Clinical Trials /

Talazoparib for Cohesin-Mutated AML and MDS With Excess Blasts

NCT03974217

Description:

This research study is testing if Talazoparib is an effective treatment for patients with AML and MDS that have a mutation in the cohesin complex.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Talazoparib for Cohesin-Mutated AML and MDS With Excess Blasts
  • Official Title: A Pilot Proof-of-Concept Study of Talazoparib for Cohesin-Mutated AML and MDS With Excess Blasts

Clinical Trial IDs

  • ORG STUDY ID: 19-152
  • NCT ID: NCT03974217

Conditions

  • Leukemia

Interventions

DrugSynonymsArms
TalazoparibTalzennaTalazoparib

Purpose

This research study is testing if Talazoparib is an effective treatment for patients with AML and MDS that have a mutation in the cohesin complex.

Detailed Description

      This research study is a Pilot Study, which is the first time investigators are examining
      this study drug for a selected subgroup of patients with AML and MDS whose disease features a
      mutation in the cohesin complex.

      The FDA (the U.S. Food and Drug Administration) has approved Talazoparib as a treatment for
      certain kinds of breast cancer. It is not currently approved for treating your disease.

      Talazoparib is a drug that stops the activity of a protein called poly (adenosine diphosphate
      [ADP]-ribose) polymerase or PARP. PARP is involved in repairing damage to the DNA within your
      cells. DNA is the set of instructions found within all of your cells that tells them how to
      behave. The DNA is damaged all the time by things around in the environment, and is repaired
      by several different methods, one of which uses PARP. When PARP is turned off by Talazoparib
      in the normal cells, other methods can still work to repair damage to DNA. However, in some
      cancer cells these other methods are broken and cannot be used. When PARP is turned off by
      Talazoparib in these cancer cells, DNA damage cannot be repaired and leads to the death of
      the cancer cells. Talazoparib is a drug that is safe and active in breast cancer and
      gynecologic cancers. However, there were no responses among 33 unselected patients with
      hematologic malignancies, including 21 with AML (acute myeloid leukemia) and 4 with MDS
      (myelodysplastic syndrome), when they received treatment with Talazoparib by itself. It is
      not known if there were any patients with cohesin-mutations that were on the clinical trial
      (these mutations are rare).

      In this research study, the investigators are testing if Talazoparib is an effective
      treatment for patients with AML and MDS that have a mutation in the cohesin complex. The
      cohesin complex is made up of a group of proteins that are critical for normal DNA
      replication activity. Mutations in the cohesin complex occur in patients with MDS/AML and may
      represent a new therapeutic target. In a chemical screen experiment in a Dana-Farber Cancer
      Institute laboratory, the investigators found that leukemia cells featuring a mutated cohesin
      complex were sensitive to Talazoparib (meaning the leukemia cells went away after treatment
      with Talazoparib) by a mechanism called synthetic lethality (this means that the lab
      experiments showed that leukemia cells with a mutation in cohesin were dependent on PARP
      activity to survive; when inhibiting PARP with a PARP inhibitor like Talazoparib, the
      leukemia cells died). The investigators thus identified Talazoparib to be a possible
      treatment for actual patients with MDS or AML that have a mutation in cohesin complex.
    

Trial Arms

NameTypeDescriptionInterventions
TalazoparibExperimentalTalazoparib is administered orally on a daily basis Hydroxyurea is allowed for up to two cycles per institutional guidelines
  • Talazoparib

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must be considered ineligible to receive intensive chemotherapy by
             treating investigator and must have a diagnosis of one of the following:

               -  Secondary AML (can be untreated secondary AML if previously treated for MDS,
                  MDS/MPN, or any MPN with any anti-leukemic therapy; or previously treated
                  secondary AML)

               -  Relapsed or refractory AML or relapsed/refractory AML without available approved
                  AML therapy

               -  MDS with a minimum history of at least 4 cycles of decitabine or 6 cycles of
                  azacitidine or sooner if they experience intolerance/progression while on
                  HMA-based therapy.

          -  Participants must have measurable disease defined as 5% or more blasts (blood or bone
             marrow).

          -  Age 18 years and older.

