Clinical trial NCT01704287
Conditions: Malignant Melanoma
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2012-11-20; Completion date: 2019-01-31
Enrollment: 540 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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) arm 2: 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) arm 3: 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) arm 4: 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) arm 5: 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)
Interventions: intervention 1: Pembrolizumab intervention 2: Carboplatin intervention 3: Paclitaxel intervention 4: Dacarbazine intervention 5: Temozolomide
Intervention descriptions: intervention 1: IV infusion intervention 2: Carboplatin per institutional standard intervention 3: Paclitaxel per institutional standard intervention 4: Dacarbazine per institutional standard intervention 5: Temozolomide per institutional standard

Protocol documents: