment 03. With Amendment 03, all ongoing pembrolizumab participants were to be treated with open label, fixed dose pembrolizumab 200 mg, instead of a weight-based dosing of pembrolizumab.

Switch-to-Pembrolizumab Treatment Period:

Participants who were initially randomized to receive ICC and experienced progressive disease (PD) may have been eligible to switch to receiving pembrolizumab provided they met protocol-specified requirements for switching. Qualified participants were re-randomized to receive either pembrolizumab 2 mg/kg or pembrolizumab 10 mg/kg in a double-blind fashion. Participants who qualified to switch to pembrolizumab must have completed a washout period of ≥28 days from last dose of chemotherapy before receiving pembrolizumab. With Amendment 03, all switched-to-pembrolizumab participants were to be treated with open-label, fixed dose pembrolizumab 200 mg instead of a weight-based dosing of pembrolizumab.

Read the detailed description

Two interim and one final statistical analyses were planned for and conducted during this study:

Interim Analysis 1 (futility analysis),
Interim Analysis 2 (~18 months into study): database cutoff date 12-May-2014, and
Final Analysis (~36 months into study): database cutoff date 16-Nov-2015. The End of Trial Analysis for the study was conducted at ~75 months into the study: database cutoff date 31-Jan-2019.

Conditions: Malignant Melanoma
Being tested: Pembrolizumab, Carboplatin, Paclitaxel, Dacarbazine, Temozolomide
Keywords: Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)
Medical subject headings: Melanoma, Parkinson Disease 4, Autosomal Dominant Lewy Body

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

PembrolizumabBiological
Also called SCH 900475, MK-3475, KEYTRUDA®
IV infusion
CarboplatinDrug
Also called PARAPLATIN®
Carboplatin per institutional standard
PaclitaxelDrug
Also called TAXOL®
Paclitaxel per institutional standard
DacarbazineDrug
Also called DTIC
Dacarbazine per institutional standard
TemozolomideDrug
Also called TEMODAR®
Temozolomide per institutional standard

Study groups in NCT01704287
Study group	Role	What they receive
Pembrolizumab 2 mg/kg	Experimental	Participants were initially randomized to receive pembrolizumab 2 mg/kg intravenously (IV) once every 3 weeks (Q3W). With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months) Receives: Biological: Pembrolizumab
Pembrolizumab 10 mg/kg	Experimental	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months) Receives: Biological: Pembrolizumab
Investigator-Choice Chemotherapy (ICC)	Active comparator	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months) Receives: Drug: Carboplatin; Drug: Paclitaxel; Drug: Dacarbazine; Drug: Temozolomide
ICC→Pembrolizumab 2 mg/kg	Experimental	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months) Receives: Biological: Pembrolizumab; Drug: Carboplatin; Drug: Paclitaxel; Drug: Dacarbazine; Drug: Temozolomide
ICC→Pembrolizumab 10 mg/kg	Experimental	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months) Receives: Biological: Pembrolizumab; Drug: Carboplatin; Drug: Paclitaxel; Drug: Dacarbazine; Drug: Temozolomide

What is being measured

The primary outcome is the main question the study is designed to answer.

Progression-free Survival (PFS) - Initial Treatment Period
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Criteria in Solid Tumors version 1.1 (RECIST 1.1), PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. Analysis of PFS was based on an integrated radiology and oncology (IRO) assessment and was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median PFS based on the product limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for PFS.
Measured: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Interim Overall Survival (OS) - Initial Treatment Period
OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the interim analysis for OS.
Measured: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Final Overall Survival (OS) - Initial Treatment Period
OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for OS.
Measured: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)

Secondary outcomes (7)

Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period
OS was defined as the time from randomization to death due to any cause. Participants with an Allred Proportion Score (APS) ≥2 (membranous staining in ≥1% of cells for PD-L1) were considered to be PD-L1 Positive and participants with an APS of 0 or 1 were considered to be PD-L1 Negative. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data by PD-L1 tumor expression status is presented.
Measured: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
Overall Response Rate (ORR) - Initial Treatment Period
ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. Analysis of ORR was not planned or conducted for the switch-to-pembrolizumab treatment groups. The percentage of participants who experienced a CR or PR is presented. This was the final analysis for ORR.
Measured: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Best Overall Response (BOR) - Initial Treatment Period
BOR was assessed by independent radiology review using RECIST 1.1 and was recorded from randomization until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. BOR for the Initial Treatment Period was based on IRO. BOR for participants during the Initial Treatment Period is presented.
Measured: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period
The BOR was assessed using RECIST 1.1 and was recorded from the start of the second line of study drug (pembrolizumab) until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For the switch-to-pembrolizumab treatment groups, BOR was based on independent review committee (IRC) assessment. The BOR for switched-to pembrolizumab treatment groups is presented.
Measured: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Duration of Response (DOR) - Initial Treatment Period
For participants who demonstrated a confirmed response (Complete Response [CR]: disappearance of all target lesions or Partial Response [PR]: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. DOR analysis was based on IRO assessment. Analysis of DOR was not planned or analyzed for the switch-to-pembrolizumab treatment groups. Median DOR for participants who demonstrated a confirmed response is presented.
Measured: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Number of Participants Who Experienced an Adverse Event (AE) - Overall Study
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 study drug, 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 study drug, was also an AE. Participants were included in the treatment group in which an AE was experienced. The number of participants who experienced at least one AE is presented.
Measured: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study
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 study drug, 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 is temporally associated with the use of study drug, was also an AE. The number of participants who discontinued study drug due to an AE is presented.
Measured: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

20 Nov 201231 Jan 2019

First posted11 Oct 2012 (estimated)
Study start20 Nov 2012
Primary completion16 Nov 2015
Study completion31 Jan 2019

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (9)Papers the sponsor has linked to this study.
Other trials for Malignant MelanomaStudies of the same condition, open and under way.
More trials run by Merck Sharp & Dohme LLCThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind
Who is masked: Participant, Investigator
Enrolment: 540 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01704287
Sponsor's protocol ID: P08719
Other IDs: MK-3475-002, 2012-003030-17, KEYNOTE-002, P08719
Status last verified: Apr 2020
First submitted: 8 Oct 2012
Last updated: 18 May 2020
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Publications

Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. doi: 10.1016/S1470-2045(15)00083-2. Epub 2015 Jun 23.
PubMed 26115796
Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. doi: 10.1016/j.ejca.2017.07.022.
PubMed 28961465
Cristescu R, Aurora-Garg D, Albright A, Xu L, Liu XQ, Loboda A, Lang L, Jin F, Rubin EH, Snyder A, Lunceford J. Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors. J Immunother Cancer. 2022 Jan;10(1):e003091. doi: 10.1136/jitc-2021-003091.
PubMed 35101941
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.
PubMed 33360855
Lala M, Li TR, de Alwis DP, Sinha V, Mayawala K, Yamamoto N, Siu LL, Chartash E, Aboshady H, Jain L. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer. 2020 May;131:68-75. doi: 10.1016/j.ejca.2020.02.016. Epub 2020 Apr 15.
PubMed 32305010
van Vugt MJH, Stone JA, De Greef RHJMM, Snyder ES, Lipka L, Turner DC, Chain A, Lala M, Li M, Robey SH, Kondic AG, De Alwis D, Mayawala K, Jain L, Freshwater T. Immunogenicity of pembrolizumab in patients with advanced tumors. J Immunother Cancer. 2019 Aug 8;7(1):212. doi: 10.1186/s40425-019-0663-4.
PubMed 31395089
Wang M, Chen C, Jemielita T, Anderson J, Li XN, Hu C, Kang SP, Ibrahim N, Ebbinghaus S. Are tumor size changes predictive of survival for checkpoint blockade based immunotherapy in metastatic melanoma? J Immunother Cancer. 2019 Feb 8;7(1):39. doi: 10.1186/s40425-019-0513-4.
PubMed 30736858
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.
PubMed 30202085
Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. doi: 10.1016/j.ejca.2016.07.018. Epub 2016 Sep 2.
PubMed 27596353

