A Multicenter Study Evaluating the Safety, Efficacy, and Pharmacokinetics of IDE892 as Monotherapy and Combination Therapy in Participants With MTAP-Deleted Advanced Solid Tumors
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- IDEAYA Biosciences
- Enrollment
- 260
- Locations
- 17
- Primary Endpoint
- Incidence of Dose-limiting Toxicities (DLTs) of IDE892 (Parts 1 and 3)
Study Overview
Brief Summary
This is a multicenter clinical study to evaluate the safety, efficacy, and Pharmacokinetics (PK) of IDE892 as monotherapy and in combination with other agents including IDE397 in participants with methylthioadenosine phosphorylase (MTAP)-deleted advanced solid tumors within indications of interest.
Detailed Description
The purpose of this study is to evaluate safety, efficacy, and PK of IDE892 as monotherapy and combination therapy in adult participants with MTAP-deleted tumors who have progressed after standard therapy and represent a high unmet need. In the current stage, the combination will be focused on IDE892 with IDE397, an oral inhibitor of methionine adenosyltransferase 2A (MAT2A), to fully exploit the vulnerabilities associated with methylthioadenosine (MTA) accumulation in MTAP-deleted tumors while maintaining a substantial therapeutic index. The mechanistic rationale for this study is discussed in the following sections.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Are ≥ 18 years of age (or the minimum age of consent in accordance with local regulations) at the time of signing the ICF.
- •Have a histologically confirmed diagnosis of a locally advanced recurrent or metastatic solid tumor type of interest with MTAP deletion (for dose escalation: mesothelioma [pleural or peritoneal], gastroesophageal cancers [squamous and adenocarcinoma of esophagus, gastric adenocarcinoma, gastroesophageal junction cancers], pancreatic adenocarcinoma and biliary tract carcinomas (intrahepatic and extrahepatic cholangiocarcinoma, and gallbladder cancer), NSCLC [adenocarcinoma, squamous cell carcinoma, and adeno-squamous] or UC [including mixed urothelial-squamous histology]; for dose expansion: NSCLC that has progressed on at least one prior line of treatment and for which additional effective standard therapy is not available or for which the participant is not a candidate due to intolerance).
- •Are willing and able to provide blood/tumor tissue samples for biomarker testing. An archival tumor tissue specimen must be provided for central confirmation of MTAP loss.
- •Must be willing and able to provide the blood/serum/plasma samples
- •Have evidence of homozygous loss of MTAP or MTAP deletion (pre-screening available after signing pre-screening ICF)
- •Have at least 1 measurable lesion according to RECIST version 1.1
- •Have Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1
- •Have life expectancy > 3 months
- •Have adequate bone marrow and organ function
- •Able to swallow and retain orally administered study drug/IMP.
- •Are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures
- •Male and female: willing to use contraception
Exclusion Criteria
- •Known symptomatic brain metastases requiring supraphysiologic doses of systemic corticosteroids
- •Have a known primary central nervous system (CNS) malignancy
- •Have had other malignancies within 2 years prior to the first dose, with some exceptions
- •Impaired cardiac function or clinically significant cardiac diseases
- •Have presence of uncontrolled pleural, peritoneal, or pericardial effusion within 2 weeks before the first study dose, requiring recurrent drainage procedures or an indwelling drainage catheter
- •Have a history of severe infections within 4 weeks prior to the start of study treatment
- •Hypertension (e.g., > 150/100 mmHg) that cannot be controlled by medications despite optimal medical therapy
- •Other acute or chronic medical or psychiatric condition
- •Have a history of immunodeficiency, with a positive human immunodeficiency virus(HIV) test at screening
- •Known or suspected viral hepatitis with a positive test at screening
- •Had an adverse reaction to a previous antitumor treatment that has not recovered to CTCAE Grade ≤ 1
