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.

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.

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