A PHASE 2, RANDOMIZED, OPEN-LABEL STUDY OF ENCORAFENIB AND BINIMETINIB PLUS PEMBROLIZUMAB VERSUS NIVOLUMAB AND IPILIMUMAB IN PARTICIPANTS WITH BRAF V600E/K MUTATION-POSITIVE MELANOMA WHO PROGRESSED DURING OR AFTER PRIOR TREATMENT WITH ANTI-PD-1 THERAPY
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 38
- 试验地点
- 43
- 主要终点
- Objective Response Rate (ORR) is defined as the proportion of participants in each treatment arm with a confirmed best overall response of either Complete Response (CR) or Partial Response (PR), as determined by investigator assessment per RECIST v1.1
研究概览
简要总结
The purpose of this study is to learn about the effects of 3 study medicines (encorafenib, binimetinib, pembrolizumab) compared to 2 study medicines (ipilimumab and nivolumab) given for the treatment of melanoma.
Melanoma is a type of cancer that starts in the cells that give color to your skin.
The study is seeking participants who:
- have advanced or metastatic melanoma (has spread to other parts of the body);
- have a certain abnormal gene called "BRAF".
- have taken nivolumab or pembrolizumab treatment before this study.
Participants will either receive:
- pembrolizumab given by intravenous infusion (directly into a vein) every 3 weeks at the study clinic. Participants will also receive encorafenib and binimetinib by mouth every day at home,
- or will receive ipilimumab and nivolumab given by intravenous infusion (directly into a vein) every 3 weeks at the study clinic 4 times. This will be followed by nivolumab given by intravenous infusion every 4 weeks at the study clinic.
Both pembrolizumab and nivolumab will be given for a maximum of around 2 years. However, there is no time limit for encorafenib and binimetinib treatment.
The study team will see how each participant is doing after receiving the study treatments during regular visits to the study clinic.
详细描述
The purpose of the study is to compare the efficacy of a triplet therapy (encorafenib, binimetinib, pembrolizumab) versus a doublet/control therapy (nivolumab and ipilimumab). Participants will have metastatic or unresectable locally advanced BRAF V600E/K-mutant melanoma, which progressed during or after prior treatment in the adjuvant or first-line metastatic setting, with an approved anti-PD-1 monotherapy (pembrolizumab or nivolumab),
Approximately 150 participants will be randomized in a 1:1 ratio to the triplet or the doublet/control therapy (75 participants in each arm). Randomization will be stratified by baseline serum LDH level, and by type of PD-1 resistance.
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
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female participants ≥18 years of age at the time of informed consent.
- •Histologically confirmed unresectable (Stage IIIB, IIIC, or IIID) or metastatic (Stage IV) cutaneous melanoma, according to the AJCC 8th edition.
- •Documented evidence of a BRAF V600E or V600K mutation.
- •Availability of adequate tumor tissue (archival or newly obtained; block or slides) to submit to the sponsor central laboratory(ies) during the screening period for central biomarker analyses .
- •Must have received only 1 prior line of systemic therapy for melanoma (either adjuvant therapy or first-line anti-PD-1 monotherapy (ie, nivolumab or pembrolizumab)
- •Must have anti-PD-1 resistant disease (primary or secondary) with confirmed disease progression per RECIST v1.1 either during or after receipt of an approved anti-PD-1 monotherapy (ie, nivolumab or pembrolizumab) for melanoma, defined according to the SITC Immunotherapy Resistance Taskforce (Kluger et al, 2020).
- •Have at least one measurable lesion per RECIST v1.
- •ECOG PS of 0-1, and adequate organ and cardiac function, including LVEF ≥50% by cardiac imaging.
排除标准
- •Mucosal or ocular melanoma.
- •Diagnosis of immunodeficiency or an active autoimmune disease that required systemic treatment with chronic systemic steroid therapy or any other form of immunosuppressive therapy within the past 2 years.
- •Clinically significant cardiovascular diseases.
- •History of thromboembolic or cerebrovascular events ≤12 weeks prior to randomization.
- •History or current evidence of RVO or current risk factors for RVO.
