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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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NCI 10147: A Phase II Randomized Study of Topotecan/Carboplatin With or Without Veliparib in Advanced Myeloproliferative Disorders and Chronic Myelomonocytic Leukemia (CMML)

Conditions
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Acute Myeloid Leukemia, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome, Atypical Chronic Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Essential Thrombocythemia, Myelodysplastic/Myeloproliferative Neoplasm, Myelofibrosis, Polycythemia Vera, Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Topotecan
* Drug: Topotecan Hydrochloride
* Drug: Veliparib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (veliparib, topotecan hydrochloride, carboplatin)<br>Patients receive veliparib PO BID on days 1-21 and topotecan hydrochloride 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. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Topotecan<br>* Given IV<br>* Other names: Topotecan Lactone;Drug: Topotecan Hydrochloride<br>* Given IV<br>* Other names: topotecan hydrochloride (oral);Drug: Veliparib<br>* Given PO<br>* Other names: PARP-1 inhibitor ABT-888;|
| Active Comparator: Arm B (topotecan hydrochloride, carboplatin)<br>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. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Topotecan<br>* Given IV<br>* Other names: Topotecan Lactone;Drug: Topotecan Hydrochloride<br>* Given IV<br>* Other names: topotecan hydrochloride (oral);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response defined as complete response/complete response with incomplete recovery | Will be reported at the end of the study separately for Arm A and Arm B with exact binomial 95% confidence intervals. The final analysis will be by a multivariable logistic regression model for the probability of response as a function of treatment arm, blast count group, and prior therapy status, which tests for an overall treatment difference while adjusting for disease subgroup. The primary analysis will conclude a significant benefit for Arm A over Arm B if the two-sided p value for the coefficient for treatment arm < 0.10. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of toxicities | Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 and reported for Arm A and Arm B separately and together with exact binomial 95% confidence intervals. | Up to 30 days after the last administration of study treatment | 
| 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. | 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. | Baseline | 
| 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. | Pre-treatment, day 1, day 8, day 14, day 15, and day 22 (approximately 24 hours post last dose) |