A Phase I/II Study of Quizartinib in Combination With Decitabine and Venetoclax for the Treatment of Patients With Acute Myeloid Leukemia (AML)
Overview
- Phase
- Phase 1
- Intervention
- Decitabine
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 73
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose of the combination drugs (Phase I)
- Status
- Recruiting
- Last Updated
- 3 months ago
Overview
Brief Summary
This phase I/II trial studies how well quizartinib, decitabine, and venetoclax work in treating participants with acute myeloid leukemia or high risk myelodysplastic syndrome that is untreated or has come back (relapsed). Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as decitabine and venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving quizartinib and decitabine may work better at treating acute myeloid leukemia and myelodysplastic syndrome.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the overall response rate (ORR) including CR (complete remission) + CRp (complete remission with incomplete platelet recovery) + CRi (complete remission with incomplete count recovery) + partial remission (PR) within 3 months of treatment initiation of quizartinib and decitabine + venetoclax combination in patients with newly diagnosed or relapsed acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS) (\> 10% blasts). II. To determine the safety and maximum tolerable dose (MTD) of this combination. SECONDARY OBJECTIVES: I. To determine CR and CR+CRh rates within 3 months of treatment initiation of quizartinib and decitabine + venetoclax combination in patients with newly diagnosed or relapsed AML or high risk MDS (\> 10% blast). II. To determine the duration of response (DOR), event-free survival (EFS), overall survival (OS), MRD status at response and best MRD response attained by flow-cytometry (all patients) and by FLT3-PCR (if applicable) or variant allele frequency monitoring (if applicable) and number of patients bridged to hematopoietic stem cell transplant (HSCT) and median duration to HSCT from the initiation of the combination. III. To investigate correlations of response to this combination with a pre-therapy, on-therapy, and progression 81-gene panel of gene mutations in AML. EXPLORATORY OBJECTIVES: I. To investigate possible relationships between response and non-response to the combination with pretherapy, on-therapy, and progression gene expression signatures. II. To investigate the characterization of genetic heterogeneity in tumor cell populations, by performing targeted single-cell sequencing on longitudinally collected AML tumor populations from patients using a novel microfluidic approach that barcodes amplified genomic DNA from thousands of individual leukemia cells confined to droplets (single cell sequencing). III. To identify individual treatment-resistant cell populations and how their signaling state in disease relates to clinical outcomes we will perform CyTOF (mass cytometry) on patients' bone marrow samples and peripheral blood at diagnosis, remission and relapse. IV. To store and/or analyze surplus blood or tissue including bone marrow, if available, for potential future exploratory research into factors that may influence development of AML and/or response to the combination (where response is defined broadly to include efficacy, tolerability or safety). OUTLINE: This is a phase I, dose escalation study followed by a phase II study. Patients receive decitabine intravenously (IV) over 1 hour on days 1-10, quizartinib orally (PO) every day beginning on day 1 of cycle 1, and venetoclax PO on days 1-14 (days 1-21 if persistent leukemia). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3-6 months for up to 5 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Diagnosis of 1) AML (World Health Organization \[WHO\] classification definition of \>= 20% blasts) excluding acute promyelocytic leukemia (APL) or 2) MDS with \> 10% blasts (defined by the International Prognostic Scoring System \[IPSS\] classification).
- •For frontline Cohort: Patients aged \>= 60 years old who are not candidates for intensive induction therapy and agree to receive the proposed combination therapy will be enrolled.
- •Not considered candidates for intensive remission induction chemotherapy at time of enrollment based on EITHER:
- •75 years of age OR
- •\< 75 years of age with at least 1 of the following:
- •Poor performance status (Eastern Cooperative Oncology Group \[ECOG\]) score of 2-
- •Clinically significant heart or lung comorbidities, as reflected by at least 1 of:
- •Left ventricular ejection fraction (LVEF) =\< 50%.
- •Lung diffusing capacity for carbon monoxide (DLCO) =\< 65% of expected.
- •Forced expiratory volume in 1 second (FEV1) =\< 65% of expected.
Exclusion Criteria
- •Patients with known allergy or hypersensitivity to quizartinib, mannitol, decitabine or any of their components.
- •Prior quizartinib use.
- •Patients with known uncontrolled CNS leukemia.
- •Only for frontline cohort: patients who are fit for intensive chemotherapy.
- •Patients with electrolyte abnormalities at study entry defined as follows: Serum potassium \< 3.5 mEq/L despite supplementation, or \> 5.5 mEq/L Serum magnesium above or below the institutional normal limit despite adequate management. Serum calcium (corrected for albumin levels) above or below institutional normal limit despite adequate management.
- •Patients with known significant impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of quizartinib.
- •Patients with any other known concurrent severe and/or uncontrolled medical condition including but not limited to diabetes, cardiovascular disease including hypertension, renal disease, or active uncontrolled infection, which could compromise participation in the study. Patients on active antineoplastic or radiation therapy for a concurrent malignancy at the time of screening. Maintenance therapy, hormonal therapy, or steroid therapy for well-controlled malignancy is allowed.
- •Patients with a known human immunodeficiency virus (HIV) infection.
- •Patients with known positive hepatitis B or C infection by serology, with the exception of those with an undetectable viral load within 3 months. (Hepatitis B or C testing is not required prior to study entry). Subjects with serologic evidence of prior vaccination to HBV \[i.e., hepatitis B surface antigen \[HBs Ag\]-, and anti-HBs+\] may participate.
- •Patients who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment.
Arms & Interventions
Treatment (decitabine, quizartinib, venetoclax)
Patients receive decitabine IV over 1 hour on days 1-10, quizartinib PO every day beginning on day 1 of cycle 1, and venetoclax PO on days 1-14 (days 1-21 if persistent leukemia). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Decitabine
Treatment (decitabine, quizartinib, venetoclax)
Patients receive decitabine IV over 1 hour on days 1-10, quizartinib PO every day beginning on day 1 of cycle 1, and venetoclax PO on days 1-14 (days 1-21 if persistent leukemia). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Quizartinib
Treatment (decitabine, quizartinib, venetoclax)
Patients receive decitabine IV over 1 hour on days 1-10, quizartinib PO every day beginning on day 1 of cycle 1, and venetoclax PO on days 1-14 (days 1-21 if persistent leukemia). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Venetoclax
Outcomes
Primary Outcomes
Maximum tolerated dose of the combination drugs (Phase I)
Time Frame: Up to 28 days
Incidence of adverse events (Phase II)
Time Frame: Within 3 months
Overall response rate (ORR) including CR (complete remission) + CRp (complete remission with incomplete platelet recovery) + CRi (complete remission with incomplete count recovery) + partial remission (PR) (Phase II)
Time Frame: Within 3 months