- •Have received chemotherapy within 4 weeks of the first dose of IMP; immunotherapy or biologic targeted antitumor treatments within 2 weeks before the first dose of IMP; small molecule inhibitors within 2 weeks before the first dose of IMP, or other investigational products within 4 weeks
- •Current radiation-related toxicity or radiation therapy within 2 weeks before the first dose of IMP
- •Administration of any of the following within 2 weeks before the first dose of IDE892 as a monotherapy: Strong inhibitors or inducers of cytochrome P450, Strong inhibitors of P-glycoprotein, Narrow therapeutic index and sensitive substrates of multidrug and toxin extrusion (MATE)1 and MATE2-K, Narrow therapeutic index and sensitive substrates of P-gp and breast cancer resistance protein
- •Administration of any of the following within 2 weeks before the first dose of IDE892: Strong inhibitors or inducers of CYP3A4/5, Strong inhibitors of P-gp and/or BCRP, Narrow therapeutic index and sensitive substrates of MATE1 and MATE2-K, Narrow therapeutic index and sensitive substrates of P-gp and BCRP
- •Use of proton pump inhibitors (PPIs) within 7 days prior to the first dose of IMP or planned use during the study
- •Use of drugs with known risk for QT prolongation within 2 weeks prior to the first dose of IDE892
- •Previous treatment with a Amethionine adenosyltransferase 2A (MAT2A) inhibitor and/or Protein arginine N-methyltransferase (PRMT) inhibitor
- •Major surgery within 4 weeks before study entry
- •Prior irradiation to > 25% of the bone marrow
- •Known or suspected hypersensitivity to IDE892
- •Disease-Specific Eligibility Criteria Eligibility Criteria for Participants with NSCLC (All Parts)
- •Must have histologically confirmed diagnosis of advanced or metastatic NSCLC that has progressed after prior treatment with platinum chemotherapy and a PD-1/PD-L1 inhibitor (unless contraindicated or participant developed intolerance) in the metastatic setting
- •Treatment with no more than 3 prior lines in the setting of advanced or metastatic disease.
- •If considered standard of care and available, participants whose cancers have proven targetable oncogene alterations must have had disease progression on (unless contraindicated or participant developed intolerance) at least 1 prior line containing appropriate targeted therapy.
- •Eligibility Criteria for Participants with Urothelial Cancer (Bladder and Upper Urinary Tract), Mesothelioma (Pleural or Peritoneal), Pancreatic Adenocarcinoma or Biliary Tract Carcinomas (Intrahepatic and Extrahepatic Cholangiocarcinoma, and Gallbladder Cancer) (Parts 1 and 3)
- •Must have histologically confirmed diagnosis of advanced or metastatic UC, mesothelioma, gastroesophageal cancer or pancreatic and biliary tract tumors
- •Must have progressed following at least 1 prior line of therapy
- •Treatment with no more than 3 prior lines in the setting of advanced or metastatic disease
Arms & Interventions
Part 1: IDE892 Monotherapy Dose Escalation (MTAP-deleted advanced solid tumors)
Participants with advanced or metastatic solid tumors harboring MTAP deletion (including mesothelioma, gastroesophageal cancers, pancreatic and biliary tract tumors, non-small cell lung cancer, and urothelial cancer) will receive IDE892. Dose levels will be escalated sequentially using a Bayesian Optimal Interval (BOIN) design to evaluate safety, tolerability, and to determine the maximum tolerated dose and/or recommended dose for expansion. PK and pharmacodynamics (PD) and preliminary antitumor activity will also be assessed.
Intervention: IDE892 (Drug)
Part 3: IDE892 + IDE397 Combination Dose Escalation (MTAP-Deleted Solid Tumors)
Participants with advanced or metastatic solid tumors harboring MTAP deletion (including mesothelioma, gastroesophageal cancers, pancreatic and biliary tract tumors, non-small cell lung cancer, and urothelial cancer) will receive IDE892 in combination with IDE397. Dose levels will be escalated using a modified toxicity probability interval (mTPI) design to evaluate safety, tolerability, and to determine the maximum tolerated dose and/or recommended dose for expansion. PK, PD, and preliminary antitumor activity will also be assessed.
