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

NCT ID: NCT01704287

Last Updated: 2020-05-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 540 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-11-20
• Study Completion Date: 2019-01-31

Brief 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.

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.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Pembrolizumab 2 mg/kg

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)

Group Type: EXPERIMENTAL

Pembrolizumab

Intervention Type: BIOLOGICAL

IV infusion

Pembrolizumab 10 mg/kg

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)

Group Type: EXPERIMENTAL

Pembrolizumab

Intervention Type: BIOLOGICAL

IV infusion

Investigator-Choice Chemotherapy (ICC)

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)

Group Type: ACTIVE_COMPARATOR

Carboplatin

Intervention Type: DRUG

Carboplatin per institutional standard

Paclitaxel

Intervention Type: DRUG

Paclitaxel per institutional standard

Dacarbazine

Intervention Type: DRUG

Dacarbazine per institutional standard

Temozolomide

Intervention Type: DRUG

Temozolomide per institutional standard

ICC→Pembrolizumab 2 mg/kg

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)

Group Type: EXPERIMENTAL

Pembrolizumab

Intervention Type: BIOLOGICAL

IV infusion

Carboplatin

Intervention Type: DRUG

Carboplatin per institutional standard

Paclitaxel

Intervention Type: DRUG

Paclitaxel per institutional standard

Dacarbazine

Intervention Type: DRUG

Dacarbazine per institutional standard

Temozolomide

Intervention Type: DRUG

Temozolomide per institutional standard

ICC→Pembrolizumab 10 mg/kg

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)

Group Type: EXPERIMENTAL

Pembrolizumab

Intervention Type: BIOLOGICAL

IV infusion

Carboplatin

Intervention Type: DRUG

Carboplatin per institutional standard

Paclitaxel

Intervention Type: DRUG

Paclitaxel per institutional standard

Dacarbazine

Intervention Type: DRUG

Dacarbazine per institutional standard

Temozolomide

Intervention Type: DRUG

Temozolomide per institutional standard

Interventions

Pembrolizumab

IV infusion

Intervention Type: BIOLOGICAL

Carboplatin

Carboplatin per institutional standard

Intervention Type: DRUG

Paclitaxel

Paclitaxel per institutional standard

Intervention Type: DRUG

Dacarbazine

Dacarbazine per institutional standard

Intervention Type: DRUG

Temozolomide

Temozolomide per institutional standard

Intervention Type: DRUG

Other Intervention Names

SCH 900475; MK-3475; KEYTRUDA®; PARAPLATIN®; TAXOL®; DTIC; TEMODAR®

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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
• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Merck Sharp & Dohme LLC

References

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.

Reference Type: BACKGROUND

PMID: 26115796 (View on PubMed)

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.

Reference Type: RESULT

PMID: 28961465 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35101941 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33360855 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32305010 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31395089 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30736858 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30202085 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27596353 (View on PubMed)

Related Links

http://merckoncologyclinicaltrials.com

Merck Oncology Clinical Trials Information

Other Identifiers

MK-3475-002

Identifier Type: OTHER

Identifier Source: secondary_id

2012-003030-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

KEYNOTE-002

Identifier Type: OTHER

Identifier Source: secondary_id

P08719

Identifier Type: OTHER

Identifier Source: secondary_id

P08719

Identifier Type: -

Identifier Source: org_study_id