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

Official record

RecruitingPhase 1/2
Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)
Solid Tumor, Non-Small Cell Lung Cancer
RecruitingPhase 1
IL-17 Blockade to Decrease irAEs (REPLAY)
Metastatic Melanoma
Enrolling by invitationObservational study
Natural History Study of Early Life Exposures in Agriculture (ELEA)
Prostate Cancer, Leukemia
RecruitingPhase 1
A Feasibility Study Utilizing Immune Recall to Increase Response to Checkpoint Therapy
Melanoma
Active, not recruitingPhase 1/2
A Study of Dapansutrile Plus Pembrolizumab in Patients With PD-1 Refractory Advanced Melanoma
Melanoma

All Malignant Melanoma trials

Study at a glance

From the registry record, last updated by the sponsor on 18 May 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Randomized, Phase II Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Patients With Advanced Melanoma (KEYNOTE 002)
ClinicalTrials.gov ID: NCT01704287
Acronym / sponsor ID: P08719
Conditions: Malignant Melanoma
Keywords: Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 540 participants (actual)
Lead sponsor: Merck Sharp & Dohme LLCIndustry (pharma, biotech, devices)
Study start: 20 Nov 2012 (actual)
Primary completion: 16 Nov 2015 (actual)
Study completion: 31 Jan 2019 (actual)
First posted: 11 Oct 2012 (estimated)
Results: Posted 28 Mar 2017

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

This study was conducted to compare survival using pembrolizumab (SCH 900475, MK-3475) or standard chemotherapy in participants with advanced melanoma (MEL) who had progressed after prior therapy.

Initial Treatment Period:

Switch-to-Pembrolizumab Treatment Period:

Detailed description

Two interim and one final statistical analyses were planned for and conducted during this study:

Interim Analysis 1 (futility analysis),
Interim Analysis 2 (~18 months into study): database cutoff date 12-May-2014, and
Final Analysis (~36 months into study): database cutoff date 16-Nov-2015. The End of Trial Analysis for the study was conducted at ~75 months into the study: database cutoff date 31-Jan-2019.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind (participant, investigator)
Number of arms: 5

Arm	Type	Receives
Pembrolizumab 2 mg/kg	Experimental	Biological: PembrolizumabParticipants were initially randomized to receive pembrolizumab 2 mg/kg intravenously (IV) once every 3 weeks (Q3W). With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Pembrolizumab 10 mg/kg	Experimental	Biological: PembrolizumabParticipants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Investigator-Choice Chemotherapy (ICC)	Active comparator	Drug: Carboplatin, Drug: Paclitaxel, Drug: Dacarbazine, Drug: TemozolomideParticipants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
ICC→Pembrolizumab 2 mg/kg	Experimental	Biological: Pembrolizumab, Drug: Carboplatin, Drug: Paclitaxel, Drug: Dacarbazine, Drug: TemozolomideParticipants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
ICC→Pembrolizumab 10 mg/kg	Experimental	Biological: Pembrolizumab, Drug: Carboplatin, Drug: Paclitaxel, Drug: Dacarbazine, Drug: TemozolomideParticipants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (6 listed)

Histologically or cytologically confirmed diagnosis of unresectable Stage III or metastatic MEL not amenable to local therapy
Participants must be refractory to ipilimumab
Participants with BRAF gene mutant melanoma must have had a prior treatment regimen that included vemurafenib, dabrafenib, or an approved BRAF gene and/or mitogen-activated protein kinase (MEK) protein inhibitor
Must consent to allow correlative studies; must provide a newly obtained tissue/biopsy specimen (or specimen obtained within 60 days of consenting)
Radiographically measurable disease

Key exclusion criteria (14 listed)

Chemotherapy, radiation therapy, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or not recovered from the AEs due to cancer therapies administered more than 4 weeks earlier
Disease progression within 24 weeks of last dose of ipilimumab
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
Chronic systemic steroid therapy within 2 weeks before the planned date for first dose randomized treatment or on any other form of immunosuppressive medication

