Decitabine and Talazoparib in Untreated AML and R/R AML
Decitabine and Talazoparib in Untreated AML and R/R AML
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.
In this clinical trial, invvestigators 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.
Inclusion Criteria:

 1. Diagnosis of AML based on 2008 WHO criteria. AML may be de novo, following a prior
 hematologic disorder, including MDS or Philadelphia chromosome-negative
 myeloproliferative neoplasm, and/or therapy-related.

 2. PHASES 1 AND 2: Patients with AML that has relapsed after, or is refractory to,
 first-line therapy, with or without subsequent additional therapy, and are currently
 considered unfit for, or unlikely to respond to, cytotoxic chemotherapy.

 3. PHASE 2 ONLY: Patients previously untreated for AML who are considered unfit for
 cytotoxic chemotherapy by virtue of performance status, comorbidities, advanced age
 and/or low likelihood of response based on disease characteristics, or who decline
 cytotoxic induction chemotherapy.

 4. Patients who have undergone autologous stem cell transplantation (autoSCT) are
 eligible provided that they are ≥ 4 weeks from stem cell infusion.

 5. Patients who have undergone allogeneic SCT (alloSCT) are eligible if they are ≥ 60
 days from stem cell infusion, have no evidence of graft versus host disease (GVHD) >
 Grade 1, and are ≥ 2 weeks off all immunosuppressive therapy.

 6. Previous cytotoxic chemotherapy must have been completed at least 3 weeks and
 radiotherapy at least 2 weeks prior to Day 1 of treatment on the study, and all
 adverse events (excluding alopecia) due to agents administered more than 4 weeks
 earlier should have recovered to < Grade 1. Patients with hematologic malignancies are
 expected to have hematologic abnormalities at study entry. Hematologic abnormalities
 that are thought to be primarily related to leukemia are not considered to be
 toxicities (AE) and do not need to resolve to < Grade 1.

 7. Prior DNA methyl transferase inhibitor administration (azacitidine, decitabine, or
 guadecitabine) for AML or for antecedent MDS is allowed if this clinical trial is
 considered the best treatment option, but azacitidine, decitabine, or guadecitabine
 must have been stopped at least 3 weeks prior to Day 1 of treatment on the study.

 8. All biologic agents including hematopoietic growth factors must have been stopped at
 least 1 week prior to Day 1 of treatment on the study.

 9. Age ≥18 years. Because no dosing or adverse event data are currently available on the
 use of decitabine or talazoparib in patients <18 years of age, children are excluded
 from this study, but will be eligible for future pediatric trials.

 10. ECOG performance status ≤2 (Karnofsky ≥60%).

 11. Life expectancy of greater than 2 months.

 12. Patients must have normal organ and marrow function as defined below:

 -  Total bilirubin within normal institutional limits unless thought due to
 hemolysis or to Gilbert's syndrome;

 -  AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal;

 -  Creatinine within normal institutional limits;

 OR

 • Creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above
 institutional normal.

 13. Female patients of childbearing potential must have a negative pregnancy test, and
 female patients of childbearing potential and male patients must agree to use adequate
 contraception.

 Decitabine has been assigned to pregnancy category D by the FDA. Pregnant women must
 not take decitabine and female subjects must immediately stop taking decitabine and
 inform their doctor if they become pregnant during treatment. Decitabine is expected
 to result in adverse reproductive effects and can cause fetal harm when administered
 to a pregnant woman. In preclinical studies in mice and rats, decitabine was
 teratogenic, fetotoxic, and embryotoxic.

 Studies in pregnant animals to evaluate the effect of talazoparib on pregnancy have
 not been performed.

 Because decitabine is known to be teratogenic and the effects of talazoparib on the
 developing human fetus are unknown, 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 that she is pregnant while she or her partner is
 participating in this study, she should inform the 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 study participation, and 4 months after
 completion of decitabine and talazoparib administration.

 It is not known whether decitabine is excreted in human milk. Similarly, studies in
 lactating animals to evaluate the effect of talazoparib have not been performed, and
 thus, it is not known whether talazoparib is excreted in human milk. Therefore,
 breast-feeding should be stopped during decitabine and talazoparib treatment.

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

 Exclusion Criteria:

 1. Patients with acute promyelocytic leukemia.

 2. Patients with active central nervous system leukemia or requiring maintenance
 intrathecal chemotherapy.

 3. Patients receiving concurrent chemotherapy, radiation therapy, or immunotherapy for
 AML.

 4. Patients receiving any other investigational agents.

 5. Hyperleukocytosis with >50,000 blasts/μl. Hydroxyurea for blast count control is
 permitted before starting treatment, but must be stopped prior to starting treatment
 on the study. Patients will be withdrawn from the study if > 50,000 blasts/μl occur or
 recur > 14 days after starting treatment on the study.

 6. Active, uncontrolled infection. Patients with infection controlled with antibiotics
 are eligible.

 7. Uncontrolled intercurrent illness including, but not limited to, symptomatic
 congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
 illness/social situations that per investigator's judgment would limit compliance with
 study requirements.

 8. Patients who are pregnant or nursing.

 9. Patients who have had chemotherapy within 3 weeks (6 weeks for nitrosoureas or
 mitomycin C) or radiotherapy within 2 weeks for antecedent malignancies prior to
 entering the study, or those who have not recovered from adverse events due to agents
 administered more than 4 weeks earlier.

 10. History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to decitabine or talazoparib.

 11. Known HIV infection.

 HIV-positive patients are at increased risk of lethal infections when treated with
 marrow-suppressive therapy. Appropriate studies will be undertaken in patients
 receiving combination antiretroviral therapy when indicated.

 12. Previous treatment with talazoparib.