This 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 (advanced), 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 compared to topotecan hydrochloride and carboplatin alone.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
25
Los Angeles General Medical Center
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
USC Norris Oncology/Hematology-Newport Beach
Newport Beach, California, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, United States
Number of Participants With a Response
Based on published standards for acute leukemias, Complete Response (CR) means less than 5% leukemic blasts in the bone marrow, no blasts in the blood, no longer presence of cytogenetic abnormalities, no longer presence of extramedullary disease, with or without absolute neutrophil count or platelet count recovery; Partial Remission (PR) includes the criteria for Complete Remission except there are 5-25% leukemic blasts in the bone marrow and there is absolute neutrophil count and platelet count recovery; Hematologic Improvement (HI) means the disease has not gotten worse and there is at least a 20% decrease in the leukemic blasts in the bone marrow and/or a decrease in leukemia symptoms. Response = CR, PR, or HI.
Time frame: Up to 7 months
The Highest Grade Adverse Event Experienced
Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Time frame: Up to 7 months
Number of Participants Without Disease at Study Completion
Study completion was either death or completion of all protocol-specified activities, whichever came first. Participants who came off study due to disease-related death were counted as having disease.
Time frame: Up to 7 months
Duration of Disease-free Survival
Disease-free survival is defined as participants who are still alive and without disease at study completion. Study completion was either death or completion of all protocol-specified activities, whichever came first.
Time frame: Up to 7 months
Number of Participants Still Alive at Study Completion
Study completion was either death or completion of all protocol-specified activities, whichever came first.
Time frame: Up to 7 months
Duration of Overall Survival at the Time of Study Completion
Study completion was either death or completion of all protocol-specified activities, whichever came first. Duration was measured from the date of registration to the participant's study completion date.
Time frame: Up to 7 months
Number of Participants With Minimal Residual Disease (MRD) After Treatment
Minimal residual disease (MRD) refers to a small number of leukemic cells that remain after treatment.
Time frame: Up to 7 months
Distribution of Mutations in Deoxyribonucleic Acid (DNA) Repair Defects Via Assessment in Leukemia Mutation Panel
Will be summarized using descriptive statistics. The association response will be described with appropriate tests for continuously measured biomarkers (t tests, Wilcoxon rank sum tests) and categorical biomarkers (Fisher's exact test). Descriptive analyses will be performed for the whole cohort and also separately for Arms A and B. Differential treatment outcomes for patient subgroups may be explored using appropriate tests for interactions.
Time frame: Baseline
Frequency of Patients With Functional Impairment of DNA Damage Response Via Assessment With RAD51 Assay
Will be reported with exact binomial 95% confidence intervals. The association response will be described with appropriate tests for continuously measured biomarkers (t tests, Wilcoxon rank sum tests) and categorical biomarkers (Fisher's exact test). Descriptive analyses will be performed for the whole cohort and also separately for Arms A and B. Differential treatment outcomes for patient subgroups may be explored using appropriate tests for interactions.
Time frame: Baseline
Topotecan-induced Stabilization of Topoisomerase I-DNA Covalent Complexes
Topotecan-induced stabilization of topoisomerase I-DNA covalent complexes from peripheral blood
Time frame: Up to 7 months
Pharmacokinetic Sampling Studies Measured Using a Validated Liquid Chromatography/Tandem Mass Spectrometric Method in Plasma and Bone Marrow
Plasma trough levels will be obtained weekly through the first cycle to provide a steady-state assessment. Steady-state plasma concentrations will be calculated for each patient. Exploratory correlative studies between veliparib exposure (plasma and bone marrow) with pharmacodynamic (biological endpoints, toxicity and efficacy) will be analyzed using nonparametric statistics. Significance for comparisons will be at the p \< 0.05 level.
Time frame: Pre-treatment, day 1, day 8, day 14, day 15, and day 22 (approximately 24 hours post last dose)
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