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
PembrolizumabAlso: SCH 900475, MK-3475, KEYTRUDA®IV infusion	Biological	ICC→Pembrolizumab 10 mg/kg, ICC→Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg, Pembrolizumab 2 mg/kg
CarboplatinAlso: PARAPLATIN®Carboplatin per institutional standard	Drug	ICC→Pembrolizumab 10 mg/kg, ICC→Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
PaclitaxelAlso: TAXOL®Paclitaxel per institutional standard	Drug	ICC→Pembrolizumab 10 mg/kg, ICC→Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
DacarbazineAlso: DTICDacarbazine per institutional standard	Drug	ICC→Pembrolizumab 10 mg/kg, ICC→Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
TemozolomideAlso: TEMODAR®Temozolomide per institutional standard	Drug	ICC→Pembrolizumab 10 mg/kg, ICC→Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)

Primary outcome

Progression-free Survival (PFS) - Initial Treatment Period
Time frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Criteria in Solid Tumors version 1.1 (RECIST 1.1), PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. Analysis of PFS was based on an integrated radiology and oncology (IRO) assessment and was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median PFS based on the product limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for PFS.
Interim Overall Survival (OS) - Initial Treatment Period
Time frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the interim analysis for OS.
Final Overall Survival (OS) - Initial Treatment Period
Time frame: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for OS.

7 secondary outcomes

Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period
Time frame: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
Overall Response Rate (ORR) - Initial Treatment Period
Time frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Best Overall Response (BOR) - Initial Treatment Period
Time frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period
Time frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Duration of Response (DOR) - Initial Treatment Period
Time frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Number of Participants Who Experienced an Adverse Event (AE) - Overall Study
Time frame: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study
Time frame: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)

Results and safety

Results posted to the registry on 28 Mar 2017, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Pembrolizumab 2 mg/kg	180	33
Pembrolizumab 10 mg/kg	181	47
Investigator-Choice Chemotherapy (ICC)	179	6
ICC→Pembrolizumab 2 mg/kg	0	0
ICC→Pembrolizumab 10 mg/kg	0	0

Primary outcome: Progression-free Survival (PFS) - Initial Treatment Period

Time frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015). Median (95% Confidence Interval). Unit: Months

Measure	Pembrolizumab 2 mg/kg n = 180	Pembrolizumab 10 mg/kg n = 181	Investigator-Choice Chemotherapy (ICC) n = 179
Value	2.9 (2.8 to 3.8)	3.0 (2.8 to 5.2)	2.8 (2.6 to 2.8)

Pembrolizumab 2 mg/kg vs Investigator-Choice Chemotherapy (ICC): Hazard Ratio (HR): 0.58 (95% CI 0.46 to 0.73), p <0.0001, Log Rank
Pembrolizumab 10 mg/kg vs Investigator-Choice Chemotherapy (ICC): Hazard Ratio (HR): 0.47 (95% CI 0.37 to 0.60), p <0.0001, Log Rank
Pembrolizumab 2 mg/kg vs Pembrolizumab 10 mg/kg: Hazard Ratio (HR): 0.83 (95% CI 0.66 to 1.05), p = 0.1247, Log Rank

Population analysed: The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.

Primary outcome: Interim Overall Survival (OS) - Initial Treatment Period

Time frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015). Median (95% Confidence Interval). Unit: Months

Measure	Pembrolizumab 2 mg/kg n = 180	Pembrolizumab 10 mg/kg n = 181	Investigator-Choice Chemotherapy (ICC) n = 179
Value	13.4 (11.0 to 16.4)	14.7 (11.3 to 19.5)	11.0 (8.9 to 13.8)

Pembrolizumab 2 mg/kg vs Investigator-Choice Chemotherapy (ICC): Hazard Ratio (HR): 0.86 (95% CI 0.67 to 1.10), p = 0.1173, Log Rank
Pembrolizumab 10 mg/kg vs Investigator-Choice Chemotherapy (ICC): Hazard Ratio (HR): 0.74 (95% CI 0.57 to 0.96), p = 0.0106, Log Rank
Pembrolizumab 2 mg/kg vs Pembrolizumab 10 mg/kg: Hazard Ratio (HR): 0.87 (95% CI 0.67 to 1.12), p = 0.2905, Log Rank

Primary outcome: Final Overall Survival (OS) - Initial Treatment Period

Time frame: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019). Median (95% Confidence Interval). Unit: Months