          -  ECOG performance status ≤2 (see Appendix A)

          -  Participants must have normal organ function as defined below:

               -  total bilirubin ≤ 2.5 × institutional upper limit of normal (unless considered to
                  be secondary to leukemia)

               -  AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal (unless
                  considered to be secondary to leukemia)

               -  creatinine clearance ≥ 60 mL/min/1.73 m2

          -  Documented pathogenic mutation in cohesin complex including a mutation in STAG2,
             SMC1A, RAD21, PDS5B, or SMC3 gene from a CLIA-approved test (local testing allowed;
             will be centrally confirmed). Patient must have a minimum VAF of 5%. Historical
             testing (up to 3 months) allowed for treatment start on study as long as no
             disease-modifying agent was received since testing.

          -  The effects of Talazoparib on the developing human fetus are unknown. For this reason
             and because PARP inhibitor agents are suspected to be teratogenic, women of
             child-bearing potential and men must agree to use adequate contraception (hormonal or
             barrier method of birth control; abstinence) prior to study entry and for the duration
             of study participation. Should a woman become pregnant or suspect she is pregnant
             while she or her partner is participating in this study, she should inform her
             treating physician immediately. Men treated or enrolled on this protocol must also
             agree to use adequate contraception prior to the study, for the duration of the study
             participation, and 4 months after completion of Talazoparib administration.

          -  Patients must have a white blood cell count < 10 K/uL by date of registration.

          -  For women of child bearing potential only, must have a negative urine or serum
             pregnancy test.

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Participants who have had chemotherapy within 2 weeks prior to registering for the
             study or those who have not recovered from adverse events (to at least grade 1 with
             exception of alopecia) due to agents administered more than 2 weeks earlier. Patients
             must not have required cytoreductive therapy within 2 weeks of starting study drug
             except for hydroxyurea. Prior palliative radiotherapy is permitted if completed within
             5 days prior to study registration and patient has no clinically significant
             toxicities such as mucositis or esophagitis.

          -  No limitations to prior therapy. However, patient may not have received prior PARP
             inhibitor for any indication. If a patient is post allogeneic hematopoietic stem cell
             transplant, he/she must be > 2 months from day of donor cell infusion to date of study
             registration. They must be off immunosuppression therapy for at least 14 days prior to
             registration (topical steroids are permitted).

          -  Participants who are receiving any other investigational agents.

          -  Participants with known CNS leukemia.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements or compromise safety assessment, in the judgement of the
             investigator.

          -  Pregnant women are excluded from this study because Talazoparib is a PARP inhibitor
             agent with the potential for teratogenic or abortifacient effects. Because there is an
             unknown but potential risk for adverse events in nursing infants secondary to
             treatment of the mother with Talazoparib, breastfeeding should be discontinued if the
             mother is treated with Talazoparib. These potential risks may also apply to other
             agents used in this study.

          -  Patient has known active HIV, HCV or HBV.

          -  Patients with prior malignancy are eligible however patient must either be in
             remission from prior malignancy OR have inactive (note: meaning they do not require
             treatment) and asymptomatic disease. Maintenance therapy such as hormone therapy is
             allowed
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of participants with ≥ 50% leukemic blast reduction with Talazoparib monotherapy as a marker of anti-leukemic activity.
Time Frame:1 year
Safety Issue:
Description:The investigators will measure the reduction in bone marrow blast percentage before and after therapy at the end of cycle 1 and determine the proportion of patients who have a 50% or greater reduction.

Secondary Outcome Measures

Measure:Number of participants with reduction in blasts over time on study treatment
Time Frame:1 year
Safety Issue:
Description:The investigators will measure the changes in bone marrow blast percentage at day +15, end of cycle 1, end of cycle 2 and every other cycle to determine the best response to talazoparib.
Measure:To evaluate for the rate of relative and absolute cohesin mutation clearance on treatment (changes in VAF) in participants
Time Frame:1 year
Safety Issue:
Description:Using next-generation sequencing techniques, the investigators will measure for changes in variant allele frequency of the cohesin mutation while on talazoparib and determine if mutant VAF reduction correlates with blast reduction
Measure:Determine overall response rate in study participants
Time Frame:1 year
Safety Issue:
Description:The investigators will determine the best disease response according to IWG response criteria for MDS and ELN response criteria for AML
Measure:To determine the tolerability of Talazoparib in AML and MDS in participants
Time Frame:1 year
Safety Issue:
Description:The investigators will capture the AEs on and attribution to characterize the safety and toxicity profile of talazoparib in patients with AML or MDS

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Leukemia

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