CPX-351 and Ivosidenib for the Treatment of IDH1 Mutated Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Prior treatment

• Patients who have previously received CPX-351.
• Patients with prior anthracycline exposure of \> 360 mg/m2 daunorubicin (or equivalent), or \> 210 mg/m2 daunorubicin (or equivalent) in patients with prior mediastinal radiation.
• Subjects taking strong CYP3A4 inducers are excluded from the study unless they can be transferred to other medications within ≥ 5 half-lives prior to dosing
• Unresolved toxicities \> grade 1 from prior treatment including chemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, or surgery.

Other illness

• The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions (1) intrathecal chemotherapy for prophylactic use or for controlled CNS leukemia. (2) use of hydroxyurea, and/or cytarabine (1 or 2 doses; up to 2 g/m2) for patients with rapidly proliferative disease is allowed before the start of study therapy.
• Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant (patients without active GVHD on chronic suppressive immunosuppression and/or phototherapy for chronic skin GVHD are permitted after discussion with the PI).
• Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications.
• Subjects with a known medical history of progressive multifocal leukoencephalopathy (PML).

Lab values

• Patients with any concurrent uncontrolled clinically significant medical condition including infection, laboratory abnormality, or psychiatric illness, which could place the patient at unacceptable risk of study treatment.
• Patients with symptomatic congestive heart failure (NYHA Class III or IV), unstable angina, or an ejection fraction \< 45%.
• QTc interval using Fridericia's formula (QTcF) \> 470 msec. A prolonged QTc interval in the setting of right bundle branch block is permitted after discussion with the PI.
• Nursing women, women of childbearing potential (WOCBP) with positive urine or serum pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception
  • Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, IUD, and double barrier methods (for example a condom in combination with a spermicide).

Other

• Patients with a diagnosis of acute promyelocytic leukemia (APL).

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• IDH1-R132 mutated disease status as assessed by local laboratory. 2HG-producing IDH1 variants outside of R132 (i.e. R100) may be eligible after discussion with the principal investigator (PI)
• Treatment naive or relapsed/refractory AML who are eligible for intensive chemotherapy. Patients with high-risk MDS or MPN (defined as International Prognostic Scoring System Revised \[IPSS-R\] score ≥ 4 or dynamic \[D\]-IPSS ≥ 3) may also be eligible after discussion with the PI
• Adequate hepatic function (direct bilirubin ≤ 2 x upper limit of normal (ULN), Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3 x ULN unless deemed to be related to underlying leukemia
• Adequate renal function including creatinine clearance ≥ 30 ml/min based on the Cockcroft-Gault equation.
• Willing and able to provide informed consent
• In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 7 days for cytotoxic or non-cytotoxic (immunotherapy) agents.
• Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug