This phase I study hopes to explore how safe and tolerable is the combination of gemtuzumab ozogamicin (GO) and midostaurin, with the standard induction therapy (cytarabine and daunorubicin) in patients with newly diagnosed FLT-3 mutated Acute Myeloid Leukemia (AML). GO is FDA approved for the treatment of adults with newly diagnosed CD33 positive AML and used in combination with chemotherapy, cytarabine and daunorubicin. Midostaurin is FDA approved for use with cytarabine and daunorubicin in patients with FLT3-mutated AML. By combining standard induction therapy with GO and midostaurin, our aim is to investigate a novel approach to treating patients with newly diagnosed FLT3-mutated AML.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03900949.
PRIMARY OBJECTIVE:
I. To assess the maximum tolerated dose (MTD) of combining gemtuzumab ozogamicin (GO) to the induction regimen of cytarabine and daunorubicin (DA) and midostaurin.
SECONDARY OBJECTIVES:
I. To assess the frequency of early death associated with study treatment.
II. To evaluate the preliminary efficacy of the study treatment.
III. To assess the safety profile of the study treatment.
EXPLORATORY OBJECTIVES:
I. Quantify CD33 expression on acute myeloid leukemia (AML) blasts.
II. Determine the CD33 single-nucleotide polymorphism (SNP) status previously reported to correlate with response and correlate clinical outcomes of patients with the CD33 genotype.
OUTLINE: This is a dose finding study to identify the maximum tolerated dose (MTD) schedule of GO, and its safety and tolerability in combination with midostaurin in FLT3-mutated newly diagnosed AML patients.
INDUCTION THERAPY: Patients receive cytarabine intravenously (IV) on days 1-7, daunorubicin IV on days 1-3 and midostaurin 50mg orally (PO) twice daily (BID) on days 8-21. Patients also receive gemtuzumab ozogamicin IV either on day 1, days 1 and 4, or days 1, 4 and 7 depending on dose level in the absence of disease progression or unacceptable toxicity.
RE-INDUCTION THERAPY: Between days 14 and 21 of Induction Therapy, patients who achieve at least 5% bone marrow blasts after an optional bone marrow biopsy may receive a single 28-day cycle of cytarabine and daunorubicin with or without midostaurin per the treating physician. Patients who achieve a complete remission (CR) or complete remission with incomplete blood count recovery (CRi) may undergo allogeneic stem cell transplantation (SCT) or receive consolidation therapy.
CONSOLIDATION THERAPY:
PATIENTS < 60 YEARS: Patients receive high dose cytarabine (HiDAC) IV on days 1, 3, and 5 and gemtuzumab ozogamicin IV on day 1 of cycle 1 and midostaurin 50mg PO BID on days 8-21. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.
PATIENTS >= 60 YEARS: Patients receive cytarabine (MiDAC) IV on days 1, 3, and 5 and gemtuzumab ozogamicin IV on day 1 of cycle 1 and midostaurin 50mg PO BID on days 8-21. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.
All patients undergo echocardiogram (ECHO) during screening and as clinically indicated on the trial. Patients may undergo lumbar puncture (LP) at the discretion of the principal investigator (PI) or treating physician during screening. Patients also undergo bone marrow aspiration and blood sample collection during screening and on the trial.
After completion of study treatment, patients are followed up every 3 months for 24 months.
Lead OrganizationOhio State University Comprehensive Cancer Center
Principal InvestigatorUma M Borate
