Clinical Trial 23058

• Overview

  Study Title:

  A Phase I/II Study of Quizartinib in Combination with Decitabine and Venetoclax for the Treatment of Patients with Acute Myeloid Leukemia (AML)

  Objective:

  Primary Objectives: 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 AML or high risk MDS (>10% blasts). To determine the safety and Maximum Tolerable Dose (MTD) of this combination. Secondary Objectives: 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% blasts). To determine the duration of response (DOR), event-free survival (EFS), overall survival (OS), MRD status at response and bst 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 hematopoetic stem cell transplant (HSCT) and median duration to HSCT from the initiation of the combination. To investigate correlations of response to this combination with a pre- therapy, on-therapy, and progression 81-gene panel of gene mutations in AML.

• Treatments

  Therapies:

  Chemotherapy (NOS); Therapy (NOS)

  Medications:

  GDC-0199 (Venetoclax); Quizartinib (); Venetoclax (); decitabine (5-aza-2'-deoxycytidine)

• Inclusion Criteria

  Key Inclusion Criteria:
  • Diagnosis of 1) Newly diagnosed AML (WHO classification definition of ≥20% blasts, excluding acute promyelocytic leukemia (APL)), or 2) For relapsed AML, blast >/= 5% by ELN definition, or 3) MDS with >10% blasts (defined by the 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.
  • Patients with newly diagnosed AML with poor risk complex karyotype and/or TP53 deletions/mutations equal or younger than 60 year old.
  • For relapsed cohort: Patients aged ≥18 years old, (Patients who are candidates for relapse cohort will be enrolled into the study regardless of their fitness for intensive chemotherapy).
  • Patients with FLT3-ITD mutation or FLT3-ITD/TKD co-mutations in bone marrow and/or peripheral blood samples within 30 days prior to study enrollment will be enrolled in cohort A (newly diagnosed) or cohort B (relapsed/refractory). Patients with no detectable FLT3-ITD mutation or FLT3-ITD/TKD co-mutations in bone marrow and/or peripheral blood samples within 30 days prior to study enrollment will be enrolled in cohort C (newly diagnosed).
  • For frontline cohorts: Patients must be chemonaïve, i.e., not have received any chemotherapy (except hydrea or ara-C for transient control of hyperleukocytosis) for AML or MDS. They may have received transfusions, hematopoietic growth factors or vitamins for an antecedent hematological disorder (AHD) or for AML. Temporary prior measures such as apheresis, ATRA, steroids or hydrea while diagnostic work-up is being performed are allowed and not counted as a prior salvage. Supportive care therapy for MDS (growth factors, transfusions) will not be considered as prior therapy for MDS/AML and these patients will be enrolled to the frontline cohort of the study if they are otherwise eligible.
  • For relapsed cohort: Patients who have received at least one prior therapy for AML or for MDS with >10% blasts will be eligible. Patients may have received prior salvages for AML and/or MDS (defined by the IPSS classification). Prior therapy for AML or MDS will be counted as a prior salvage. Patients who receive MDS directed therapies considered not purely supportive such as HMAs, lenalidomide, investigational therapies, will be enrolled to the salvage cohort if they are otherwise eligible.
  • In the absence of rapidly progressing disease, the interval from prior treatment to time of initiation of protocol therapy will be at least 2 weeks for cytotoxic agents or at least 5 half-lives for cytotoxic/noncytotoxic agents (whichever is shorter). 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: (1) intrathecal (IT) therapy for patients with controlled CNS leukemia at the discretion of the PI. (2) Use of one or more doses of cytarabine (total dose up to 2 g/m2 ) or hydroxyurea for patients with rapidly proliferative disease is allowed before the start of study therapy and for the first four weeks on therapy. These medications will be recorded in the case-report form.
  • ECOG performance status ≤2.
  • Serum biochemical values with the following limits unless considered due to leukemia, hemolysis or congenital disorder (Creatinine > Other inclusion criteria may apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Patients with known allergy or hypersensitivity to quizartinib, venetoclax, mannitol, decitabine or any of their components.
  • Patients with known uncontrolled CNS leukemia.
  • Only for frontline cohort: Patients who are fit for intensive chemotherapy.
  • Patients with electrolyte abnormalities at study entry.
  • 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 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., 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.
  • Patients who have had any major surgical procedure within 14 days of Day 1.
  • Impaired cardiac function.
  • Other exclusion criteria may apply.

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