Decitabine and Talazoparib in Untreated AML and R/R AML

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.