Venetoclax and Quizartinib in Treating Patients With FLT3-mutated Recurrent or Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This phase Ib/II trial studies the side effects and best dose of venetoclax in combination with quizartinib and how well they work in treating patients with acute myeloid leukemia that has come back or does not respond to treatment, and who are FLT3-mutation positive. Venetoclax and quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of the combination of venetoclax with quizartinib in FLT3-internal tandem duplication (ITD) mutated patients with relapsed/refractory acute myeloid leukemia (AML). (Phase Ib) II. To determine the composite complete remission (CR) (CRc) rate including CR + CRp (complete remission with incomplete platelet recovery) + CRi (complete remission with incomplete count recovery) within 3 months of treatment initiation in FLT3-ITD mutated patients with relapsed/refractory AML. (Phase II) SECONDARY OBJECTIVES: I. To determine the composite CRc rate including CR + CRp + CRi within 3 months of treatment initiation in FLT3-ITD mutated patients with relapsed/ refractory AML. (Phase Ib) II. To determine the overall response rate (ORR) including CRc + partial remission (PR) within 3 months of treatment initiation in FLT3-ITD mutated patients with relapsed/refractory AML. (Phase Ib) III. To determine the duration of response (DOR), progression free survival, event-free survival (EFS), overall survival (OS), and number of patients bridged to hematopoietic stem cell transplant (HSCT) and median duration to HSCT from the initiation of the combination in FLT3-ITD mutated patients with relapsed/ refractory AML. (Phase Ib) IV. To characterize the pharmacokinetic (PK) profiles of combination therapy of venetoclax and quizartinib in FLT3-ITD mutated patients with relapsed/refractory AML. (Phase Ib) V. To determine the ORR within 3 months of treatment initiation in FLT3-ITD mutated patients with relapsed/ refractory AML. (Phase II) VI. To determine the DOR, progression-free survival (PFS), EFS, OS, and number of patients bridged to HSCT and median duration to HSCT from the initiation of the combination in FLT3-ITD mutated patients with relapsed/refractory AML. (Phase II) VII. To determine the safety and tolerability of the combination in FLT3-ITD mutated patients with relapsed/refractory AML. (Phase II) EXPLORATORY OBJECTIVES: I. To investigate possible relationships between baseline next generation gene sequencing and clinical response to the combination. II. To investigate quantitative changes of FLT3-ITD allelic burden with time and the extent of pharmacodynamics biomarker (such as phosphorylated [p]-FLT3, p-ribosomal protein S6 kinase beta-1 [p70S6K], pERK, pSTAT) inhibition, and the induction of apoptosis in the bone marrow and peripheral blasts in patients treated with the combination. III. To investigate possible relationships between baseline gene expression signatures, Bcl-2 family messenger ribonucleic acid (mRNA) and protein levels of AML blasts and/or stem cell sub-population, BH3 profiling of Bcl-2 family member dependency and ex vivo functional screen and clinical response to the combination. IV. To analyze immune modulation including alterations in total and percent of CD3+ T-cells, total and percent of various T-cell subsets (CD4-effector, CD4-regs, CD8 cytotoxic T-cells), and total and percent of T-cell/T-cell subsets expressing specific checkpoint receptors/ligands with the combination. V. To store and/or analyze surplus blood or tissue including bone marrow, if available, for potential future exploratory research into molecular and immune factors that may influence response to venetoclax and/or quizartinib (where response is defined broadly to include efficacy, tolerability or safety). OUTLINE: This is a phase Ib dose-escalation study of quizartinib, followed by a phase II study. Patients receive quizartinib orally (PO) once daily (QD) on days 1-28 and venetoclax PO QD beginning on day 8 of cycle 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment beyond 24 cycles at the discretion of the treating physician. After completion of study treatment, patients are followed up at 30 days and then every 3-6 months for up to 5 years.

