A Phase 1/2 Study of AMG 193 in Combination With IDE397 in Participants With Advanced Methylthioadenosine Phosphorylase (MTAP)-Null Solid Tumors

Study Overview
=================
Brief Summary
-----------------
The main aims of this study are to evaluate the safety and tolerability, and to determine the maximum tolerated dose (MTD) or the recommended combination dose of AMG 193 in combination with IDE397 in adult participants with metastatic or locally advanced MTAP-null solid tumors, and to evaluate the preliminary anti-tumor activity of AMG 193 in combination with IDE397 in adult participants with metastatic or locally advanced MTAP-null Non-Small-Cell Lung Cancer (NSCLC).

Official Title
-----------------
A Phase 1/2 Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 193 in Combination With IDE397 in Subjects With Advanced MTAP-null Solid Tumors

Conditions
-----------------
MTAP-null Non-Small-Cell Lung Cancer, MTAP-null Solid Tumors

Intervention / Treatment
-----------------
* Drug: AMG 193
* Drug: IDE397


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Evidence of homozygous loss of MTAP (null) and/or MTAP deletion. Presence of advanced/metastatic solid tumor not amenable to curative treatment Part 1: MTAP-null or lost MTAP expression solid tumor for which no standard therapy exists Part 2: MTAP-null or lost MTAP expression NSCLC with progression after 1 to 2 prior lines of systemic therapy. Able to swallow and retain PO administered study treatment and willing to record adherence to investigational product Disease measurable as defined by RECIST v1.1 Adequate organ function as defined in the protocol. Archived tumor tissue. Participants without archived tumor tissue available may be allowed to enroll by undergoing tumor biopsy before cycle 1 day 1 dosing. Exclusion Criteria Prior treatment with an MAT2A inhibitor or a PRMT5 inhibitor. Radiologic or clinical evidence of spinal cord compression, untreated or symptomatic brain metastases or leptomeningeal disease. 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 bowel obstruction, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of study entry. Prior irradiation to > 25% of the bone marrow Use of prescription medications that are known strong CYP3A4/5 inducers or strong CYP3A4/5 inhibitors within 7 days for CYP3A4/5 inhibitors, 14 days for CYP3A4/5 inducers or 5 half-lives, whichever is longer, prior to any dose of investigational medical product.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 1: Dose Exploration of AMG 193 Combined With IDE397<br>Participants will receive escalating doses of AMG 193 and IDE397 administered orally (PO) in cycles of 21 days. | Drug: AMG 193<br>* Administered PO<br>Drug: IDE397<br>* Administered PO<br>|
| Experimental: Part 2: Dose Expansion of AMG 193 Combined With IDE397<br>AMG 193 and IDE397 will be administered PO in cycles of 21 days. | Drug: AMG 193<br>* Administered PO<br>Drug: IDE397<br>* Administered PO<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants Experiencing Dose Limiting Toxicities (DLTs) |  | Day 1 up to Day 21 | 
| Part 1: Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) | Any clinically significant changes in vital signs, electrocardiogram (ECG), or clinical laboratory test results will be recorded as adverse events | Day 1 up to approximately 2.5 years | 
| Part 1: Number of Participants Experiencing Serious Adverse Events (SAEs) |  | Day 1 up to approximately 2.5 years | 
| Part 2: Objective Response (OR) per modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 |  | Day 1 up to approximately 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and 2: Maximal Plasma Concentration (Cmax) of AMG 193 |  | Day 1 pre-dose up to Cycle 5 (Cycle= 21 days) | 
| Part 1 and 2: Cmax of IDE397 |  | Day 1 pre-dose up to Cycle 5 (Cycle= 21 days) | 
| Part 1 and 2: Time to Achieve Maximal Plasma Concentration (Tmax) of AMG 193 |  | Day 1 pre-dose up to Cycle 5 (Cycle= 21 days) | 
| Part 1 and 2: Tmax of IDE397 |  | Day 1 pre-dose up to Cycle 5 (Cycle= 21 days) | 
| Parts 1 and 2: Area Under The Curve (AUC) After Single Dose of AMG 193 |  | Day 1 pre-dose up to Cycle 5 (Cycle= 21 days) | 
| Parts 1 and 2: Area Under The Curve (AUC) After Multiple Doses of AMG 193 |  | Day 1 pre-dose up to Cycle 5 (Cycle= 21 days) | 
| Parts 1 and 2: AUC After Single Dose of IDE397 |  | Day 1 pre-dose up to Cycle 5 (Cycle= 21 days) | 
| Parts 1 and 2: AUC After Multiple Doses of IDE397 |  | Day 1 pre-dose up to Cycle 5 (Cycle= 21 days) | 
| Parts 1: Overall Response per RECIST 1.1 |  | Day 1 up to end-of-study (EOS) (approximately 2.5 years) | 
| Parts 1 and 2: Disease Control Rate |  | Day 1 up to EOS (approximately 2.5 years) | 
| Parts 1 and 2: Time to Response (TTR) |  | Day 1 up to EOS (approximately 2.5 years) | 
| Parts 1 and 2: Duration of Response (DOR) |  | Day 1 up to EOS (approximately 2.5 years) | 
| Parts 1 and 2: Duration of Stable Disease |  | Day 1 up to EOT (approximately 6 months) | 
| Parts 1 and 2: Progression-free Survival (PFS) |  | Day 1 up to EOS (approximately 2.5 years) | 
| Parts 1 and 2: Overall Survival (OS) |  | Day 1 up to EOS (approximately 2.5 years) | 
| Part 2: Number of Participants Experiencing TEAEs | Any clinically significant changes in vital signs, electrocardiogram (ECG), or clinical laboratory test results will be recorded as adverse events | Day 1 up to approximately 2.5 years | 
| Part 2: Number of Participants Experiencing SAEs |  | Day 1 up to approximately 2.5 years | 
| Parts 1 and 2: Change From Baseline in Symmetric Dimethylation of Arginine (SDMA) in Blood |  | Baseline (Day 1) to EOT plus 30 days (approximately 7 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Oncology, AMG 193, IDE397