- •Concurrent neuromuscular disorder that is associated with the potential of elevated CK.
- •Active bacterial, fungal, or viral infection requiring systemic therapeutic treatment within 2 weeks prior to randomization.
- •Current non-infectious pneumonitis/interstitial lung disease or history of noninfectious pneumonitis/interstitial lung disease requiring steroids.
- •Prior or current symptomatic brain metastasis, leptomeningeal disease or other active CNS metastases.
- •Participants who permanently discontinued prior anti-PD-1 therapy due to toxicity or will be unable to tolerate combination therapy based on investigator judgement are excluded.
- •Prior treatment with ipilimumab; prior combined immunotherapy blockade with anti-PD-1/L-1; prior treatment with a BRAFi and/or MEKi; or previous administration of an investigational anti-cancer agent for the adjuvant or first-line treatment of melanoma prior to randomization.
研究组 & 干预措施
Triplet
encorafenib and binimetinib in combination with pembrolizumab
干预措施: encorafenib (Drug)
Triplet
encorafenib and binimetinib in combination with pembrolizumab
干预措施: binimetinib (Drug)
Triplet
encorafenib and binimetinib in combination with pembrolizumab
干预措施: pembrolizumab (Drug)
Doublet
ipilimumab and nivolumab
干预措施: ipilimumab (Drug)
Doublet
ipilimumab and nivolumab
干预措施: nivolumab (Drug)
结局指标
主要结局
Objective Response Rate (ORR) is defined as the proportion of participants in each treatment arm with a confirmed best overall response of either Complete Response (CR) or Partial Response (PR), as determined by investigator assessment per RECIST v1.1
时间窗: Time from the date of randomization to the earliest date disease progression, or start of subsequent anticancer therapy, or death due to any cause (assessed up to approximately 48 months).
次要结局
- Progression Free Survival in each treatment arm(Time from the date of randomization to the earliest date of disease progression, as determined by investigator assessment per RECIST v1.1, or death due to any cause, whichever occurs first (assessed up to approximately 48 months))
- Overall Survival in each treatment arm(Time from date of randomization to the date of death due to any cause or the last known alive date (assessed up to approximately 48 months))
- Duration of Response (CR or PR) in each treatment arm(Time from the date of the first documented response (CR or PR) to the earliest date of disease progression, as determined by investigator assessment per RECIST v1.1, or death due to any cause (assessed up to approximately 48 months))
- Disease Control Rate (proportion of participants with a confirmed best overall response of CR, PR or SD) in each treatment arm(Time from the date of randomization to the earliest date of disease progression, or start of subsequent anticancer therapy (assessed up to approximately 48 months))
- Time to Response (CR or PR)(Time from the date of randomization to the date of first documented response (CR or PR), as determined by investigator assessment per RECIST v1.1 (assessed up to approximately 48 months))
- Progression Free Survival 2 in each treatment arm(Time from date of randomization to date of discontinuation of next-line treatment after 1st disease progression, 2nd disease progression after initiation of next line treatment, or death due to any cause (assessed up to approximately 48 months))
- Incidence and severity of Adverse Events (AEs) and changes in clinical laboratory parameters, vital signs, and cardiac assessments.(Time from first dose of study intervention through 28 days after the last dose of study intervention)
- Patient Reported Outcomes using EORTC QLQ-C30 questionnaires in each treatment arm(Change from Baseline until Progressive Disease, death, withdrawal of consent, lost to follow-up, or end of study, whichever occurs first (assessed up to approximately 48 months))
- Patient Reported Outcomes using EuroQOL EQ-5D-5L questionnaires in each treatment arm(Change from Baseline until Progressive Disease, death, withdrawal of consent, lost to follow-up, or end of study, whichever occurs first (assessed up to approximately 48 months))
- BRAF V600E/K Variant Allele Frequency and/or overall mean Variant Allele Frequency from circulating tumour DNA analysis in each treatment arm(Change from baseline, Day 1 of Cycle 2 (after 3 weeks), and End of Treatment (assessed up to approximately 48 months))