AMG 193, Methylthioadenosine (MTA) Cooperative Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor, Alone and in Combination With Docetaxel in Advanced Methylthioadenosine Phosphorylase (MTAP)-Null Solid Tumors

Study Overview
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Brief Summary
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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 AMG 193 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 objective response rate (ORR) of AMG 193 in adult participants with metastatic or locally advanced MTAP-null solid tumors.

Official Title
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A Phase 1/1b/2 Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 193 Alone and in Combination With Docetaxel in Subjects With Advanced MTAP-null Solid Tumors

Conditions
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Advanced MTAP-null Solid Tumors

Intervention / Treatment
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* Drug: AMG 193
* Drug: Docetaxel
* Drug: Comparator AMG 193 Test Tablet


Participation Criteria
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Eligibility Criteria
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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). 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. A total of 25 slides of 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. Part 1i: Enrollment criteria for Part 1i are to match the criteria of the expansion arm from which the indication was selected. 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 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, unless anti-tumor therapy is a therapy with 5 times the half-life being shorter than 28 days 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1a, Phase 1: AMG 193 Monotherapy Dose Exploration<br>Participants with MTAP-null solid tumors will receive escalating doses of AMG 193 to estimate the MTD and/or the RP2D. A group of these participants in the United States (US) will have the option to take part in a Drug Substance Particle Size (DSPS) assessment. These participants will receive escalating doses of AMG 193 and a dose of a comparator AMG 193 test tablet. | Drug: AMG 193<br>* AMG 193: Orally via tablet<br>* Other names: MTA Cooperative PRMT5 inhibitor;Drug: Comparator AMG 193 Test Tablet<br>* Comparator AMG 193 test tablet: Orally via tablet. Only participants in the DSPS group of the Part 1a, Phase 1: AMG 193 Monotherapy Dose Exploration, and Part 1j, Phase 1 arms will receive comparator AMG 193 test tablet.<br>|
| Experimental: Part 1c, Phase 1: AMG 193 Monotherapy Dose Expansion<br>Participants will receive the identified MTD/RP2D of AMG 193 in the following cohort: MTAP-null or lost MTAP expression NSCLC. | Drug: AMG 193<br>* AMG 193: Orally via tablet<br>* Other names: MTA Cooperative PRMT5 inhibitor;|
| Experimental: Part 2a, Phase 1: AMG 193 Dose Exploration + Docetaxel<br>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. | Drug: AMG 193<br>* AMG 193: Orally via tablet<br>* Other names: MTA Cooperative PRMT5 inhibitor;Drug: Docetaxel<br>* Docetaxel: Intravenous infusion<br>|
| Experimental: Part 2b, Phase 1: AMG 193 + Docetaxel Dose Expansion<br>Participants with MTAP-null NSCLC will receive the identified MTD/RP2D of AMG 193 + docetaxel. | Drug: AMG 193<br>* AMG 193: Orally via tablet<br>* Other names: MTA Cooperative PRMT5 inhibitor;Drug: Docetaxel<br>* Docetaxel: Intravenous infusion<br>|
| Experimental: Part 3: AMG 193 Phase 2<br>Participants with MTAP-null solid tumors will receive AMG 193. | Drug: AMG 193<br>* AMG 193: Orally via tablet<br>* Other names: MTA Cooperative PRMT5 inhibitor;|
| Experimental: Part 1e, Phase 1: AMG 193 Monotherapy Dose Expansion<br>Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort: MTAP-null BTC. | Drug: AMG 193<br>* AMG 193: Orally via tablet<br>* Other names: MTA Cooperative PRMT5 inhibitor;|
| Experimental: Part 1f, Phase 1: AMG 193 Monotherapy Dose Expansion<br>Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort: MTAP-null head and neck squamous cell carcinoma (HNSCC) | Drug: AMG 193<br>* AMG 193: Orally via tablet<br>* Other names: MTA Cooperative PRMT5 inhibitor;|
| Experimental: Part 1g, Phase 1: AMG 193 Monotherapy Dose Expansion<br>Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort: MTAP-null pancreatic adenocarcinoma | Drug: AMG 193<br>* AMG 193: Orally via tablet<br>* Other names: MTA Cooperative PRMT5 inhibitor;|
| Experimental: Part 1h, Phase 1: AMG 193 Monotherapy Dose Expansion<br>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). | Drug: AMG 193<br>* AMG 193: Orally via tablet<br>* Other names: MTA Cooperative PRMT5 inhibitor;|
| Experimental: Part 1i, Phase 1: AMG 193 Dose Optimization<br>Participants will receive a randomized dose optimization evaluation of AMG 193. | Drug: AMG 193<br>* AMG 193: Orally via tablet<br>* Other names: MTA Cooperative PRMT5 inhibitor;|
| Experimental: Part 1j, Phase 1: AMG 193 DSPS Substudy (US Sites Only)<br>Participants will receive doses of AMG 193 and comparator AMG 193 test tables at different times in a fasted state. | Drug: AMG 193<br>* AMG 193: Orally via tablet<br>* Other names: MTA Cooperative PRMT5 inhibitor;Drug: Comparator AMG 193 Test Tablet<br>* Comparator AMG 193 test tablet: Orally via tablet. Only participants in the DSPS group of the Part 1a, Phase 1: AMG 193 Monotherapy Dose Exploration, and Part 1j, Phase 1 arms will receive comparator AMG 193 test tablet.<br>|
| Experimental: Part 1k, Phase 1: AMG 193 Food Effect Substudy (US Sites Only)<br>Participants will receive AMG 193 once on a fasted state and once after eating a standardized high-fat, high calorie meal. | Drug: AMG 193<br>* AMG 193: Orally via tablet<br>* Other names: MTA Cooperative PRMT5 inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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 | Up to approximately 2 years | 
| Part 3: Objective Response Rate (ORR) |  | Up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 2 years | 
| Parts 1, 2 and 3: Disease Control Rate (DCR) |  | Up to approximately 2 years | 
| Parts 1, 2 and 3: Duration of Response (DoR) |  | Up to approximately 2 years | 
| Parts 1, 2 and 3: Time to Response (TTR) |  | Up to approximately 2 years | 
| Parts 1, 2 and 3: Duration of Stable Disease (SD) |  | Up to approximately 2 years | 
| Parts 1, 2 and 3: Progression-Free Survival (PFS) |  | Up to approximately 2 years | 
| Parts 1, 2 and 3: Overall Survival (OS) |  | Up to approximately 2 years | 
| Part 3 Only: Number of Participants Who Experience TEAE | 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 | Up to approximately 2 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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