Measure	Pembrolizumab 2 mg/kg n = 180	Pembrolizumab 10 mg/kg n = 181	Investigator-Choice Chemotherapy (ICC) n = 179
Value	13.4 (11.0 to 16.4)	14.7 (11.3 to 19.5)	11.0 (8.9 to 13.8)

Pembrolizumab 2 mg/kg vs Investigator-Choice Chemotherapy (ICC): Hazard Ratio (HR): 0.86 (95% CI 0.68 to 1.10), p = 0.1146, Log Rank
Pembrolizumab 10 mg/kg vs Investigator-Choice Chemotherapy (ICC): Hazard Ratio (HR): 0.71 (95% CI 0.55 to 0.90), p = 0.0023, Log Rank
Pembrolizumab 2 mg/kg vs Pembrolizumab 10 mg/kg: Hazard Ratio (HR): 0.84 (95% CI 0.66 to 1.07), p = 0.1490, Log Rank

7 secondary outcomes are reported in the full results.

Adverse events

Time frame: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019). Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Investigator-Choice Chemotherapy (ICC) Only	33 of 73 (45.2%)	66 of 73 (90.4%)	71 of 73
ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab)	15 of 53 (28.3%)	52 of 53 (98.1%)	0 of 53
ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab)	9 of 45 (20%)	44 of 45 (97.8%)	0 of 45
Pembrolizumab 2 mg/kg	91 of 178 (51.1%)	158 of 178 (88.8%)	139 of 178
Pembrolizumab 10 mg/kg	78 of 179 (43.6%)	176 of 179 (98.3%)	129 of 179
ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab)	18 of 53 (34%)	48 of 53 (90.6%)	35 of 53
ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)	18 of 45 (40%)	36 of 45 (80%)	37 of 45

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 18 May 2020.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 26115796Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. doi: 10.1016/S1470-2045(15)00083-2. Epub 2015 Jun 23.
Results publication: PubMed 28961465Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. doi: 10.1016/j.ejca.2017.07.022.
Derived from this study: PubMed 35101941Cristescu R, Aurora-Garg D, Albright A, Xu L, Liu XQ, Loboda A, Lang L, Jin F, Rubin EH, Snyder A, Lunceford J. Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors. J Immunother Cancer. 2022 Jan;10(1):e003091. doi: 10.1136/jitc-2021-003091.
Derived from this study: PubMed 33360855Robert 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.
Derived from this study: PubMed 32305010Lala M, Li TR, de Alwis DP, Sinha V, Mayawala K, Yamamoto N, Siu LL, Chartash E, Aboshady H, Jain L. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer. 2020 May;131:68-75. doi: 10.1016/j.ejca.2020.02.016. Epub 2020 Apr 15.
Derived from this study: PubMed 31395089van Vugt MJH, Stone JA, De Greef RHJMM, Snyder ES, Lipka L, Turner DC, Chain A, Lala M, Li M, Robey SH, Kondic AG, De Alwis D, Mayawala K, Jain L, Freshwater T. Immunogenicity of pembrolizumab in patients with advanced tumors. J Immunother Cancer. 2019 Aug 8;7(1):212. doi: 10.1186/s40425-019-0663-4.
Derived from this study: PubMed 30736858Wang M, Chen C, Jemielita T, Anderson J, Li XN, Hu C, Kang SP, Ibrahim N, Ebbinghaus S. Are tumor size changes predictive of survival for checkpoint blockade based immunotherapy in metastatic melanoma? J Immunother Cancer. 2019 Feb 8;7(1):39. doi: 10.1186/s40425-019-0513-4.
Derived from this study: PubMed 30202085Hamid 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.
Derived from this study: PubMed 27596353Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. doi: 10.1016/j.ejca.2016.07.018. Epub 2016 Sep 2.
Merck Oncology Clinical Trials InformationLink provided by the sponsor.
Individual participant dataSharing planned: Yes. http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Medical Director study director

Merck Sharp & Dohme LLC

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Pembrolizumab, Carboplatin and Paclitaxel in people with Malignant Melanoma, run by Merck Sharp & Dohme LLC.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 May 2020. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Mar 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-free Survival (PFS) - Initial Treatment Period (time frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01704287, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 May 2020.