A Phase 1/1b/2 Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Anvumetostat Alone and in Combination With Docetaxel in Subjects With Advanced MTAP-null Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- Amgen
- 入组人数
- 329
- 试验地点
- 148
- 主要终点
- Parts 1 and 2: Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE)
研究概览
简要总结
The primary objective of Parts 1 and 2 of this study is to evaluate the safety, tolerability, and to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of Anvumetostat alone and in combination with docetaxel in adult participants with metastatic or locally advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors.
The primary objective of Part 3 of this study is to evaluate the efficacy of Anvumetostat in adult participants with metastatic or locally advanced MTAP-null solid tumors.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Participant has provided informed consent/assent before initiation of any study specific activities/procedures.
- •Age ≥ 18 years.
- •Evidence of homozygous loss of cyclin dependent kinase inhibitor 2A (CDKN2A) (null) (Parts 1a, 1j, 1k, and 2a only) and/or methylthioadenosine phosphorylase (MTAP) (null) in the tumor tissue or blood (Parts 1a to 1k, Parts 2a and 2b) or lost MTAP expression in the tumor tissue (Parts 1a to 1k, Parts 2a and 2b).
- •Histologically confirmed metastatic or locally advanced solid tumor not amenable to curative treatment with surgery and/or radiation.
- •Able to swallow and retain orally (PO) administered study treatment and willing to record daily adherence to investigational product.
- •Disease measurable as defined by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). Note: except participants enrolling to Part 1m.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Adequate hematopoietic function per local laboratory
- •Adequate renal function per local laboratory
- •Adequate glucose control per local laboratory (Part 1 only)
- •Adequate liver function per local laboratory
- •Adequate coagulation parameters
- •Adequate pulmonary function
- •Adequate cardiac function
- •Minimum life expectancy of 12 weeks as per investigator judgement.
- •Archived tumor tissue (formalin-fixed, paraffin-embedded [FFPE] sample collected within 5 years) or an archival block must be available.
- •For Part 1f (MTAP-null or lost MTAP expression HNSCC): Must be willing to undergo tumor biopsy.
- •For Part 1a: Must be willing to undergo tumor biopsy, before start of treatment (archival sample acceptable if obtained with 6 months of enrollment and subject has not received any other treatment since sample was obtained) and while on treatment.
- •For DSPS study (Part 1j): Must be willing to participate in DSPS substudy (US sites only).
- •Food Effect Substudy (Part 1k): Specific Inclusion Criteria
- •Subject able and willing to eat a standardized high-fat, high-caloric meal
- •Subject able and willing to fast for ≥ 6 hours
- •Specific Inclusion Criteria for subjects with glioma (Part 1m only)
- •- Disease measurable as defined per Modified Response Assessment in Neuro-Oncology Criteria 2.0 (mRANO 2.0)
排除标准
- •Spinal cord compression or untreated brain metastases or leptomeningeal disease.
- •History of other malignancy within the past 2 years
- •Any evidence of current interstitial lung disease
- •Active infection
- •Evidence of active severe acute respiratory syndrome coronavirus 2 (SARS-COV2) infection.
- •History of arterial thrombosis
- •Myocardial infarction and/or symptomatic congestive heart failure.
- •Gastrointestinal tract disease
- •History of bowel obstruction, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
- •History of solid organ transplant.
- •Diagnosis of Congenital Short QT Syndrome.
- •Major surgery
- •Anti-tumor therapy within 28 days of study day
- •Prior treatment with an methionine adenosyltransferase 2α (MAT2A) inhibitor or a protein arginine methyltransferase 5 (PRMT5) inhibitor.
- •Prior treatment with docetaxel (Part 2 only)
- •Prior irradiation to 25% of the bone marrow.
- •Therapeutic or palliative radiation therapy within 2 weeks of study day
- •Live vaccine therapy within 4 weeks before study drug administration.
- •Use of therapeutic anti-coagulation for treatment of active thromboembolic events.
- •Use of prescription medications that are known strong inducers of cytochrome P450 3A4 (CYP3A4) within 14 days or 5 half-lives (whichever is longer) before study day 1
- •Unresolved toxicity from prior anti-cancer therapy
- •Currently receiving treatment in another investigational device or drug study.
- •Known positive test for Human Immunodeficiency Virus (HIV).
- •Positive hepatitis B surface antigen
- •positive hepatitis C virus ribonucleic acid (RNA) by polymerase chain reaction (PCR)
- •Female participants of childbearing potential unwilling to use protocol specified method of contraception
研究组 & 干预措施
Part 1a, Phase 1: AMG 193 Monotherapy Dose Exploration
Participants with MTAP-null solid tumors will receive escalating doses of AMG 193 to estimate the MTD and/or the RP2D.
干预措施: AMG 193 (Drug)
Part 1c, Phase 1: AMG 193 Monotherapy Dose Expansion
Participants will receive the identified MTD/RP2D of AMG 193 in the following cohort: MTAP-null NSCLC.
