Decitabine and Talazoparib in Untreated AML and R/R AML
Condition: Acute Myeloid Leukemia
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The purpose of this study is to find the best way to combine a new chemotherapy drug with one
      that is already in use to treat AML. The new experimental drug is called talazoparib (also
      known as BMN-673), and it is not approved by the Federal Drug Administration (FDA). The FDA
      is allowing the use of talazoparib for the purposes of this study.

      Decitabine is used to treat bone marrow diseases called myelodysplastic syndromes (MDS), as
      well as off label for AML.

      Lab work suggests that talazoparib will increase the effects of decitabine in leukemia cells.

      Investigators hope that treating patients with decitabine and talazoparib together will be
      more successful that treating patients with decitabine alone.

      This study has two parts. The purpose of part one the study is to find out the best doses of
      decitabine and talazoparib to use when they are given together to treat AML. The purpose of
      part two is to see how well the drugs work together to treat AML.

      All participants in the study will be treated with decitabine and talazoparib.

      Part one of the study will include as few as two people and as many as 36 people to find the
      best dose levels of the study drugs. Part one will begin enrolling first. Part two of the
      study will not start until the Part one of the study is complete. Participants will be told
      which part of the study they may be enrolled in. Part two of the study may include as few as
      79 people and as many as 135 people. Part two includes three separate arms. Participants
      enrolled in Part two of the study, will be assigned to one of the three arms below in order
      to test the success rate of the study drug dose determined by Part one:

        -  Arm A will enroll adult patients with AML who are thought not to be likely to tolerate
           or respond to standard chemotherapy;

        -  Arm B will enroll adult patients with AML that has not responded to previous treatment
           or has come back after responding to previous treatment;

        -  Arm C will enroll adult patients previously treated with a DNA methyltransferase
           inhibitor (decitabine, azacitidine or guadecitabine).

      This is a multi-center study. Up to 171 people may take part in this study globally.
    

Detailed description: 
      In this clinical trial, investigators combine decitabine and talazoparib in the treatment of
      patients with AML. Decitabine will be given in the established regimen of IV daily dosing for
      5 days every 28 days. Talazoparib will be initiated orally daily on a continuous basis,
      beginning on Day 1 of Course 1. In this phase 1 trial, decitabine and talazoparib will be
      tested at 3 and 4 dose levels, respectively, yielding up to 6 combinations. Doses will be
      escalated based on tolerability using a 'classic' 3+3 design. Once the MTD for decitabine
      combined with 0.25 mg talazoparib is established, the dose of talazoparib will be escalated
      with the dose of decitabine kept fixed at the provisional MTD dose. There is no further
      stepping up or down of the drugs in the combination.

      The regimen for phase 2 testing will be chosen based on tolerability, but also based on
      available pharmacodynamic and efficacy data. In phase 2, the selected combination regimen
      will be studied for efficacy.

      Each patient will be treated until occurrence of either unacceptable toxicity or disease
      progression. Bone marrow aspirate and biopsy will be performed on approximately day 28 of
      each treatment course unless circulating blasts persist in the peripheral blood, until
      documentation of CR or CRi. Bone marrow aspirate and biopsy will then be repeated at time of
      clinical concern for disease progression.

      In Phase 1, the clinical trial will enroll patients with relapsed and refractory AML in order
      to test the novel combination initially in patients with less favorable outcomes with
      decitabine alone. This is being done to avoid the possibility of compromising the outcomes of
      untreated patients, who have up to a 40% response rate to 5-day decitabine as a single agent,
      in the unlikely possibility that the combination is inferior. The regimen will then also be
      tested in previously untreated AML patients unfit for chemotherapy in phase 2.
    

Intervention name(s): Decitabine; talazoparib
Intervention type(s): Drug; Drug
Intervention description(s): DNA methyltransferase inhibitor; poly ADP ribose polymerase (PARP) inhibitor
Other intervention name(s): dacogen; BMN673; MDV3800
Intervention MeSH terms: Decitabine; Talazoparib
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: AML