Clinical Trials /

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

NCT03735875

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax and Quizartinib in Treating Patients With FLT3-mutated Recurrent or Refractory Acute Myeloid Leukemia
  • Official Title: A Phase Ib/II Study of Venetoclax in Combination With Quizartinib in FLT3-Mutated Acute Myelogenous Leukemia (AML)

Clinical Trial IDs

  • ORG STUDY ID: 2018-0608
  • SECONDARY ID: NCI-2018-02396
  • SECONDARY ID: 2018-0608
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03735875

Conditions

  • Acute Myeloid Leukemia With FLT3/ITD Mutation
  • FLT3 Gene Mutation
  • FLT3 Internal Tandem Duplication
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Leukemia

Interventions

DrugSynonymsArms
QuizartinibAC-220, AC010220, AC220Treatment (venetoclax, quizartinib)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, VenclextaTreatment (venetoclax, quizartinib)

Purpose

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, 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

      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 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 course 1. Treatment repeats every 28 days for up to 24 courses in the
      absence of disease progression or unacceptable toxicity. Patients may continue treatment
      beyond 24 courses 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (venetoclax, quizartinib)ExperimentalPatients receive quizartinib PO QD on days 1-28 and venetoclax PO QD beginning on day 8 of course 1. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Patients may continue treatment beyond 24 courses at the discretion of the treating physician.
  • Quizartinib
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  FLT3-ITD mutated patients with relapsed/refractory AML (up to two prior therapeutic
             regimens for AML i.e. up to salvage 2 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

          -  Calculated creatinine clearance >= 50 mL/min; determined via urine collection for
             24-hour creatinine clearance or by the Cockcroft Gault formula (or Modification of
             Diet in Renal Disease [MDRD] formula

          -  Patients must provide written informed consent

          -  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 brochure's, 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%

          -  Females must be surgically (including have undergone a hysterectomy, bilateral
             salpingectomy or bilateral oophorectomy); or biologically sterile or postmenopausal
             (amenorrheic for at least 12 months) or if of childbearing potential (considered as
             following menarche and until becoming postmenopausal no menstrual period for a minimum
             of 12 months), must have a negative serum or urine pregnancy test within 72 hours
             before the start of the treatment

          -  Women of childbearing potential must agree to use an adequate method of contraception
             during the study and until 90 days after the last treatment. Males must be surgically
             or biologically sterile or agree to use an adequate method of contraception during the
             study until 90 days after the last treatment. Adequate methods of contraception
             include: Total abstinence when this is in line with the preferred and usual lifestyle
             of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
             post-ovulation methods) and withdrawal are not acceptable methods of contraception.
             Female sterilization (have had surgical bilateral oophorectomy with or without
             hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
             case of oophorectomy alone, only when the reproductive status of the woman has been
             confirmed by follow up hormone level assessment

          -  Male sterilization (at least 6 months prior to screening). For female patients on the
             study, the vasectomized male partner should be the sole partner for that patient.
             Combination of any of the two following (a+b or a+c or b+c) a. Use of oral, injected
             or implanted hormonal methods of contraception or other forms of hormonal
             contraception that have comparable efficacy (failure rate <1%), for example hormone
             vaginal ring or transdermal hormone contraception b. Placement of an intrauterine
             device (IUD) or intrauterine system (IUS) c. Barrier methods of contraception: Condom
             or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal
             foam/gel/film/cream/vaginal suppository in case of use of oral contraception, women
             should have been stable on the same pill before taking study treatment

               -  Note: Oral contraceptives are allowed but should be used in conjunction with a
                  barrier method of contraception due to unknown effect of drug-drug interaction

          -  Women are considered post-menopausal and not of child bearing potential if they have
             had 24 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
             (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral
             oophorectomy (with or without hysterectomy) or tubal ligation that was done at least 6
             weeks prior to the planned start of protocol therapy. In the case of oophorectomy
             alone, only when the reproductive status of the woman has been confirmed by follow up
             hormone level assessment is she considered not of child bearing potential

        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 venetoclax or quizartinib at any time in the past

          -  Patients with known allergy or hypersensitivity to quizartinib, venetoclax or any of
             their components

          -  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

          -  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 prior to study entry, with the exception
             of: a. Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ
             of breast; b. Basal cell carcinoma of the skin or localized squamous cell carcinoma of
             the skin; c. Previous malignancy confined and surgically resected (or treated with
             other modalities) with curative intent. d. 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

               -  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)

               -  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

               -  Atrial fibrillation documented within 2 weeks prior to first dose of study drug

               -  Patients who are actively taking a moderate or strong CYP3A inhibitors
                  medication. Moderate and strong CYP3A4 inhibitors should be stopped at least 3
                  days prior to the first dose of quizartinib and are prohibited at any time on
                  study

               -  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

               -  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, except when
                  administered as standard premedication

               -  Known family history of congenital long QT syndrome
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) as determined by dose limiting toxicity (Phase Ib)
Time Frame:Up to 28 days
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Composite CRc rate including CR + CRp + CRi (Phase Ib)
Time Frame:Within 3 months of treatment initiation
Safety Issue:
Description:
Measure:Overall response rate (ORR) including CRc + partial remission (PR) (Phase Ib)
Time Frame:Within 3 months of treatment initiation
Safety Issue:
Description:
Measure:Duration of response (DOR) (Phase Ib)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Progression free survival (PFS) (Phase Ib)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Event-free survival (EFS) (Phase Ib)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Overall survival (OS) (Phase Ib)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Number of patients bridged to hematopoietic stem cell transplant (HSCT) (Phase Ib)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Median duration to HSCT (Phase Ib)
Time Frame:From the start of study treatment up to 5 years
Safety Issue:
Description:
Measure:Pharmacokinetic (PK) profile of Quizartinib: Cmax
Time Frame:7 days
Safety Issue:
Description:The PK of quizartinib summarized statistically as Cmax of quizartinib.
Measure:ORR (Phase II)
Time Frame:Within 3 months of treatment initiation
Safety Issue:
Description:
Measure:DOR (Phase II)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:PFS (Phase II)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:EFS (Phase II)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:OS (Phase II)
Time Frame:up to 5 years
Safety Issue:
Description:
Measure:Number of patients bridged to hematopoietic stem cell transplant (HSCT) (Phase II)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Median duration to HSCT (Phase II)
Time Frame:From the start of study treatment up to 5 years
Safety Issue:
Description:
Measure:Incidence of adverse events (Phase II)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Pharmacokinetic (PK) profile of Venetoclax: Cmax
Time Frame:Day -1 and Day 8
Safety Issue:
Description:The PK of venetoclax summarized statistically as Cmax.
Measure:Pharmacokinetic (PK) profile of Quizartinib: AUC0-24h
Time Frame:7 days
Safety Issue:
Description:The PK of quizartinib summarized statistically as AUC0-24h of quizartinib.
Measure:Pharmacokinetic (PK) profile of Venetoclax: AUC0-24h
Time Frame:Day -1 and Day 8
Safety Issue:
Description:The PK of venetoclax summarized statistically as AUC0-24h.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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