干预措施: AMG 193 (Drug)
Part 2a, Phase 1: AMG 193 Dose Exploration + Docetaxel
Participants with MTAP-null NSCLC will receive escalating doses of AMG 193 + a fixed dose of docetaxel to estimate the MTD/RP2D of the combination.
干预措施: AMG 193 (Drug)
Part 2a, Phase 1: AMG 193 Dose Exploration + Docetaxel
Participants with MTAP-null NSCLC will receive escalating doses of AMG 193 + a fixed dose of docetaxel to estimate the MTD/RP2D of the combination.
干预措施: Docetaxel (Drug)
Part 2b, Phase 1: AMG 193 + Docetaxel Dose Expansion
Participants with MTAP-null NSCLC will receive the identified MTD/RP2D of AMG 193 + docetaxel.
干预措施: AMG 193 (Drug)
Part 2b, Phase 1: AMG 193 + Docetaxel Dose Expansion
Participants with MTAP-null NSCLC will receive the identified MTD/RP2D of AMG 193 + docetaxel.
干预措施: Docetaxel (Drug)
Part 3: AMG 193 Phase 2
Participants with MTAP-null solid tumors will receive AMG 193.
干预措施: AMG 193 (Drug)
Part 1e, Phase 1: AMG 193 Monotherapy Dose Expansion
Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort: MTAP-null BTC.
干预措施: AMG 193 (Drug)
Part 1f, Phase 1: AMG 193 Monotherapy Dose Expansion
Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort:
MTAP-null head and neck squamous cell carcinoma (HNSCC).
干预措施: AMG 193 (Drug)
Part 1g, Phase 1: AMG 193 Monotherapy Dose Expansion
Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort:
MTAP-null pancreatic adenocarcinoma.
干预措施: AMG 193 (Drug)
Part 1h, Phase 1: AMG 193 Monotherapy Dose Expansion
Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort: MTAP-null or lost MTAP expression solid tumors (other than lymphoma or primary brain tumor).
干预措施: AMG 193 (Drug)
Part 1i, Phase 1: AMG 193 Dose Optimization
Participants will receive a randomized dose optimization evaluation of AMG 193.
干预措施: AMG 193 (Drug)
Part 1j, Phase 1: AMG 193 DSPS Substudy (US Sites Only)
Participants will receive doses of AMG 193 and comparator AMG 193 test tables at different times in a fasted state.
干预措施: AMG 193 (Drug)
Part 1k, Phase 1: AMG 193 Food Effect Substudy (US Sites Only)
Participants will receive AMG 193 once on a fasted state and once after eating a standardized high-fat, high calorie meal.
干预措施: AMG 193 (Drug)
Part 1l, Phase 1: AMG 193 Monotherapy Dose Expansion
Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort: MTAP-null esophageal/gastric cancer.
干预措施: AMG 193 (Drug)
Part 1m, Phase 1: AMG 193 Monotherapy Dose Expansion
Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort: MTAP-null glioma.
干预措施: AMG 193 (Drug)
结局指标
主要结局
Parts 1 and 2: Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE)
时间窗: Up to approximately 3 years
Adverse events (AEs) are defined as any untoward medical occurrence in clinical study participant irrespective of a causal relationship with the study treatment. TEAEs are any event that occurs after the participant has received study treatment. Any clinically significant changes in vital signs, electrocardiograms (ECGs) and clinical laboratory tests will be recorded as TEAEs. Serious AEs (SAEs) are defined as any event that meets at least 1 of the following serious criteria: * Results in death (fatal) * Requires in-patient hospitalization or prolongation of existing hospitalization * Results in persistent or significant disability/incapacity * Is a congenital anomaly/birth defect * Other medically important serious event
Part 3: Objective Response Rate (ORR)
时间窗: Up to approximately 3 years
Parts 1 and 2: Number of Participants Who Experience a Dose-Limiting Toxicity (DLT)
时间窗: 28 days
Parts 1 and 2: Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE)
时间窗: Up to approximately 3 years
Adverse events (AEs) are defined as any untoward medical occurrence in clinical study participant irrespective of a causal relationship with the study treatment. TEAEs are any event that occurs after the participant has received study treatment. Any clinically significant changes in vital signs, electrocardiograms (ECGs) and clinical laboratory tests will be recorded as TEAEs. Serious AEs (SAEs) are defined as any event that meets at least 1 of the following serious criteria: * Results in death (fatal) * Requires in-patient hospitalization or prolongation of existing hospitalization * Results in persistent or significant disability/incapacity * Is a congenital anomaly/birth defect * Other medically important serious event
