A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Anvumetostat in Combination With Other Therapies in Subjects With Advanced Gastrointestinal, Biliary Tract, or Pancreatic Cancers With Homozygous MTAP-deletion
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- Amgen
- 入组人数
- 120
- 试验地点
- 147
- 主要终点
- Number of Participants Experiencing Dose Limiting Toxicities (DLT)
研究概览
简要总结
The study aims to determine maximum tolerated dose (MTD) or recommended combination dose of the MTA-cooperative PRMT5 inhibitor Anvumetostat administered in combination with other therapies in adult participants with metastatic or locally advanced methylthioadenosine phosphorylase (MTAP)-deleted gastrointestinal, biliary tract, or pancreatic cancers. The study also aims to determine the safety profile of Anvumetostat administered in combination with other therapies in adult participants with metastatic or locally advanced MTAP-deleted gastrointestinal, biliary tract, or pancreatic cancers.
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 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subprotocol B
- •Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years).
- •Histologically or cytologically confirmed diagnosis of metastatic and/or unresectable (locally advanced) adenocarcinoma of the pancreas.
- •Tumor tissue (FFPE sample) or an archival block must be available. Participants without archived tumor tissue available may be allowed to enroll by undergoing tumor biopsy before dosing.
- •Homozygous MTAP-deletion.
- •Disease measurable as defined by RECIST v1.
- •Adequate organ function as defined in the protocol.
- •Prior treatment with a MAT2A inhibitor or a PRMT5 inhibitor.
- •Radiation therapy within 28 days of first dose.
- •Major surgery within 28 days of first dose of Anvumetostat.
- •Cardiovascular and pulmonary
排除标准
- •as defined in the protocol.
- •Gastrointestinal tract disease causing the inability to take PO medication, malabsorption syndrome, requirement for IV alimentation, gastric/jejunal tube feeds, uncontrolled inflammatory gastrointestinal disease (eg, Crohn's disease, ulcerative colitis).
- •History of solid organ transplantation.
- •Subprotocol C
- •Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years).
- •Histologically or cytologically confirmed diagnosis of metastatic and/or unresectable (locally advanced) adenocarcinoma of the pancreas.
- •Homozygous MTAP-deletion.
- •Rat Sarcoma Viral Oncogene Homolog (RAS) mutation
- •Received at least 1 prior systemic therapy for advanced or metastatic PDAC.
- •Disease measurable as defined by RECIST v1.
- •Adequate organ function as defined in the protocol.
- •Prior treatment with aMAT2A inhibitor, a PRMT5 inhibitor, or a MAPK pathway inhibitor, including KRAS inhibitors.
- •Cardiovascular and pulmonary exclusion criteria as defined in the protocol.
- •Gastrointestinal tract disease causing the inability to take PO medication, malabsorption syndrome, requirement for IV alimentation, gastric/jejunal tube feeds, uncontrolled inflammatory gastrointestinal disease (eg, Crohn's disease, ulcerative colitis).
- •History of solid organ transplantation.
研究组 & 干预措施
Subprotocol C: Dose Expansion
Part 2: Participants with MTAP-deleted PDAC will receive oral doses of Anvumetostat andRMC-6236.
干预措施: RMC-6236 (Drug)
Subprotocol B: Pancreatic Ductal Adenocarcinoma (PDAC) Arm A
Part 1: Participants with MTAP-deleted PDAC will receive doses of Anvumetostat orally in combination with gemcitabine and nab-paclitaxel IV.
Part 2: Participants with MTAP-deleted PDAC will receive the recommended dose of Anvumetostat in combination with gemcitabine and nab-paclitaxel.
干预措施: Gemcitabine (Drug)
Subprotocol B: Pancreatic Ductal Adenocarcinoma (PDAC) Arm A
Part 1: Participants with MTAP-deleted PDAC will receive doses of Anvumetostat orally in combination with gemcitabine and nab-paclitaxel IV.
Part 2: Participants with MTAP-deleted PDAC will receive the recommended dose of Anvumetostat in combination with gemcitabine and nab-paclitaxel.
干预措施: Nab-paclitaxel (Drug)
Subprotocol C: Dose Exploration
Part 1: Participants with MTAP-deleted PDAC will receive oral doses of Anvumetostat and RMC-6236.
干预措施: RMC-6236 (Drug)
Subprotocol B: PDAC Arm B
Part 1: Participants with MTAP-deleted PDAC will receive doses of Anvumetostat orally in combination with mFOLFIRINOX (irinotecan, fluorouracil, leucovorin calcium, oxaliplatin) IV.