Intervention: IDE892 (Drug)
Part 2: IDE892 Monotherapy Dose Expansion (MTAP-Deleted NSCLC)
Participants with advanced or metastatic NSCLC with MTAP deletion will receive IDE892. One or more dose levels at or below the maximum tolerated dose from Part 1 will be further evaluated to determine the recommended Phase 2 dose and to assess antitumor activity.
Intervention: IDE892 (Drug)
Part 4: IDE892 + IDE397 Combination Dose Expansion (MTAP-Deleted NSCLC)
Participants with advanced or metastatic NSCLC with MTAP deletion will receive IDE892 in combination with IDE397. One or more dose levels at or below the maximum tolerated dose from Part 3 will be further evaluated to determine the recommended Phase 2 dose and to assess antitumor activity.
Intervention: IDE397 (Drug)
Part 3: IDE892 + IDE397 Combination Dose Escalation (MTAP-Deleted Solid Tumors)
Participants with advanced or metastatic solid tumors harboring MTAP deletion (including mesothelioma, gastroesophageal cancers, pancreatic and biliary tract tumors, non-small cell lung cancer, and urothelial cancer) will receive IDE892 in combination with IDE397. Dose levels will be escalated using a modified toxicity probability interval (mTPI) design to evaluate safety, tolerability, and to determine the maximum tolerated dose and/or recommended dose for expansion. PK, PD, and preliminary antitumor activity will also be assessed.
Intervention: IDE397 (Drug)
Part 4: IDE892 + IDE397 Combination Dose Expansion (MTAP-Deleted NSCLC)
Participants with advanced or metastatic NSCLC with MTAP deletion will receive IDE892 in combination with IDE397. One or more dose levels at or below the maximum tolerated dose from Part 3 will be further evaluated to determine the recommended Phase 2 dose and to assess antitumor activity.
Intervention: IDE892 (Drug)
Outcomes
Primary Outcomes
Incidence of Dose-limiting Toxicities (DLTs) of IDE892 (Parts 1 and 3)
Time Frame: 21 days following the first dose of IDE892 (each cycle is 21 days)
Incidence of DLTs of IDE892 will be determined in Parts 1 and 3
Incidence of AEs and SAEs (Parts 1, 2, 3, and 4)
Time Frame: From first dose until 28 days after last dose (each cycle is 21 days)
Incidence and severity of adverse events (AEs)/serious adverse events (SAEs) (graded based on Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0) will be determined in Parts 1, 2, 3, and 4.
Objective response rate (ORR) and duration of response (DOR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Parts 2 and 4)
Time Frame: Approximately 2 years
Objective response rate (ORR: best objective response of complete response \[CR\] + partial response \[PR\]) and duration of response (DOR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as assessed by the Investigator
Secondary Outcomes
- Maximum Observed Plasma Concentration (Cmax) (Parts 1, 2, 3, and 4)(Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 21 days))
- Time to Maximum Observed Concentration (Tmax)(Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 21 days))
- Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast)(Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 21 days))
- Time of Last Quantifiable Concentration (Tlast)(Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 21 days))
- Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf)(Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 21 days))
- Terminal Elimination Half-Life (t½)(Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 21 days))
- Maximum Observed Plasma Concentration at Steady State (Cmax,ss)(Cycle 1 Day 15 (each cycle is 21 days))
- Time to Maximum Concentration at Steady State (Tmax,ss)(Cycle 1 Day 15 (each cycle is 21 days))
- Trough Plasma Concentration at Steady State (Ctrough)(Cycle 1 Day 15 (each cycle is 21 days))
- Area Under the Plasma Concentration-Time Curve Over the Dosing Interval (AUCtau)(Cycle 1 Day 15 (each cycle is 21 days))
- Apparent Clearance (CL/F)(Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 21 days))
- Apparent Volume of Distribution (Vz/F)(Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 21 days))
- Accumulation Ratio (Rac)(Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 21 days))
- Overall response rate (ORR) and duration of response (DOR) per RECIST version 1.1 (Parts 1 and 3)(Approximately 2 years)
- Disease control rate (DCR) and duration of stable disease per RECIST version 1.1 (Parts 1, 2, 3, and 4)(Approximately 2 years)