a study of the anti-pd1 antibody pdr001, in combination with dabrafenib and trametinib in advanced melanoma

Conditions: Melanoma

Summary: 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.

Keywords: spartalizumab (pdr001) dabrafenib trametinib melanoma immunotherapy pd 1 inhibitor anti pd1 pd-1 anti-pd-1 combination treatment malignant skin cancer skin cancer braf v600 unresectable braf v600 mutated melanoma metastatic braf v600 mutated melanoma