Part 2: Participants with MTAP-deleted PDAC will receive the recommended dose of Anvumetostat in combination with mFOLFIRINOX.
干预措施: Modified FOLFIRINOX (Drug)
Subprotocol B: Pancreatic Ductal Adenocarcinoma (PDAC) Arm A
Part 1: Participants with MTAP-deleted PDAC will receive doses of Anvumetostat orally in combination with gemcitabine and nab-paclitaxel IV.
Part 2: Participants with MTAP-deleted PDAC will receive the recommended dose of Anvumetostat in combination with gemcitabine and nab-paclitaxel.
干预措施: Anvumetostat (Drug)
Subprotocol B: PDAC Arm B
Part 1: Participants with MTAP-deleted PDAC will receive doses of Anvumetostat orally in combination with mFOLFIRINOX (irinotecan, fluorouracil, leucovorin calcium, oxaliplatin) IV.
Part 2: Participants with MTAP-deleted PDAC will receive the recommended dose of Anvumetostat in combination with mFOLFIRINOX.
干预措施: Anvumetostat (Drug)
Subprotocol C: Dose Exploration
Part 1: Participants with MTAP-deleted PDAC will receive oral doses of Anvumetostat and RMC-6236.
干预措施: Anvumetostat (Drug)
Subprotocol C: Dose Expansion
Part 2: Participants with MTAP-deleted PDAC will receive oral doses of Anvumetostat andRMC-6236.
干预措施: Anvumetostat (Drug)
结局指标
主要结局
Number of Participants Experiencing Dose Limiting Toxicities (DLT)
时间窗: Up to 28 days
Number of Participants Experiencing Serious Adverse Events (SAE)
时间窗: Up to approximately 2 years
Number of Participants Experiencing Treatment Emergent Adverse Events (TEAE)
时间窗: Up to approximately 2 years
Any clinically significant changes in vital signs, electrocardiogram, or lab parameters will be recorded as TEAEs.
次要结局
- Duration of Response (DOR) per RECIST v1.1(Up to approximately 2 years)
- Time to Response (TTR) per RECIST v1.1(Up to approximately 2 years)
- Overall Survival (OS) per RECIST v1.1(Up to approximately 2 years)
- Progression-free Survival (PFS) per RECIST v1.1(Up to approximately 2 years)
- Cmax of RMC-6236(Up to Day 1 of Cycle 5 (one cycle = 21 days))
- Tmax of RMC-6236(Up to Day 1 of Cycle 5 (one cycle = 21 days))
- AUC of RMC-6236(Up to Day 1 of Cycle 5 (one cycle = 21 days))
- Objective Response (OR) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1)(Up to approximately 2 years)
- Disease Control (DC) per RECIST v1.1(Up to approximately 2 years)
- Objective Response (OR) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1)(Up to approximately 2 years)
- Disease Control (DC) per RECIST v1.1(Up to approximately 2 years)
- Duration of Response (DOR) per RECIST v1.1(Up to approximately 2 years)
- Time to Response (TTR) per RECIST v1.1(Up to approximately 2 years)
- Overall Survival (OS) per RECIST v1.1(Up to approximately 2 years)
- Progression-free Survival (PFS) per RECIST v1.1(Up to approximately 2 years)
- Maximum Plasma Concentration (Cmax) of AMG193(Up to Day 1 of Cycle 5 (one cycle = 21 or 28 days))
- Time to Maximum Plasma Concentration (tmax) of AMG193(Up to Day 1 of Cycle 5 (one cycle = 21 or 28 days))
- Area Under the Plasma Concentration-time Curve (AUC) of AMG 193(Up to Day 1 of Cycle 5 (one cycle = 21 or 28 days))
- Cmax of RMC-6236(Up to Day 1 of Cycle 5 (one cycle = 21 days))
- Tmax of RMC-6236(Up to Day 1 of Cycle 5 (one cycle = 21 days))
- AUC of RMC-6236(Up to Day 1 of Cycle 5 (one cycle = 21 days))
- Time to Maximum Plasma Concentration (tmax) of Anvumetostat(Up to Day 1 of Cycle 5 (one cycle = 21 or 28 days))
- Area Under the Plasma Concentration-time Curve (AUC) of Anvumetostat(Up to Day 1 of Cycle 5 (one cycle = 21 or 28 days))
- Maximum Plasma Concentration (Cmax) of Anvumetostat(Up to Day 1 of Cycle 5 (one cycle = 21 or 28 days))