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



Status:Recruiting
Conditions:Cancer, Blood Cancer, Blood Cancer, Blood Cancer, Blood Cancer, Blood Cancer, Hematology, Hematology, Hematology, Hematology
Therapuetic Areas:Hematology, Oncology
Healthy:No
Age Range:18 - Any
Updated:4/5/2019
Start Date:June 8, 2018
End Date:June 1, 2020

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A Phase II Randomized Study of Topotecan/Carboplatin With or Without Veliparib or Placebo in Advanced Myeloproliferative Disorders and CMML

This randomized phase II trial studies how well topotecan hydrochloride and carboplatin with
or without veliparib work in treating patients with myeloproliferative disorders that have
spread to other places in the body and usually cannot be cured or controlled with treatment,
and acute myeloid leukemia or chronic myelomonocytic leukemia. Drugs used in chemotherapy,
such as topotecan hydrochloride and carboplatin, work in different ways to stop the growth of
cancer cells, either by killing the cells, by stopping them from dividing, or by stopping
them from spreading. Veliparib may stop the growth of cancer cells by blocking some of the
enzymes needed for cell growth. Giving topotecan hydrochloride, carboplatin, and veliparib
may work better in treating patients with 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
We found this trial at
5
sites
401 North Broadway
Baltimore, Maryland 21287
410-955-5000
Principal Investigator: Keith W. Pratz
Phone: 410-955-8804
Johns Hopkins University-Sidney Kimmel Cancer Center The name Johns Hopkins has become synonymous with excellence...
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Chapel Hill, North Carolina 27599
Principal Investigator: Joshua F. Zeidner
Phone: 877-668-0683
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Chapel Hill, NC
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1441 Eastlake Ave
Los Angeles, California 90033
(323) 865-3000
Principal Investigator: Mojtaba Akhtari
Phone: 323-865-0451
U.S.C./Norris Comprehensive Cancer Center The USC Norris Comprehensive Cancer Center, located in Los Angeles, is...
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1983 Marengo St
Los Angeles, California 90033
(323) 226-2622
Principal Investigator: Mojtaba Akhtari
Phone: 323-865-0451
Los Angeles County-USC Medical Center The origins of LAC+USC Medical Center date back to 1878,...
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Los Angeles, CA
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Newport Beach, California 92663
Principal Investigator: Mojtaba Akhtari
Phone: 323-865-0451
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Newport Beach, CA
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