LY3214996 in Patients With AML Who Are Not Candidates for Standard Therapy

Inclusion Criteria:

* Participants must have histologically confirmed acute myeloid leukemia (AML) diagnosed per WHO criteria.
* Participants must have relapsed or refractory AML.
* Age ≥ 18 years.
* ECOG performance status ≤ 2
* Participants must have adequate organ function as defined below:

  * Direct Bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)
  * AST (SGOT) and ALT(SGPT) ≤ 2.5 × institutional ULN, OR
  * AST (SGOT) and ALT (SGPT) ≤ 5 × institutional ULN if elevation is a result of leukemia
  * Creatinine Clearance ≥ 60 mL/min/1.73 m2 (calculated via the Cockcroft-Gault equation)
* The effects of LY3214996 on the developing human fetus are unknown. For this reason and because anti-cancer agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men and women treated or enrolled on this protocol must agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of LY3214996 administration.
* Ability to understand and the willingness to sign a written informed consent document.
* Ability to swallow and retain oral medication.
* Participants must have resolution of adverse events related to prior anti-cancer therapies to ≤ CTCAE Grade 2 or baseline
* Considerations of concurrent use of CYP3A4 inhibitors

Dose escalation phase:

* ARM A: Participants must not be receiving any concurrent antifungal agents that are moderate/strong CYP3A4 inhibitors. These include but are not limited to: isavuconazole, itraconazole, fluconazole, ketoconazole, posaconazole, and voriconazole.
* ARM B: Participants must be receiving concurrent antifungal agents that are moderate/strong CYP3A4 inhibitors. These include but are not limited to: isavuconazole, itraconazole, fluconazole, ketoconazole, posaconazole, and voriconazole.

Expansion Phase:

Participants not receiving concurrent antifungal agents that are moderate/strong CYP3A4 inhibitors are eligible to enroll at MTD determined upon completion of dose-escalation cohort Arm A. Participants receiving concurrent antifungal agents that are moderate/strong CYP3A4 inhibitors are eligible to enroll at MTD determined upon completion of dose-escalation cohort Arm B.

Exclusion Criteria:

* Participants who have had chemotherapy, other investigational therapy, immunotherapy, or radiotherapy within 2 weeks prior to the first dose of study medication. ATRA treatment is permitted with no required washout if treatment duration was for less than 1 week. Hydroxyurea is allowed with no required washout. For participants with an absolute peripheral blast count \> 20 K/µL, hydroxyurea may be administered up to day 14 of protocol therapy with a maximum allowed dose of 6 g per day.
* Participants who have received oral tyrosine kinase inhibitors (TKIs) within 5 half-lives of the first dose of study medication.
* Participants who have had major surgery within 4 weeks prior to the first dose of study medication.
* Participants who have had a prior stem cell transplant (SCT) within 90 days prior to the first dose of study medication. Additionally, participants having undergone prior SCT must be off calcineurin inhibitor therapy for at least 28 days prior to the first dose of study medication.
* Participants with active \> Grade 1 acute or chronic Graft v. Host Disease (GvHD) who are receiving immunosuppressive therapy other than prednisone. Use of prednisone is permitted only if participants have been maintained at a steady dose of \< 20 mg/day for at least 5 days prior to the first dose of study medication.
* Participants with known active CNS leukemia involvement. Participants with no known history of CNS leukemia are not required to undergo lumbar puncture (LP) for trial eligibility unless the participant is symptomatic as judged by the treating investigator. Participants with a history of CNS leukemia involvement are eligible provided that the CNS disease has been adequately treated and cleared prior to study enrollment as judged by the treating investigator.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to LY3214996.
* Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant women are excluded from this study because LY3214996 is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with LY3214996, breastfeeding should be discontinued if the mother is treated with LY3214996. A negative serum pregnancy test is required for women of childbearing potential prior to study entry.
* Participants who are known to be seropositive for human immunodeficiency virus (HIV) or hepatitis B or C. Testing is not required for eligibility.
* Participants with a history or findings of central or branch retinal artery or venous occlusion with significant vision less, or other retinal diseases causing visual impairment as determined by an ophthalmologist.