A Study of IDE892 as Monotherapy and Combination in MTAP-deleted Advanced Solid Tumors

Ideaya Biosciences

Status and phase: Enrolling; Phase 1

Conditions: Non-Small Cell Lung Cancer NSCLC; Pleural Mesothelioma; Adenocarcinoma of Esophagus; Bladder Cancer; Gastroesophageal Cancer (GC); Urothelial Carcinoma (UC); NSCLC Adenocarcinoma; Peritoneal Mesothelioma; Mesothelioma; Squamous Cell Car. - Esophagus; Gastric Adenocarcinoma

Treatments: Drug: IDE892; Drug: IDE397

Study type: Interventional

Funder types: Industry

Identifiers

NCT07277413

IDE892-001

Details and patient eligibility

About

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.

Full 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.

Enrollment: 260 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Are ≥ 18 years of age 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], NSCLC [adenocarcinoma, squamous cell carcinoma, and adeno-squamous] and 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 retain administered study drug/IMP.
• 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
• Had an adverse reaction to a previous antitumor treatment that has not recovered to CTCAE Grade ≤ 1
• Have received chemotherapy within 3 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 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 NSCLC

• 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, including no more than 2 prior lines of chemotherapy.
• 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.

Urothelial Cancer (Bladder and Upper Urinary Tract), Mesothelioma (Pleural or Peritoneal) and Gastroesophageal Cancers

• Must have histologically confirmed diagnosis of advanced or metastatic UC, mesothelioma, or gastroesophageal cancer
• Must have progressed following at least 1 prior line of therapy
• Treatment with no more than 3 prior lines, including no more than 2 prior lines of chemotherapy

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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260 participants in 4 patient groups

Part 1: IDE892 Monotherapy Dose Escalation (MTAP-deleted advanced solid tumors)

Experimental group

Description:

Participants with advanced or metastatic solid tumors harboring MTAP deletion (including mesothelioma, gastroesophageal cancers, 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.

Treatment:

Drug: IDE892

Part 2: IDE892 Monotherapy Dose Expansion (MTAP-Deleted NSCLC)

Experimental group

Description:

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.

Treatment:

Drug: IDE892

Part 3: IDE892 + IDE397 Combination Dose Escalation (MTAP-Deleted Solid Tumors)

Experimental group

Description:

Participants with advanced or metastatic solid tumors harboring MTAP deletion (including mesothelioma, gastroesophageal cancers, 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.

Treatment:

Drug: IDE397

Drug: IDE892

Part 4: IDE892 + IDE397 Combination Dose Expansion (MTAP-Deleted NSCLC)

Experimental group

Description:

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.

Treatment:

Drug: IDE397

Drug: IDE892