Ivosidenib and Combination Chemotherapy for the Treatment of IDH1 Mutant Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVE: I. To determine the maximum tolerated dose (MTD) of ivosidenib in combination with fludarabine, cytarabine, plus granulocyte-colony stimulating factor (G-CSF) (FLAG) ± Idarubicin chemotherapy. SECONDARY OBJECTIVES: I. To evaluate the safety profile of ivosidenib in combination with FLAG ± Idarubicin chemotherapy. II. To determine the rate of complete remission (CR + complete remission with incomplete hematological recovery \[CRi\] + complete remission with incomplete platelet recovery \[CRp\]) with ivosidenib in combination with FLAG ± Idarubicin chemotherapy. III. To evaluate the 1 year progression free survival. IV. To evaluate the 1 year overall survival. V. To assess the number of patients that receive allogeneic stem cell transplant after ivosidenib in combination with FLAG ± Idarubicin chemotherapy. EXPLORATORY OBJECTIVES: I. To assess for minimal residual disease negativity by polymerase chain reaction (PCR) for IDH1 mutations after treatment with ivosidenib in combination with FLAG ± Idarubicin chemotherapy. II. To assess for minimal residual disease negativity by PCR for IDH1 mutations after 3 cycles of maintenance therapy. OUTLINE: INDUCTION: Patients receive filgrastim subcutaneously (SC) once daily (QD) on days 0-6, fludarabine phosphate intravenously (IV) QD over 30 minutes on days 1-5, cytarabine IV QD over 4 hours on days 1-5, and ivosidenib orally (PO) QD on days 7-28. The addition of idarubicin to FLAG (FLAG ± IDA) will be per treating investigator and is to be to be administered at 8 mg/m2 by IV infusion over 30 minutes on days 4-6 of cycle 1, when given in combination with FLAG. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients that complete the induction cycle are eligible to receive consolidation therapy with 1 cycle of FLAG ± IDA and ivosidenib based on treating physician discretion. Eligible patients for consolidation therapy are those who have CR, CRi, CRp, or PR. Patients are not required to receive consolidation therapy. Patients receive filgrastim SC QD on days 0-5, fludarabine phosphate IV QD over 30 minutes on days 1-4, cytarabine IV QD over 4 hours on days 1-4, and ivosidenib PO QD on days 1-28. The addition of idarubicin to FLAG (FLAG ± IDA) will be per treating investigator and is to be to be administered at 8 mg/m2 by IV infusion over 30 minutes on days 4-6. Treatment continues for 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients that have completed 1 cycle of induction with ivosidenib and FLAG ± IDA may start maintenance. Patients are not required to receive consolidation treatment in order to proceed to maintenance. Patients receive ivosidenib PO QD on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients complete follow up at 30 days and then every month for up to 1 year from start of study treatment to document survival and disease progression.