Inclusion Criteria:

• Evidence of IDH1 R132 mutation in tumor tissue (any solid tumor) or circulating tumor DNA (cholangiocarcinoma, chondrosarcoma, and glioma) as determined by molecular testing [polymerase chain reaction (PCR) or next-generation sequencing (NGS)] routinely performed at a CLIA, ISO/IEC, CAP, or other similarly certified laboratory.
• An archived tumor tissue sample is available. Patients enrolling to the dose expansion portion of the study who do not have adequate archival tumor tissue available should undergo a fresh tumor biopsy. If a fresh biopsy cannot be safely performed, the patient may be eligible with sponsor approval. Patients without an available archival tumor tissue sample must be discussed with the sponsor’s Medical Monitor prior to enrollment.
• Eastern Cooperative Oncology Group (ECOG) 0-1.
• At least 18 years of age.
• 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.
• For cholangiocarcinoma patients, must have adequate biliary drainage (per investigator's discretion), with no evidence of ongoing infection.
• 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. Patients enrolled to Dose Expansion Cohort 4 shall also follow cisplatin/gemcitabine contraception duration requirements as determined by labels and/or local guidelines.
• A locally advanced or metastatic solid tumor, where standard curative or palliative measures are no longer effective or are not considered appropriate or safe in the opinion of the investigator.
• Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate by tumor type.
• Prior IDH1 inhibitor treatment is permitted.
• Cholangiocarcinoma patients with IDH1 R132, IDH2 R140, or IDH2 R172 mutations are eligible; for all other tumor types, only patients with IDH1 R132 mutations are eligible.
• Histologically or cytologically confirmed diagnosis of advanced or metastatic cholangiocarcinoma, following 1 to 2 lines of prior systemic treatment for advanced disease. Prior IDH1 inhibitor treatment is not permitted.
• Measurable disease as determined by RECIST 1.1.
• Patients with IDH1 R132 mutations.
• A locally advanced or metastatic solid tumor, where standard curative or palliative measures are no longer effective or are not considered appropriate or safe in the opinion of the Investigator. If the available standard therapy is not considered appropriate or safe in the opinion of the Investigator, the rationale for ineligibility shall be provided and documented in the CRF. Furthermore, in the opinion of the Investigator, if the patient is intolerant to standard therapy, drug information, toxicity, and grade will be documented in the CRF.
• Nonmeasurable disease only as determined by RECIST 1.1 or RANO, as appropriate by tumor type.
• Patients with IDH1 R132 mutations.
• Cholangiocarcinoma patients with IDH1 R132, IDH2 R140, or IDH2 R172 mutations.
• Histologically or cytologically confirmed diagnosis of advanced or metastatic cholangiocarcinoma not eligible for curative resection.
• No prior systemic therapy for advanced or metastatic disease with the following exceptions:
  • Patients who received adjuvant chemotherapy are eligible if the adjuvant therapy was completed at least 6 months prior to the development of advanced or metastatic disease;
  • Patients are allowed to receive up to 2 cycles of cisplatin plus gemcitabine as the first line systemic therapy while waiting for results of locally obtained molecular profiling including IDH1/IDH2 mutational status. These patients are eligible provided that a radiographic assessment during Screening demonstrates the absence of interval disease progression since initiation of chemotherapy treatment, and all other eligibility criteria are met.
• Measurable disease as determined by RECIST 1.1.

Exclusion Criteria:

• An investigational agent or anticancer therapy (including Tumor Treating Fields) within 2 weeks, or investigational monoclonal antibody within 4 weeks prior to planned start of LY3410738.
• Major surgery within 4 weeks prior to planned start of LY3410738.
• Radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of study treatment, except for patients receiving whole brain radiotherapy, which must be completed at least 4 weeks prior to the first dose of study treatment.
• Cholangiocarcinoma:
  • Underwent hepatic radiation, chemoembolization, radiofrequency ablation, radioembolization, or other locoregional therapy < 4 weeks;
  • Have history of hepatic encephalopathy of any grade;
  • Have ascites requiring intervention such as diuretics or paracentesis;
  • Have ongoing cholangitis;
  • Have mixed hepatocellular biliary tract cancer histology;
  • History of liver transplant.
• Active central nervous system (CNS) metastases are not eligible. Patients with asymptomatic and treated brain metastases may participate provided that they are stable and are not requiring steroid treatment.
• Patients with suspected or confirmed Leptomeningeal Disease are not eligible even if treated.
• Primary CNS tumors are eligible provided that they do not have Leptomeningeal Disease and are on a stable or decreasing steroid dose for 7 days prior to Screening.
• Patients with evidence of intracranial hemorrhage either by magnetic resonance imaging (MRI) or computerized tomography (CT) are not eligible.
• Any unresolved toxicities from prior therapy greater than CTCAE (version 5.0) Grade 2 at the time of starting study treatment, except for alopecia.
• Clinically significant, active cardiovascular disease, or history of myocardial infarction within 6 months prior to planned start of LY3410738, or prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec on at least 2/3 consecutive electrocardiograms (ECGs), and mean QTcF > 470 msec on all 3 ECGs during Screening. QTcF is calculated using Fridericia’s Formula (QTcF): QTcF = QT/(RR^0.33).
  • Note: Correction of suspected drug-induced QTcF prolongation can be attempted at the Investigator’s discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
• Active uncontrolled systemic bacterial, viral, fungal, parasitic infection (except for fungal nail infection), or other clinically significant active disease process which, in the opinion of the Investigator and the Sponsor, makes it undesirable for the patient to participate in the trial. Screening for chronic conditions is not required.
• Active hepatitis B virus (HBV).
  • Note: Controlled (treated) hepatitis will be allowed if they meet the following criteria: antiviral therapy for HBV must be given for at least 1 month prior to first dose of study drug, and HBV viral load must be less than 2000 IU/mL (104 copies/mL) prior to the first dose of study drug. Those on active HBV therapy with viral loads under 2000 IU/mL (104 copies/mL) should stay on the same therapy throughout the study treatment.
• Active hepatitis C virus (HCV) Note: Untreated patients with chronic infection by HCV are allowed on study. In addition, successfully treated patients with chronic infection by HCV (defined as sustained virologic response SVR12 or SVR24) are allowed as long as there is 4 weeks between achieving sustained viral response (SVR12 or SVR24) and starting study drug.
• Known human immunodeficiency virus (HIV), excluded due to potential drug-drug interactions between antiretroviral medications and LY3410738.
• Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or P-glycoprotein (P-gp inhibitors).
• Treatment with proton pump inhibitor (PPIs) within 7 days of starting LY3410738. For recommended alternatives.
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.
• Active second malignancy unless in remission and with life expectancy > 2 years. Refer to exclusion criteria for examples of allowed second malignancies.
• Pregnancy, lactation, or plans to breastfeed during the study or within 3 months of the last dose of study intervention.
• Patients with known hypersensitivity to any component of LY3410738 or its formulation.

Eligibility last updated 1/6/22. Questions regarding updates should be directed to the study team contact.