Official Title
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A Phase Ib/II Study of Venetoclax in Combination With Quizartinib in FLT3-Mutated Acute Myelogenous Leukemia (AML)

Conditions
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Acute Myeloid Leukemia With FLT3/ITD Mutation, Recurrent Acute Myeloid Leukemia, Refractory Acute Leukemia

Intervention / Treatment
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* Drug: Quizartinib
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: FLT3-ITD mutated patients with relapsed/refractory AML (up to four prior therapeutic regimens for AML i.e. up to salvage 4 AML), including patients who may have been previously exposed to prior FLT3-inhibitor/s other than quizartinib (stem cell transplant [SCT] or stem cell therapy for patients who previously underwent SCT/stem cell therapy in remission will not be considered a salvage regimen) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Serum direct bilirubin =< 1.5 x upper limit normal (ULN) (or =< 3.0 x ULN if deemed to be elevated due to leukemia) Alanine aminotransferase and/or aspartate aminotransferase (aspartate transaminase) =< 2.5 x ULN (or =< 5.0 x ULN if deemed elevated due to leukemia) Subjects with documented Gilbert's Syndrome may have a total bilirubin > 1.5 x ULN Potassium levels should be within institutional normal limits Magnesium levels should be within institutional normal limits Calcium (normalized for albumin) levels should be within institutional normal limits Adequate renal function as demonstrated by a serum creatinine =< 1.8 Patients must provide written informed consent With the exception of patients with rapidly proliferative disease, the interval from prior treatment to time of initiation of venetoclax and quizartinib administration will be at least 14 days or at least 5 half-lives (whichever is shorter) for cytotoxic/noncytotoxic agents. The half-life for the therapy in question will be based on published pharmacokinetic literature (abstracts, manuscripts, investigator brochures, or drug-administration manuals) and will be documented in the protocol eligibility document. The use of chemotherapeutic or anti-leukemic agents is not permitted during the study with the following exceptions: Intrathecal (IT) therapy for patients with controlled central nervous system (CNS) leukemia at the discretion of the principal investigator (PI). Controlled CNS leukemia is defined by the absence of active clinical signs of CNS disease and no evidence of CNS leukemia on the most recent 2 simultaneous cerebrospinal fluid (CSF) evaluations Use of one dose of cytarabine (up to 2 g/m^2) or hydroxyurea for patients with rapidly proliferative disease is allowed before the start of study therapy and on therapy. These medications will be recorded in the case-report form Baseline ejection fraction by echocardiogram (ECHO) or multigated acquisition scan (MUGA) must be >= 50% Women of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy Women of childbearing potential must agree to have a negative serum or beta human chorionic gonadotropin (beta-hCG) pregnancy test result within 7 days prior to the first dose of study drugs and must agree to use an effective contraception method during the study and for 90 days following the last dose of the study. Men who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 90 days following the last dose of study drug Exclusion Criteria: Subject has t(8;21) or inv(16) karyotype abnormalities Subject has acute promyelocytic leukemia (French-American-British Class M3 AML) Prior exposure to quizartinib at any time in the past 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 allergy or hypersensitivity to quizartinib, venetoclax or any of their components Subject with a known history of being human immunodeficiency virus (HIV) positive (due to potential drug-drug interactions between antiretroviral medications and venetoclax, as well as anticipated venetoclax mechanism-based lymphopenia that may potentially increase the risk of opportunistic infections) Note: HIV testing is not required Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit within 3 days prior to the initiation of study treatment Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator and/or the PI would adversely affect his/her participating in this study. Patients who have had any major surgical procedure within 14 days of day 1 Subject has a malabsorption syndrome or other condition that precludes enteral route of administration Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to: a. Uncontrolled systemic infection requiring intravenous (IV) therapy (viral, bacterial or fungal). Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines is acceptable. Patients with neutropenic fever considered infection related should be afebrile for at least 72 hours prior to first dose Subject has a history of other malignancies within 1 year prior to study entry, with the exception of: Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent 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 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 hepatitis B virus (HBV) (i.e., hepatitis B surface antigen negative [HBs Ag-], and hepatitis B surface antibody positive [anti-HBs+]) may participate Female subjects who are pregnant or breastfeeding Impaired cardiac function including any of the following: Screening electrocardiogram (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 1 prior to the first dose of quizartinib. The QTcF will be derived from the average QTcF in triplicate. If QTcF > 450 msec on day 1, quizartinib will not be given. Patients with congenital long QT syndrome History or presence of sustained ventricular tachycardia requiring medical intervention within 3 months prior to starting study drug Any history of clinically significant ventricular fibrillation or torsades de pointes Known history of second or third degree heart block (may be eligible if the patient currently has a pacemaker) within 3 months prior to starting study drug Sustained heart rate of < 50/minute on screening or day 1 ECG Right bundle branch block + left anterior hemiblock (i.e. bifascicular block) Isolated right bundle branch block (RBBB) will not be an exclusion criterion Complete left bundle branch block Patients with myocardial infarction or unstable angina within 6 months prior to starting study drug Congestive heart failure (CHF) New York (NY) Heart Association class III or IV within 3 months prior to starting study drug Atrial fibrillation documented within 2 weeks prior to first dose of study drug Patients who are actively taking CYP3A inducers. CYP3A4 inducers should be stopped at least 3 days prior to the first dose of quizartinib and are prohibited at any time on study. Moderate and strong CYP3A4 inhibitors should be stopped at least 3 days prior to the first dose of quizartinib and are prohibited during cycle 1. Moderate (but not strong) CYP3A4 inhibitors may be used with the below dose reductions of venetoclax after cycle 1. Patients may receive weak CYP3A4 inhibitors at any time on study. The venetoclax and quizartinib doses do not need to be adjusted for weak CYP3A4 inhibitors Patients who require treatment with concomitant drugs that prolong QT/QTc interval. QT/QTc prolonging drugs should be stopped at least 3 days prior to the first dose of quizartinib and are prohibited at any time on study Known family history of congenital long QT syndrome

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (venetoclax, quizartinib)<br>Patients receive quizartinib PO QD on days 1-28 and venetoclax PO QD beginning on day 8 of cycle 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment beyond 24 cycles at the discretion of the treating physician. | Drug: Quizartinib<br>* Given PO<br>* Other names: AC220;Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) as determined by dose limiting toxicity (Phase Ib) |  | Up to 28 days | 
| Recommended phase II dose as determined by MTD (Phase Ib) |  | Up to 28 days | 
| Composite complete remission rate (CRc) rate including CR + complete remission with incomplete platelet recovery (CRp) + complete remission with incomplete count recovery (CRi) (Phase II) |  | Within 3 months of treatment initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite CRc rate including CR + CRp + CRi (Phase Ib) |  | Within 3 months of treatment initiation | 
| Overall response rate (ORR) including CRc + partial remission (PR) (Phase Ib) |  | Within 3 months of treatment initiation | 
| Duration of response (DOR) (Phase Ib) |  | Up to 5 years | 
| Progression free survival (PFS) (Phase Ib) |  | Up to 5 years | 
| Event-free survival (EFS) (Phase Ib) |  | Up to 5 years | 
| Overall survival (OS) (Phase Ib) |  | Up to 5 years | 
| Number of patients bridged to hematopoietic stem cell transplant (HSCT) (Phase Ib) |  | Up to 5 years | 
| Median duration to HSCT (Phase Ib) |  | From the start of study treatment up to 5 years | 
| Characterization of pharmacokinetic profiles (Phase Ib) |  | Up to 5 years | 
| ORR (Phase II) |  | Within 3 months of treatment initiation | 
| DOR (Phase II) |  | Up to 5 years | 
| PFS (Phase II) |  | Up to 5 years | 
| EFS (Phase II) |  | Up to 5 years | 
| OS (Phase II) |  | up to 5 years | 
| Number of patients bridged to hematopoietic stem cell transplant (HSCT) (Phase II) |  | Up to 5 years | 
| Median duration to HSCT (Phase II) |  | From the start of study treatment up to 5 years | 
| Incidence of adverse events (Phase II) |  | Up to 5 years |