A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Anvumetostat Alone or in Combination With Other Therapies in Subjects With Advanced Thoracic Tumors With Homozygous MTAP-deletion (Master Protocol)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- Amgen
- 入组人数
- 49
- 试验地点
- 144
- 主要终点
- Number of Participants Experiencing Serious Adverse Events (SAE)
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 thoracic tumors. 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 thoracic tumors.
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 A, B, and C
- •Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years).
- •Tumor tissue (formalin-fixed, paraffin-embedded sample) or an archival block must be available. Participants without archived tumor tissue available may be allowed to enroll by undergoing tumor biopsy before Anvumetostat dosing.
- •Homozygous MTAP-deletion
- •Able to swallow and retain PO administered study treatment.
- •Disease measurable as defined by RECIST v1.
- •Subprotocol A - Histologically or cytologically confirmed diagnosis of NSCLC.
- •Arm A (Anvumetostat + carboplatin + paclitaxel + pembrolizumab):
- •- Predominantly squamous histology.
- •Arm B (Anvumetostat + carboplatin + pemetrexed + pembrolizumab):
- •- Predominantly non-squamous histology.
- •Arm C (Anvumetostat + pembrolizumab):
- •- PD-L1 positive.
- •Subprotocol B - Histologically confirmed NSCLC with homozygous MTAP-deletion and KRAS p.G12C mutation.
- •Subprotocol C
- •Histologically or cytologically confirmed diagnosis of NSCLC with brain metastases.
- •Brain lesion meeting RANO-BM criteria for measurable disease.
排除标准
- •Subprotocol A, B, and C
- •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 transplant.
- •Major surgery within 28 days of first dose of Anvumetostat.
- •Prior treatment with a MAT2A inhibitor or a PRMT5 inhibitor.
- •Radiation therapy within 28 days of first dose.
- •Subprotocol A
- •- Autoimmune disease or immunodeficiency disease as defined in the protocol'
研究组 & 干预措施
Subprotocol A: NSCLC Arm C
Participants with MTAP-deleted NSCLC will receive a combination of Anvumetostat PO and pembrolizumab IV
干预措施: Anvumetostat (Drug)
Subprotocol C: NSCLC With Brain Metastases
Participants with MTAP-deleted NSCLC with brain metastases will receive Anvumetostat PO
干预措施: Anvumetostat (Drug)
Subprotocol A: NSCLC Arm B
Participants with MTAP-deleted NSCLC will receive a regimen of Anvumetostat PO and carboplatin, pemetrexed, and pembrolizumab IV
干预措施: Anvumetostat (Drug)
Subprotocol A: Non-Small Cell Lung Cancer (NSCLC) Arm A
Participants with MTAP-deleted NSCLC will receive a regimen of Anvumetostat orally (PO) and carboplatin, paclitaxel, and pembrolizumab intravenously (IV)
干预措施: Anvumetostat (Drug)
Subprotocol B: NSCLC With KRasG12C Mutation
Participants with MTAP-deleted NSCLC and KRasG12C mutation will receive a combination of Anvumetostat and sotorasib PO
干预措施: Anvumetostat (Drug)
Subprotocol B: NSCLC With KRasG12C Mutation
Participants with MTAP-deleted NSCLC and KRasG12C mutation will receive a combination of Anvumetostat and sotorasib PO
干预措施: Sotorasib (Drug)
Subprotocol A: NSCLC Arm B
Participants with MTAP-deleted NSCLC will receive a regimen of Anvumetostat PO and carboplatin, pemetrexed, and pembrolizumab IV
干预措施: Pembrolizumab (Drug)
Subprotocol A: NSCLC Arm B
Participants with MTAP-deleted NSCLC will receive a regimen of Anvumetostat PO and carboplatin, pemetrexed, and pembrolizumab IV
干预措施: Pemetrexed (Drug)
Subprotocol A: Non-Small Cell Lung Cancer (NSCLC) Arm A
Participants with MTAP-deleted NSCLC will receive a regimen of Anvumetostat orally (PO) and carboplatin, paclitaxel, and pembrolizumab intravenously (IV)
干预措施: Carboplatin (Drug)
Subprotocol A: Non-Small Cell Lung Cancer (NSCLC) Arm A
Participants with MTAP-deleted NSCLC will receive a regimen of Anvumetostat orally (PO) and carboplatin, paclitaxel, and pembrolizumab intravenously (IV)
干预措施: Paclitaxel (Drug)
Subprotocol A: Non-Small Cell Lung Cancer (NSCLC) Arm A
Participants with MTAP-deleted NSCLC will receive a regimen of Anvumetostat orally (PO) and carboplatin, paclitaxel, and pembrolizumab intravenously (IV)
干预措施: Pembrolizumab (Drug)
Subprotocol A: NSCLC Arm B
Participants with MTAP-deleted NSCLC will receive a regimen of Anvumetostat PO and carboplatin, pemetrexed, and pembrolizumab IV
干预措施: Carboplatin (Drug)
Subprotocol A: NSCLC Arm C
Participants with MTAP-deleted NSCLC will receive a combination of Anvumetostat PO and pembrolizumab IV
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Number of Participants Experiencing Serious Adverse Events (SAE)
时间窗: Up to approximately 3 years
An SAE is defined as any AE that results in death, is life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital abnormality/birth defect or important medical events that do not meet the preceding criteria but based on appropriate medical judgment may jeopardize the participant or may require medical or surgical intervention to prevent any of the outcomes listed above.
Number of Participants Experiencing Dose Limiting Toxicities (DLT)
时间窗: Up to approximately 21 days
Number of Participants Experiencing Treatment Emergent Adverse Events (TEAE)
时间窗: Up to approximately 3 years
TEAEs are any event that occurred after the participant received study treatment. Any clinically significant changes in vital signs, electrocardiograms, and clinical laboratory tests that occurred after study treatment administration were recorded as TEAEs. A serious TEAE is any untoward medical occurrence in a clinical study participant after first dose irrespective of a causal relationship with the study treatment(s) that resulted in death, was immediately life threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or another medically important serious event.
次要结局
- Progression-free Survival (PFS) per RECIST v1.1(Up to approximately 3 years)
- Time to Response (TTR) per RECIST v1.1(Up to approximately 3 years)
- Duration of Response (DOR) per RECIST v1.1(Up to approximately 3 years)
- Intracranial objective response (IOR) per Response Assessment in Neuro Oncology Brain Metastases (RANO-BM )(Up to approximately 3 years)
- Objective Response (OR) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1)(Up to approximately 3 years)
- Overall Survival (OS) per RECIST v1.1(Up to approximately 3 years)
- Disease Control (DC) per RECIST v1.1(Up to approximately 3 years)
- Time to Maximum Plasma Concentration (tmax) of AMG 193(Up to Day 1 of Cycle 5 (one cycle = 21 days))
- Intracranial Disease Control (IDC) per RANO-BM(Up to approximately 3 years)
- Time to Intracranial Radiation Therapy per RANO-BM(Up to approximately 3 years)
- Maximum Plasma Concentration (Cmax) of AMG 193(Up to Day 1 of Cycle 5 (one cycle = 21 days))
- Area Under the Plasma Concentration-time Curve (AUC) of AMG 193(Up to Day 1 of Cycle 5 (one cycle = 21 days))
- Intracranial Duration of Response (IDOR) per RANO-BM(Up to approximately 3 years)
- Maximum Plasma Concentration (Cmax) of Anvumetostat(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 days))
- Area Under the Plasma Concentration-time Curve (AUC) of Anvumetostat(Up to Day 1 of Cycle 5 (one cycle = 21 days))