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

Novartis

Status and phase: Completed; Phase 3

Conditions: Melanoma

Treatments: Drug: Trametinib; Drug: Dabrafenib; Other: Placebo; Biological: Spartalizumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT02967692

CPDR001F2301

2016-002794-35 (EudraCT Number)

Details and patient eligibility

About

To evaluate the safety and efficacy of the combination of an anti-PD-1 antibody (Spartalizumab (PDR001)), a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in unresectable or metastatic BRAF V600 mutant melanoma

Full description

This study is designed as a Phase III, multi-center study consisting of three parts:

• Part 1, known as the Safety Run-in, is an open-label part aimed at determining the recommended Phase III regimen (RP3R) of spartalizumab in combination with dabrafenib and trametinib for previously untreated subjects with BRAF V600 mutant unresectable or metastatic melanoma (Stage IIIC/IV per AJCC edition 7). In Part 1, 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, referred to as the Biomarker Cohort, is an open-label section focused on characterizing the kinetics of immune biomarkers and potential immune resistance mechanisms. 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 receive PDR001 (spartalizumab) at a dosage of 400 mg Q4W, in combination with dabrafenib (150 mg BID) and trametinib (2 mg QD).
• Part 3 is a double-blind, randomized, placebo-controlled phase that compares 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 is 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 discontinue study treatment without disease progression as per RECIST 1.1 continue 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 enter 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).

Enrollment: 573 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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573 participants in 4 patient groups, including a placebo group

Part 1: Safety run-in Cohort

Experimental group

Description:

In Part 1, participants are treated at different dose levels to determine the recommended Phase 3 regimen of spartalizumab in combination with dabrafenib and trametinib. The starting dose of spartalizumab is 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD).

Treatment:

Biological: Spartalizumab

Drug: Dabrafenib

Drug: Trametinib

Part 2: Biomarker cohort

Experimental group

Description:

In Part 2, participants are treated with spartalizumab 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD).

Treatment:

Biological: Spartalizumab

Drug: Dabrafenib

Drug: Trametinib

Part 3- Arm 1: Spartalizumab in combination with dabrafenib and trametinib

Experimental group

Description:

In Part 3, participants are randomized to receive spartalizumab at the RP3R identified in Part 1 (400 mg Q4W) in combination with approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD)

Treatment:

Biological: Spartalizumab

Drug: Dabrafenib

Drug: Trametinib

Part 3- Arm 2: Placebo in combination with dabrafenib and trametinib

Placebo Comparator group

Description:

In Part 3, participants are randomized to receive matching placebo in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD)

Treatment:

Other: Placebo

Drug: Dabrafenib

Drug: Trametinib