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

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 2

Conditions: Malignant Melanoma

Treatments: Drug: Dacarbazine; Biological: Pembrolizumab; Drug: Carboplatin; Drug: Temozolomide; Drug: Paclitaxel

Study type: Interventional

Funder types: Industry

Identifiers

NCT01704287

P08719 (Other Identifier)

KEYNOTE-002 (Other Identifier)

2012-003030-17 (EudraCT Number)

MK-3475-002 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 540 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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540 participants in 5 patient groups

Pembrolizumab 2 mg/kg

Experimental group

Description:

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)

Treatment:

Biological: Pembrolizumab

Pembrolizumab 10 mg/kg

Experimental group

Description:

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)

Treatment:

Biological: Pembrolizumab

Investigator-Choice Chemotherapy (ICC)

Active Comparator group

Description:

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)

Treatment:

Drug: Paclitaxel

Drug: Temozolomide

Drug: Carboplatin

Drug: Dacarbazine

ICC→Pembrolizumab 2 mg/kg

Experimental group

Description:

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)

Treatment:

Drug: Paclitaxel

Drug: Temozolomide

Drug: Carboplatin

Biological: Pembrolizumab

Drug: Dacarbazine

ICC→Pembrolizumab 10 mg/kg

Experimental group

Description:

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)

Treatment:

Drug: Paclitaxel

Drug: Temozolomide

Drug: Carboplatin

Biological: Pembrolizumab

Drug: Dacarbazine