A Randomized, Double-blind, Placebo-controlled, Phase III Study Comparing the Combination of PDR001, Dabrafenib and Trametinib Versus Placebo, Dabrafenib and Trametinib in Previously Untreated Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 568
- 试验地点
- 18
- 主要终点
- Safety Run-In (Part 1): Number of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Part 1 and Part 2 are open- label. Part 3 is double-blind and randomized.
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •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.
研究组 & 干预措施
Part 1: Safety run-in Cohort
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).
干预措施: Spartalizumab (Biological)
Part 2: Biomarker cohort
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).
干预措施: Trametinib (Drug)
Part 1: Safety run-in Cohort
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).
干预措施: Dabrafenib (Drug)
Part 1: Safety run-in Cohort
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).
干预措施: Trametinib (Drug)
Part 2: Biomarker cohort
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).
干预措施: Spartalizumab (Biological)
Part 2: Biomarker cohort
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).
干预措施: Dabrafenib (Drug)
Part 3- Arm 1: Spartalizumab in combination with dabrafenib and trametinib
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)
干预措施: Spartalizumab (Biological)
Part 3- Arm 1: Spartalizumab in combination with dabrafenib and trametinib
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)
干预措施: Dabrafenib (Drug)
Part 3- Arm 1: Spartalizumab in combination with dabrafenib and trametinib
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)
干预措施: Trametinib (Drug)
Part 3- Arm 2: Placebo in combination with dabrafenib and trametinib
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)
干预措施: Placebo (Other)
Part 3- Arm 2: Placebo in combination with dabrafenib and trametinib
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)
干预措施: Dabrafenib (Drug)
Part 3- Arm 2: Placebo in combination with dabrafenib and trametinib
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)
干预措施: Trametinib (Drug)
结局指标
主要结局
Safety Run-In (Part 1): Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Up to 8 weeks (Part 1)
DLT was defined as an adverse event or abnormal laboratory value that was unrelated to disease, disease progression, inter-current illness, or concomitant medications and occured within 8 weeks of treatment with spartalizumab in combination with dabrafenib and trametinib. The DLT criteria included Grade 4 hematological adverse events, Grade 4 bilirubin elevation, specific gastrointestinal adverse events, symptomatic serum amylase or lipase elevation, Grade 3 or higher hypertension, Grade 3 or higher cardiac events, Grade 2 or higher pneumonitis, Grade 3 or higher immune-related toxicities, infusion-related reactions, other clinically significant adverse events, and toxicities leading to a dosing delay of over 12 weeks. NCI CTCAE v4.03 was used for grading DLTs
Biomarker Cohort (Part 2): Change From Baseline in CD8+ Cells Upon Treatment With Spartalizumab in Combination With Dabrafenib and Trametinib
时间窗: Baseline, Cycle 1 Day 15 and Cycle 3 Day 1 (Part 2). Each cycle is 28 days
Change from baseline in CD8+ cells (as determined by flow cytometry in blood samples) upon treatment with spartalizumab in combination with dabrafenib and trametinib in participants from Part 2
Randomized (Part 3): Progression-Free Survival (PFS) as Per Investigator's Assessment by RECIST 1.1
时间窗: Up to disease progression or death due to any cause, whichever occurs first, assessed up to 2.8 years (Part 3)
Progression-free survival was defined as the time from the date of first dose to the date of the first documented radiological progression per investigator's assessment according to RECIST 1.1 or death due to any cause. The distribution of PFS was estimated using the Kaplan-Meier (KM) method. If a patient had not had an event at the time of data cut-off, progression-free survival was censored at the date of last adequate tumor assessment.
Biomarker Cohort (Part 2): Change From Baseline in Programmed Cell Death-ligand 1 (PD-L1) Expression Upon Treatment With Spartalizumab in Combination With Dabrafenib and Trametinib
时间窗: Baseline, Cycle 1 Day 15 and Cycle 3 Day 1 (Part 2). Each cycle is 28 days
Change from baseline in PD-L1 expression (as determined by immunohistochemistry in tissue samples) upon treatment with spartalizumab in combination with dabrafenib and trametinib in participants from Part 2
次要结局
- Overall Survival (OS)(Up to death due to any cause, assessed up to approximately 7 years)
- Overall Response Rate (ORR) as Per Investigator's Assessment by RECIST 1.1(Part 1: Up to 3.3 years. Part 2: Up to 3 years. Part 3: Up to 2.8 years)
- Duration of Response (DOR) as Per Investigator's Assessment by RECIST 1.1(From first documented response to date of first documented progression or death, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3))
- Disease Control Rate (DCR) as Per Investigator's Assessment by RECIST 1.1(Part 1: Up to 3.3 years. Part 2: Up to 3 years. Part 3: Up to 2.8 year)
- Randomized (Part 3): Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Global Health Status Scores(From baseline to 60 days post progression, assessed up to 2.8 years (Part 3))
- Randomized (Part 3): Change From Baseline in EuroQoL 5-level Instrument (EQ-5D-5L)- Visual Analog Scale (VAS) Score(From baseline to 60 days post progression, assessed up to 2.8 years (Part 3))
- Randomized (Part 3): Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Physical Functioning Scale Scores(From baseline to 60 days post progression, assessed up to 2.8 years (Part 3))
- Randomized (Part 3): Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Pain Symptom Scale Scores(From baseline to 60 days post progression, assessed up to 2.8 years (Part 3))
- Randomized (Part 3): Time to 10 Point Definitive Deterioration in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Global Health Status(From baseline to date of at least 10 points relative to baseline worsening of the global health status score or death due to any cause, up to 2.8 years (Part 3))
- Randomized (Part 3): Change From Baseline in Function Assessment Cancer Therapy-melanoma (FACT-M) Melanoma Subscale Score(From baseline to 60 days post progression, assessed up to 2.8 years (Part 3))
- Randomized (Part 3): PFS as Per Investigator's Assessment by RECIST 1.1 by PD-L1 Expression(Up to disease progression or death due to any cause, up to 2.8 years (Part 3))
- Randomized (Part 3): OS by PD-L1 Expression(Up to death due to any cause, assessed up to approximately 7 years)
- Spartalizumab Anti-drug Antibody (ADA) Prevalence at Baseline(Baseline)
- Spartalizumab ADA Incidence(Throughout study until 150 days after the last dose of spartalizumab, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3).)
- Trough Concentration (Ctrough) for Spartalizumab(Pre-infusion on Day 1 of each Cycle starting from Cycle 2, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days)
- Pre-dose Plasma Concentration for Dabrafenib(Pre-infusion on Day 1 of every cycle from Cycle 2 to 12, and then every 6 cycles from Cycle 18 to 36, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days)
- Pre-dose Plasma Concentration for Trametinib(Pre-infusion on Day 1 of every cycle from Cycle 2 to 12, and then every 6 cycles from Cycle 18 to 36, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days)
- Number of Participants With Dose Interruptions(From baseline to end of treatment, assessed up to approximately 7 years)
- Number of Participants With Dose Reductions(From baseline to end of treatment, assessed up to approximately 7 years)
- Relative Dose Intensity(From baseline to end of treatment, assessed up to approximately 7 years)