Part 3: Objective Response Rate (ORR)
时间窗: Up to approximately 3 years
次要结局
- Part 2 Only: Maximal Plasma Concentration (Cmax) of Docetaxel(Cycle 1 Day 1 to Pre-Dose Cycle 5 Day 1 (Cycle =21 days))
- Part 2 Only: Time to Achieve Maximal Plasma Concentration (Tmax) of Docetaxel(Cycle 1 Day 1 to Pre-Dose Cycle 5 Day 1 (Cycle =21 days))
- Part 2 Only: Area Under the Plasma Concentration Versus Time Curve (AUC) of Docetaxel(Cycle 1 Day 1 to Pre-Dose Cycle 5 Day 1 (Cycle =21 days))
- Parts 1, 2 and 3: Duration of Response (DoR)(Up to approximately 3 years)
- Parts 1, 2 and 3: Time to Response (TTR)(Up to approximately 3 years)
- Parts 1, 2 and 3: Duration of Disease Control (DC)(Up to approximately 3 years)
- Parts 1, 2 and 3: Progression-Free Survival (PFS)(Up to approximately 3 years)
- Parts 1, 2 and 3: Overall Survival (OS)(Up to approximately 5 years)
- Part 3 Only: Number of Participants Who Experience TEAE(Up to approximately 3 years)
- Parts 1 and 2: Maximal Plasma Concentration (Cmax) of AMG 193(Cycle 1 Day 1 to Pre-Dose Cycle 5 Day 1 (Part 1 Cycle = 28 days, Part 2 Cycle =21 days))
- Parts 1 and 2: Time to Achieve Maximal Plasma Concentration (Tmax) of AMG 193(Cycle 1 Day 1 to Pre-Dose Cycle 5 Day 1 (Part 1 Cycle = 28 days, Part 2 Cycle =21 days))
- Parts 1 and 2: Area Under the Plasma Concentration Versus Time Curve (AUC) of AMG 193(Cycle 1 Day 1 to Pre-Dose Cycle 5 Day 1 (Part 1 Cycle = 28 days, Part 2 Cycle =21 days))
- Part 2 Only: Maximal Plasma Concentration (Cmax) of Docetaxel(Cycle 1 Day 1 to Pre-Dose Cycle 5 Day 1 (Cycle =21 days))
- Part 2 Only: Time to Achieve Maximal Plasma Concentration (Tmax) of Docetaxel(Cycle 1 Day 1 to Pre-Dose Cycle 5 Day 1 (Cycle =21 days))
- Part 2 Only: Area Under the Plasma Concentration Versus Time Curve (AUC) of Docetaxel(Cycle 1 Day 1 to Pre-Dose Cycle 5 Day 1 (Cycle =21 days))
- Parts 1 and 2: ORR(Up to approximately 3 years)
- Parts 1, 2 and 3: Disease Control Rate (DCR)(Up to approximately 3 years)
- Parts 1, 2 and 3: Duration of Response (DoR)(Up to approximately 3 years)
- Parts 1, 2 and 3: Time to Response (TTR)(Up to approximately 3 years)
- Parts 1, 2 and 3: Duration of Disease Control (DC)(Up to approximately 3 years)
- Parts 1, 2 and 3: Progression-Free Survival (PFS)(Up to approximately 3 years)
- Parts 1, 2 and 3: Overall Survival (OS)(Up to approximately 5 years)
- Part 3 Only: Number of Participants Who Experience TEAE(Up to approximately 3 years)
- Part 1a Only: Maximal Plasma Concentration (Cmax) of AMG 193(Cycle 2 Day 1 to pre-dose on Cycle 2 Day 2 (Cycle = 28 days))
- Part 1a Only: Time to Achieve Maximal Plasma Concentration (Tmax) of AMG 193(Cycle 2 Day 1 to pre-dose on Cycle 2 Day 2 (Cycle = 28 days))
- Part 1a Only: Area Under the Plasma Concentration Versus Time Curve (AUC) of AMG 193(Cycle 2 Day 1 to pre-dose on Cycle 2 Day 2 (Cycle = 28 days))
- Part 1a Only: Maximal Plasma Concentration (Cmax) of Comparator AMG 193 Test Tablet(Cycle 2 Day 2 to pre-dose on Cycle 2 Day 3 (Cycle = 28 days))
- Part 1a Only: Time to Achieve Maximal Plasma Concentration (Tmax) of Comparator AMG 193 Test Tablet(Cycle 2 Day 2 to pre-dose on Cycle 2 Day 3 (Cycle = 28 days))
- Part 1a Only: Area Under the Plasma Concentration Versus Time Curve (AUC) of Comparator AMG 193 Test Tablet(Cycle 2 Day 2 to pre-dose on Cycle 2 Day 3 (Cycle = 28 days))
- Part 1k Only: Cmax of AMG 193 during fasted state(Cycle 2 day 1 pre-dose up to 24 hours post-dose (Cycle = 28 days))
- Part 1k Only: Tmax of AMG 193 during fasted state(Cycle 2 day 1 pre-dose up to 24 hours post-dose (Cycle = 28 days))
- Part 1k Only: AUC of AMG 193 during fasted state(Cycle 2 day 1 pre-dose up to 24 hours post-dose (Cycle = 28 days))
- Part 1k Only: Cmax of AMG 193 during fed state(Cycle 2 day 2 pre-dose up to 24 hours post-dose (Cycle = 28 days))
- Part 1k Only: Tmax of AMG 193 during fed state(Cycle 2 day 2 pre-dose up to 24 hours post-dose (Cycle = 28 days))
- Part 1k Only: AUC of AMG 193 during fed state(Cycle 2 day 2 pre-dose up to 24 hours post-dose (Cycle = 28 days))