Advanced MTAP-null Solid Tumors
Conditions
Keywords
Metastatic MTAP-null solid tumors, Advanced MTAP-null solid tumors, Non-small cell lung cancer, Biliary Tract Cancer (BTC), Head and neck squamous cell carcinoma, Pancreatic adenocarcinoma, Esophageal cancer, Gastric cancer, Glioma
Brief summary
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.
Interventions
DRUGAnvumetostat
Anvumetostat: Orally via tablet
DRUGDocetaxel
Docetaxel: Intravenous infusion
DRUGComparator Anvumetostat Test Tablet
Comparator Anvumetostat test tablet: Orally via tablet. Only participants in the DSPS group of the Part 1a, Phase 1: Anvumetostat Monotherapy Dose Exploration, and Part 1j, Phase 1 arms will receive comparator Anvumetostat test tablet.
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* 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 1. * 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)
Exclusion criteria
* 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 1. * 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 1. * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Parts 1 and 2: Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) | 28 days | — |
| Parts 1 and 2: Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE) | 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) | Up to approximately 3 years | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parts 1 and 2: Maximal Plasma Concentration (Cmax) of Anvumetostat | 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 Anvumetostat | 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 Anvumetostat | 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 | 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, ECGs and clinical laboratory tests will be recorded as TEAEs. 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 1a Only: Maximal Plasma Concentration (Cmax) of Anvumetostat | 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 Anvumetostat | 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 Anvumetostat | Cycle 2 Day 1 to pre-dose on Cycle 2 Day 2 (Cycle = 28 days) | — |
| Part 1a Only: Maximal Plasma Concentration (Cmax) of Comparator Anvumetostat 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 Anvumetostat 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 Anvumetostat Test Tablet | Cycle 2 Day 2 to pre-dose on Cycle 2 Day 3 (Cycle = 28 days) | — |
| Part 1k Only: Cmax of Anvumetostat during fasted state | Cycle 2 day 1 pre-dose up to 24 hours post-dose (Cycle = 28 days) | — |
| Part 1k Only: Tmax of Anvumetostat during fasted state | Cycle 2 day 1 pre-dose up to 24 hours post-dose (Cycle = 28 days) | — |
| Part 1k Only: AUC of Anvumetostat during fasted state | Cycle 2 day 1 pre-dose up to 24 hours post-dose (Cycle = 28 days) | — |
| Part 1k Only: Cmax of Anvumetostat during fed state | Cycle 2 day 2 pre-dose up to 24 hours post-dose (Cycle = 28 days) | — |
| Part 1k Only: Tmax of Anvumetostat during fed state | Cycle 2 day 2 pre-dose up to 24 hours post-dose (Cycle = 28 days) | — |
| Part 1k Only: AUC of Anvumetostat during fed state | Cycle 2 day 2 pre-dose up to 24 hours post-dose (Cycle = 28 days) | — |
Countries
Australia, Austria, Belgium, Canada, China, France, Germany, Hong Kong, Japan, South Korea, Switzerland, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORMD
Amgen
Outcome results
None listed