A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma

The purpose of this study was to evaluate safety and efficacy of the combination of an anti-PD-1 antibody (PDR001), a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in patients with BRAF V600 mutant, unresectable and metastatic melanoma.

This study was designed as a phase III, multi-center study consisting of 3 parts:

* Part 1: Safety run-in part The safety run-in part aimed to determine the recommended regimen of PDR001 in combination with dabrafenib and trametinib for previously untreated patients with BRAF V600 mutant unresectable or metastatic melanoma (stage IIIC/IV). Spartalizumab was administered at a starting dose level (DL1) of 400 mg every 4 weeks (Q4W), along with fixed doses of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily). The RP3R for Part 3 was determined using the Bayesian Logistic Regression Model (BLRM) with escalation with overdose control (EWOC) criteria.
* Part 2: Biomarker cohort Part 2 was run to explore changes in the immune microenvironment and biomarker modulations upon treatment with the combination of dabrafenib, trametinib and PDR001. Part 2 started when the fourth subject in dose level 1 (DL1) of Part 1 completed approximately 4 weeks of study treatment, and fewer than 3 dose-limiting toxicities (DLTs) were observed. Participants in Part 2 received PDR001 (spartalizumab) at a dosage of 400 mg Q4W, in combination with dabrafenib (150 mg BID) and trametinib (2 mg QD).
* Part 3: Double-blind, randomized, placebo-controlled part Part 3 was comparing the efficacy and safety of spartalizumab in combination with dabrafenib and trametinib to placebo in combination with dabrafenib and trametinib. Part 3 was initiated after determining the RP3R for the combination of spartalizumab with dabrafenib and trametinib in Part 1. Subjects were randomized in a 1:1 ratio to receive either the RP3R dose of spartalizumab identified in Part 1 or placebo, along with dabrafenib (150 mg BID) and trametinib (2 mg QD).

For all parts of the study, the treatment continued until the subject experiences any of the following events: disease progression according to RECIST 1.1 as determined by the Investigator, unacceptable toxicity, initiation of a new anti-neoplastic therapy, pregnancy, withdrawal of consent, physician's decision, loss to follow-up, death, or termination of the study by the Sponsor. Safety evaluations are conducted for all subjects for up to 150 days after the last dose of spartalizumab/placebo (safety follow-up period).

Subjects who discontinued study treatment without disease progression as per RECIST 1.1 continued with tumor assessments according to the protocol until documented disease progression, withdrawal of consent, loss to follow-up, or death, regardless of the initiation of new anti-neoplastic therapy (efficacy follow-up period).

Subjects entered the survival follow-up period after completing the safety follow-up period or experiencing disease progression as per RECIST 1.1 or response criteria for immunotherapy, whichever period is longer (survival follow-up period).

Eligibility Criteria:
Inclusion criteria Part 1: Safety run-in

* Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation
* Aspartate transaminase (AST) \< 2.5× ULN and Alanine transaminase (ALT) \< 2.5× ULN
* Measurable disease according to RECIST 1.1
* ECOG performance status ≤ 1

Part 2: Biomarker cohort

* Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation
* At least two cutaneous or subcutaneous or nodal lesions for tumor sample collection
* Measurable disease according to RECIST 1.1
* ECOG performance status ≤ 2

Part 3: Double-blind, randomized, placebo-controlled part

* Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation
* ECOG performance status ≤ 2
* Measurable disease according to RECIST 1.1

Exclusion Criteria:

Part 1: Safety run-in

* Subjects with uveal or mucosal melanoma
* Any history of CNS metastases
* Prior systemic anti-cancer treatment for unresectable or metastatic melanoma
* Neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months prior to enrollmen
* Radiation therapy within 4 weeks prior to start of study treatment
* Active autoimmune disease, and/or history of autoimmune disease(s) that required treatment

Parts 2 \& 3: Biomarker cohort \& double-blind, randomized, placebo-controlled part

* Subjects with uveal or mucosal melanoma
* Prior systemic anti-cancer treatment for unresectable or metastatic melanoma
* Neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months prior to enrollment
* Radiation therapy within 4 weeks prior to start of study treatment
* Clinically active cerebral melanoma metastasis.
* Active autoimmune disease, and/or history of autoimmune disease(s) that required treatment

Other protocol-defined Inclusion/Exclusion may apply.