Phase I/II Study of the Combination of Quizartinib (AC220) With 5-Azacytidine or Low-Dose Cytarabine for the Treatment of Patients With Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)
Overview
- Phase
- Phase 1
- Intervention
- Azacitidine
- Conditions
- FLT3 Gene Mutation Negative
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 73
- Locations
- 1
- Primary Endpoint
- Maximum Tolerated Dose of Quizartinib (Phase I)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This phase I/II trial studies the side effects and best dose of quizartinib when given in combination with azacitidine or cytarabine in treating patients with acute myeloid leukemia or myelodysplastic syndrome that have come back (relapsed) or are not responding to treatment (refractory). Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine and cytarabine 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 with azacitidine or cytarabine may work better in patients with acute myeloid leukemia or myelodysplastic syndrome.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of the combination of quizartinib (AC220) with either azacitidine (5-azacitidine \[AZA\]) or low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). (Phase I) II. To determine the clinical activity of the combination of quizartinib with either AZA or LDAC in patients with AML or MDS. (Phase II) SECONDARY OBJECTIVES: I. To determine the clinical activity of the combination of quizartinib with either AZA or LDAC in patients with AML or MDS. (Phase I) II. To determine the safety of the combination of quizartinib with either AZA or LDAC in patients with AML or MDS. (Phase II) III. To determine the induction of hypomethylation, deoxyribonucleic acid (DNA) damage and FLT3 signaling during therapy with this combination and its correlation with response. (Phase I and II) IV. To determine the effect of this combination therapy on plasma levels of FLT3-ligand. (Phase I and II) V. To determine the pharmacodynamics of this combination therapy in patients with AML or high-risk MDS. (Phase I and II) OUTLINE: This is a phase I, dose-escalation study of quizartinib followed by a phase II study. Participants are assigned to 1 of 2 arms. ARM I: Patients receive quizartinib orally (PO) once daily (QD) on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and azacitidine subcutaneously (SC) or intravenously (IV) over 10-40 minutes on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and cytarabine SC twice daily (BID) on days 1-10. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6-12 months.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Refractory or relapsed disease defined as follows: patients with MDS or chronic myelomonocytic leukemia (CMML) should have failed prior therapy (e.g., with a hypomethylating agent, clofarabine, and/or with lenalidomide); patients with AML should have failed any prior induction therapy or have relapsed after prior therapy; patients (any age) with MDS or CMML who received therapy with a hypomethylating agent and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML. The World Health Organization (WHO) classification will be used for AML; patients with any of the eligible diagnoses who have received no prior therapy are eligible if not candidates to receive standard intensive therapy (i.e., high-dose cytarabine-based chemotherapy).
- •Patients are eligible regardless of their FLT3 mutation status.
- •COHORT 2A: Patients with MDS, CMML or AML who are either: age 60 years or older and newly diagnosed, previously untreated. Prior therapy with hydroxyurea or single agent ara-C for the purpose of control of white blood cells (WBC) is acceptable.; age 18 years or older and with refractory or relapse disease who have received no more than one prior treatment regimen and will be receiving first salvage. For this purpose, a second induction cycle with the same drugs used during the first cycle, consolidation chemotherapy or stem cell transplant in complete remission (CR) (or complete response with incomplete platelet recovery \[CRp\] or complete response with incomplete bone marrow recovery \[CRi\]) will be considered part of the prior regimen. Prior therapy for MDS (or other malignancies) is not considered a prior regimen for AML in patients who progress from MDS (or other malignancies).
- •COHORT 2A: Patients (any age) with MDS or CMML who received therapy with a hypomethylating agent and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML. The WHO classification will be used for AML.
- •COHORT 2A: Patients must have evidence of FLT3 ITD in their most recent assessment.
- •COHORT 2B: Patients with MDS, CMML or AML who are either: Age 60 years or older and newly diagnosed, previously untreated. Prior therapy with hydroxyurea or single agent ara-C for the purpose of control of WBC is acceptable or age 18 years or older and with refractory or relapse disease who have received no more than two prior treatment regimens and will be receiving second salvage, or who have received a prior SCT and will be receiving their first salvage. For this purposes, a second induction cycle with the same drugs used during the first cycle, consolidation chemotherapy or stem cell transplant in CR (or CRp or CRi) will be considered part of the prior regimen. Prior therapy for MDS (or other malignancies) is not considered a prior regimen for AML in patients who progress from MDS (or other malignancies)
- •COHORT 2B: Patients (any age) with MDS or CMML who received therapy with a hypomethylating agent and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML. The WHO classification will be used for AML
- •COHORT 2B: Patients must have no evidence of FLT3 mutations in their most recent assessment
- •PHASE I AND II
- •Eastern Cooperative Oncology Group (ECOG) performance status =\<
Exclusion Criteria
- •Patients with known allergy or hypersensitivity to quizartinib, mannitol, AZA, cytarabine or any of their components.
- •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 disease concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, cardiovascular disease including congestive heart failure, myocardial infarction within 6 months and poorly controlled hypertension, chronic renal disease, or active uncontrolled infection) which could compromise participation in the study. Patients with current active malignancies or any remission for \< 6 months, except patients with carcinoma in situ or with non-melanoma skin cancer who may have active disease or be in remission for less than 6 months.
- •Patients with a known confirmed diagnosis of human immunodeficiency virus (HIV) infection or active viral hepatitis.
- •Patients who have had any major surgical procedure within 14 days of day
- •Patients with known malignant disease of the central nervous system.
- •Impaired cardiac function including any of the following: screening electrocardiography (ECG) with a corrected QT (QTc) \> 450 msec. The QTc interval will be calculated by Fridericia's correction factor (QTcF) at screening and on day 5 prior to the first dose of AC
Arms & Interventions
Phase 1 Arm I (quizartinib, azacitidine)
Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and azacitidine SC or IV over 10-40 minutes on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Azacitidine
Phase 1 Arm I (quizartinib, azacitidine)
Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and azacitidine SC or IV over 10-40 minutes on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Quizartinib
Phase 1 Arm II (quizartinib, cytarabine)
Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and cytarabine SC BID on days 1-10. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Cytarabine
Phase 1 Arm II (quizartinib, cytarabine)
Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and cytarabine SC BID on days 1-10. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Quizartinib
Phase 2 Arm I (quizartinib, azacitidine)
Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and azacitidine SC or IV over 10-40 minutes on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Azacitidine
Phase 2 Arm I (quizartinib, azacitidine)
Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and azacitidine SC or IV over 10-40 minutes on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Quizartinib
Phase 2 Arm II (quizartinib, cytarabine)
Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and cytarabine SC BID on days 1-10. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Cytarabine
Outcomes
Primary Outcomes
Maximum Tolerated Dose of Quizartinib (Phase I)
Time Frame: At 28 days
Participants With a Response
Time Frame: At 56 days
(complete remission \[CR\]+complete response with incomplete bone marrow recovery \[CRI\]+partial remission \[PR\]+ hematologic improvement \[HI\]). Complete Rmission (CR) is bone marrow blasts of \</= 5%, platelets \>/= 100 and Absolute Neutrophil Count of \>/= 1000. complete response with incomplete bone marrow recovery \[CRI\] is is bone marrow blasts of \</= 5%, platelets \>/= 100 or Absolute Neutrophil Count of \>/= 1000. Hematologic improvement \[HI\]) is Bone Marrow Blasts \</= 5%. Partial remission \[PR\] is bone marrow blasts of \</= 5% with \> 50% reduction, platelets \>/= 100 and Absolute Neutrophil Count of \>/= 1000.