A Phase 1 Open-label Study of Safety and Tolerability of MEDI4736 in Subjects With Metastatic or Unresectable Melanoma in Combination With Dabrafenib and Trametinib or With Trametinib Alone
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 68
- 试验地点
- 1
- 主要终点
- Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAEs
研究概览
简要总结
The purpose of this study is to determine the maximum tolerated dose and characterize the safety profile of durvalumab (MEDI4736) in combination with dabrafenib and trametinib or with trametinib alone in participants with metastatic or unresectable melanoma with BRAF-mutation positive or wild-type (WT) BRAF, respectively.
详细描述
This is a multicenter, open-label study with a dose escalation phase followed by an expansion phase of durvalumab administered in combination with dabrafenib and trametinib or with trametinib alone in participants with BRAF V600 mutation-positive and WT unresectable or metastatic melanoma, respectively.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Adults >= 18 years old
- •Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic) and determined to be BRAF V600E or V600K mutation-positive (cohort A) or mutation-negative (cohorts B and C)
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Measurable disease by radiographic or physical examination
- •Adequate organ and marrow function
- •Willingness to provide consent for biopsies positive or BRAF WT measurable disease and adequate organ and marrow function
排除标准
- •Prior treatment with a BRAF inhibitor or MEK inhibitor
- •Any prior Grade >= 3 immune-related adverse event while receiving immunotherapy
- •Active or prior documented autoimmune disease within the past 2 years
- •History of or current risk for retinal vein occlusion (RVO) or central serous retinopathy (CSR)
- •History of or current cardiovascular risk including myocardial infarction, >= Class II congestive heart failure, uncontrolled arrhythmias, or refractory hypertension
- •Active, untreated central nervous system (CNS) metastases
- •Women who are pregnant or lactating
研究组 & 干预措施
Cohort A1: Durvalumab (3 mg/kg) + Dabrafenib +Trametinib
Participants will receive intravenous (IV) dose of 3 milligrams per kilogram (mg/kg) durvalumab every 2 weeks (Q2W) from Day 1 up to 12 months along with oral 150 mg dabrafenib capsule twice daily (BID) and oral 2 mg trametinib tablet once daily (QD) until confirmed disease progression (PD), initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 3 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib.
干预措施: Durvalumab (Biological)
Cohort A1: Durvalumab (3 mg/kg) + Dabrafenib +Trametinib
Participants will receive intravenous (IV) dose of 3 milligrams per kilogram (mg/kg) durvalumab every 2 weeks (Q2W) from Day 1 up to 12 months along with oral 150 mg dabrafenib capsule twice daily (BID) and oral 2 mg trametinib tablet once daily (QD) until confirmed disease progression (PD), initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 3 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib.
干预措施: Dabrafenib (Drug)
Cohort A1: Durvalumab (3 mg/kg) + Dabrafenib +Trametinib
Participants will receive intravenous (IV) dose of 3 milligrams per kilogram (mg/kg) durvalumab every 2 weeks (Q2W) from Day 1 up to 12 months along with oral 150 mg dabrafenib capsule twice daily (BID) and oral 2 mg trametinib tablet once daily (QD) until confirmed disease progression (PD), initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 3 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib.
干预措施: Trametinib (Drug)
Cohort A2: Durvalumab (10 mg/kg) + Dabrafenib +Trametinib
Participants will receive IV dose of 10 mg/kg durvalumab Q2W from Day 1 up to 12 months along with oral doses of dabrafenib 150 mg capsule BID and trametinib 2 mg tablet QD until confirmed PD, initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib.
干预措施: Durvalumab (Biological)
Cohort A2: Durvalumab (10 mg/kg) + Dabrafenib +Trametinib
Participants will receive IV dose of 10 mg/kg durvalumab Q2W from Day 1 up to 12 months along with oral doses of dabrafenib 150 mg capsule BID and trametinib 2 mg tablet QD until confirmed PD, initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib.
干预措施: Dabrafenib (Drug)
Cohort A2: Durvalumab (10 mg/kg) + Dabrafenib +Trametinib
Participants will receive IV dose of 10 mg/kg durvalumab Q2W from Day 1 up to 12 months along with oral doses of dabrafenib 150 mg capsule BID and trametinib 2 mg tablet QD until confirmed PD, initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib.
干预措施: Trametinib (Drug)
Cohort B: Durvalumab (10 mg/kg) +Trametinib (Concurrent)
Participants will receive concurrent doses of IV 10 mg/kg durvalumab Q2W from Day 1 up to 12 months along with oral dose of trametinib 2 mg tablet QD until confirmed PD, initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months and continued the treatment of trametinib.
干预措施: Durvalumab (Biological)
Cohort B: Durvalumab (10 mg/kg) +Trametinib (Concurrent)
Participants will receive concurrent doses of IV 10 mg/kg durvalumab Q2W from Day 1 up to 12 months along with oral dose of trametinib 2 mg tablet QD until confirmed PD, initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months and continued the treatment of trametinib.
干预措施: Trametinib (Drug)
Cohort C: Durvalumab (10 mg/kg) +Trametinib (Sequential)
Participants will receive sequential doses of oral trametinib tablet 2 mg QD from Day 1 to Day 42 and IV durvalumab 10 mg/kg Q2W starting from Day 29 (Week 5) up to 12 months. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months.
干预措施: Durvalumab (Biological)
Cohort C: Durvalumab (10 mg/kg) +Trametinib (Sequential)
Participants will receive sequential doses of oral trametinib tablet 2 mg QD from Day 1 to Day 42 and IV durvalumab 10 mg/kg Q2W starting from Day 29 (Week 5) up to 12 months. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months.
干预措施: Trametinib (Drug)
结局指标
主要结局
Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAEs
时间窗: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)
Number of participants with abnormal vital signs and physical examinations reported as TEAEs are reported.
Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: From first dose of study drug (Day 1) until the planned 3rd dose of durvalumab (Day 29)
Dose limiting toxicities are defined as any Grade 3 or higher treatment-related (related to any study drug) toxicity that occurs during the DLT evaluation period. Number of participants with DLTs are reported.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
时间窗: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event is any AE that resulted in death, life threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, is a congenital anomaly/birth defect in offspring of a study participant, is an important medical event that may jeopardize the participant or may require medical intervention. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs
时间窗: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)
Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported.
Number of Participants With Abnormal Electrocardiograms (ECGs) and Echocardiograms (ECHOs) Reported as TEAEs
时间窗: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)
Number of participants with abnormal electrocardiograms (ECGs) and echocardiograms (ECHOs) reported as TEAEs are reported.
次要结局
- Duration of Response (DOR)(From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years))
- Percentage of Participants With Objective Response (OR)(From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years))
- Overall Survival(From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years))
- Progression-free Survival (PFS)(From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years))
- Percentage of Participants With Disease Control(From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years))
- Maximum Observed Plasma Concentration after First Dose (Cmax, 1st) of Durvalumab(Cohorts A and B: End of infusion on Day 1; Cohort C: End of infusion on Day 29)
- Maximum Observed Plasma Concentration at Steady State (Cmax, ss) of Durvalumab(Cohorts A and B: end of infusion on Day 141; Cohort C: end of infusion on Day 169)
- Trough Concentration at Steady State (Ctrough) of Durvalumab(Cohorts A and B: Pre-dose on Day 141; Cohort C: Pre-dose on Day 169)
- Number of Participants With Postive Anti-Drug Antibodies (ADA) Titer to Durvalumab(Cohorts A and B: Days 1 and 29; Cohort C: Days 29 and 57)