Topotecan Hydrochloride and Carboplatin With or Without Veliparib in Treating Advanced Myeloproliferative Disorders and Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia

PRIMARY OBJECTIVES:

I. To estimate the compare the complete response/complete response with incomplete recovery
(CR/CRi) rate of induction therapy with topotecan hydrochloride (topotecan)/carboplatin (T/C)
with or without veliparib (V) or placebo (P) in myeloproliferative disorder associated
leukemias and chronic myelomonocytic leukemia (CMML).

SECONDARY OBJECTIVES:

I. To evaluate and compare the toxicities of T/C/V versus (vs.) T/C/placebo. II. To compare
the 2-year disease-free survival (DFS) and overall survival (OS) in response to T/C/V vs.
T/C/placebo.

III. To detect and compare the presence of minimal residual disease (MRD) remaining after
T/C/V vs. T/C/placebo.

IV. Evaluate predictive biomarkers of response via assessment of pretreatment impaired
homologous recombination via assessment of: next generation sequencing (NGS) panel for genes
mutated in myeloid malignancies done as standard of care per institution; functional
impairment of deoxyribonucleic acid (DNA) damage response via assessment of pretreatment
samples radiation-induced RAD51 foci; topotecan-induced stabilization of topoisomerase I-DNA
covalent complexes, which has recently been observed to be a critical predictor of response
to combination of a topoisomerase I poison and PARP inhibitor in xenografts.

V. To evaluate veliparib exposure and contribution to response (efficacy and toxicity).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive veliparib orally (PO) twice daily (BID) on days 1-21 and topotecan
hydrochloride intravenously (IV) continuously over 24 hours and carboplatin IV continuously
over 24 hours on days 3-7. Treatment repeats every 28-63 days for up to 3 courses in the
absence of disease progression or unacceptable toxicity.

ARM B: Patients receive topotecan hydrochloride and carboplatin as in Arm A. Patients also
receive placebo PO BID on days 1-21. Treatment repeats every 28-63 days for up to 3 courses
in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Newly diagnosed acute myeloid leukemia (AML) associated with antecedent
myeloproliferative disorder (polycythermia vera, essential thrombocythemia,
myelofibrosis, atypical chronic myeloid leukemia, chronic myelomonocytic leukemia and
related undifferentiated myeloproliferative/myelodysplastic disorders) or

- Relapsed/refractory AML associated with antecedent myeloproliferative disorder
(polycythermia vera, essential thrombocythemia, myelofibrosis, atypical chronic
myeloid leukemia, chronic myelomonocytic leukemia and related undifferentiated
myeloproliferative/myelodysplastic disorders) who have received two or fewer prior
induction chemotherapy courses

- Accelerated phase myeloproliferative disorders per Zeider et al with two or fewer
prior therapies

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or Karnofsky >= 60%

- Total bilirubin less than 2.0 unless due to Gilbert's syndrome

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
less than 5 x institutional upper limit of normal

- Left ventricular ejection fraction (LVEF) greater than or equal to 45%

- Interval of greater than 4 weeks since allogeneic blood or marrow transplantation
(BMT) if performed; and absence of active graft versus host disease (GVHD)

- 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 study
participation, and 4 months after completion of veliparib administration

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

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
the study with the exception of hydroxyurea for cytoreduction; therapy with tyrosine
kinase inhibitors (TKIs) directed against JAK2, BCR-ABL or FLT3 will be allowed to be
continued until 24 hours prior to start of therapy on trial

- Patients with active uncontrolled infection; antibiotic therapy for fevers, and
continuation of treatment of prior infection are allowed

- Patients who have active central nervous system (CNS) disease are excluded; patients
with known active CNS leukemia should be excluded from this clinical trial

- Patients who are receiving any other investigational agents; patients who have
completed therapy with an investigational agent should be off this therapy for at
least 5 half-lives or two weeks, whichever is shorter

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to veliparib, topotecan or carboplatin

- Uncontrolled intercurrent illness including, but not limited to, active infection,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with veliparib

- Human immunodeficiency virus (HIV)-patients positive patients are not excluded if they
have CD4+ cells >= 250/mm^3 and negligible viral load and are on a stable combination
antiretroviral therapy; appropriate studies will be undertaken in patients receiving
combination antiretroviral therapy when indicated