PRIMARY OBJECTIVE:
I. To estimate and 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) 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. II. To compare the
2-year disease-free survival (DFS) and overall survival (OS) in response to T/C/V vs. T/C.
III. To detect and compare the presence of minimal residual disease (MRD) remaining after
T/C/V vs. T/C.
IV. Evaluate predictive biomarkers of response via assessment of pretreatment impaired
homologous recombination via assessment of:
IVa. Next generation sequencing (NGS) panel for genes mutated in myeloid malignancies done as
standard of care per institution.
IVb. Functional impairment of deoxyribonucleic acid (DNA) damage response via assessment of
pretreatment samples for radiation-induced RAD51 foci.
IVc. 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 4 cycles in the
absence of disease progression or unacceptable toxicity.
ARM B: Patients receive topotecan hydrochloride IV continuously over 24 hours and carboplatin
IV continuously over 24 hours on days 1-5. Treatment repeats every 28-63 days for up to 4
cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for a minimum of 30 days, or
longer.
Inclusion Criteria:
- PRE-REGISTRATION ELIGIBILITY CRITERIA
- Newly diagnosed acute myeloid leukemia (AML) associated with antecedent
myeloproliferative disorder (polycythemia vera, essential thrombocythemia,
myelofibrosis, atypical chronic myeloid leukemia, chronic myelomonocytic leukemia and
related undifferentiated myeloproliferative/myelodysplastic disorders)
- Relapsed/refractory AML associated with antecedent myeloproliferative disorder
(polycythemia 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
- For aggressive phase myeloproliferative disorders (MPD) (polycythemia vera,
essential thrombocythemia, Philadelphia [Ph]-negative chronic myelogenous
leukemia), one or more of the following criteria must be met: marrow blasts > 5%,
peripheral blood blasts plus progranulocytes > 10%, new onset or increasing
myelofibrosis, new onset or > 25% increase in hepatomegaly or splenomegaly, new
onset constitutional symptoms (fever, weight loss, splenic pain, bone pain).
Zeider et al
- For chronic myelomonocytic leukemia (CMML), the following criteria must be met:
5-19% bone marrow blasts (aggressive) or >= 20% marrow blasts (transformation)
- Bone marrow and/or peripheral blood specimens will be submitted for correlative
studies; patients with a dry tap will still be eligible
- RANDOMIZATION ELIGIBILITY CRITERIA
- Bone marrow aspirate and/or peripheral blood specimens were submitted to the central
lab and site has confirmation by the local institution that the patient meets one of
the criteria specified above
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or Karnofsky >= 60%
- Total bilirubin less than 2.0 mg/dL unless due to Gilbert's syndrome, then less than
5.0 mg/dL
- 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
- Creatinine clearance glomerular filtration rate (GFR) greater than 30 ml/min per
modified Cockcroft-Gault formula
- Interval of greater than 4 weeks since allogeneic blood or marrow transplantation
(BMT) if performed; and absence of active graft versus host disease (GVHD)
- The effects of veliparib on the developing human fetus are unknown; for this reason
and because PARP inhibiting agents as well as topoisomerase inhibitors and platinating
agents are known to be teratogenic, women of child-bearing potential must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence) prior
to study entry, for the duration of study participation, and for 6 months following
the last dose of study drug; 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 because of
their poor prognosis and because they often develop progressive neurologic dysfunction
that would confound the evaluation of neurologic and other adverse events
- 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 because veliparib is PARP inhibiting 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 veliparib, breastfeeding should be discontinued if the
mother is treated with veliparib; these potential risks may also apply to topotecan
and carboplatin used in this study
- 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
- History of uncontrolled seizure disorder, including focal or generalized seizure
within the past year
