This is an open-label, multi-center Phase 1 study of LY3410738, an oral, covalent isocitrate dehydrogenase (IDH) inhibitor, in patients with IDH1 and/or IDH2-mutant advanced hematologic malignancies who may have received standard therapy

This study includes 2 parts: dose escalation and dose expansion. The dose escalation will enroll eligible patients with select IDH-mutant advanced hematologic malignancies. Once the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of LY3410738 is established, the dose expansion will begin and enroll into 5 cohorts to further evaluate safety and clinical activity

Inclusion Criteria:

• Advanced IDH mutant hematologic malignancy including:

  -- For Dose Escalation Arm C and Dose Expansion Cohort 5:

  • Patients with newly diagnosed AML who are 75 years or older or have comorbidities that preclude the use of intensive chemotherapy
  • Patients with R/R AML (US only)

• Patients must have received prior therapy

• Blasts at least 5% in bone marrow.

• Patients must have a qualifying IDH1 R132, IDH2 R140 or IDH2 R172 mutation

• Eastern Cooperative Oncology Group (ECOG) 0 to 2

• Adequate organ function

• Ability to swallow capsules or tablets

• Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation

• Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following the last dose of study treatment.

Exclusion Criteria:

• Investigational agent or anticancer therapy within 2 weeks or 5 half-lives, whichever is shorter; or investigational monoclonal antibody within 4 weeks prior to planned start of LY3410738

• For Dose Escalation Arm C and Dose Expansion Cohort 5:

  • Prior venetoclax treatment is not allowed.
  • Patients are allowed to receive up to 1 cycle of single agent azacitidine or azacitidine plus venetoclax while waiting for results of locally obtained molecular profiling, including IDH1/IDH2 mutational status, prior to starting on study.

• Major surgery within 4 weeks prior to planned start of LY3410738.

• Active, uncontrolled clinically significant systemic bacterial, viral, fungal or parasitic infection or an unexplained fever > 38.5ºC during Screening or on the first day of study drug administration.

• Another concurrent malignancy requiring active therapy.

• Active central nervous system involvement

• Any unresolved toxicities from prior therapy greater than CTCAE v5.0 Grade 2 at the time of starting study treatment except for alopecia.

• History of hematopoietic stem cell transplant (HSCT) or chimeric antigen receptor T-cell (CAR-T) therapy within 60 days of the first dose of LY3410738.

• Clinically significant cardiovascular disease

• Active hepatitis B virus (HBV)

• Active hepatitis C virus (HCV)

• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug

• Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or P- glycoprotein (P-gp) inhibitor, with the exception of patients being treated with allowed antifungal inhibitors of CYP3A4

• Treatment with proton pump inhibitor (PPIs) within 7 days of starting LY3410738

• Any serious underlying medical or psychiatric condition (e.g. alcohol or drug abuse), dementia or altered mental status or any issue that would impair the ability of the patient to understand informed consent or that in the opinion of the Investigator would contraindicate the patient's participation in the study or confound the results of the study

• Known human immunodeficiency virus (HIV), excluded due to potential drug-drug interactions between antiretroviral medications and LY3410738

• Pregnancy, lactation or plan to breastfeeding during the study or within 90 days of the last dose of study intervention

• Known hypersensitivity to any of the components of LY3410738 or its formulation