Veliparib and Topotecan With or Without Carboplatin in Treating Patients With Relapsed or Refractory Acute Leukemia, High-Risk Myelodysplasia, or Aggressive Myeloproliferative Disorders

Study Overview
=================
Brief Summary
-----------------
This phase I trial is studying the side effects and best dose of veliparib when given together with topotecan hydrochloride with or without carboplatin in treating patients with relapsed or refractory acute leukemia, high-risk myelodysplasia, or aggressive myeloproliferative disorders. Veliparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. 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 or by stopping them from dividing. Giving veliparib together with topotecan hydrochloride and carboplatin may kill more cancer cells.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine the feasibility, tolerability, and toxicities of ABT-888 (veliparib) when administered alone and in combination with topotecan hydrochloride with or without carboplatin in patients with relapsed or refractory acute leukemia, high-risk myelodysplasia, or aggressive myeloproliferative disorders. II. To determine the maximum tolerated dose of ABT-888 when administered with topotecan hydrochloride and carboplatin in these patients. III. To determine if ABT-888 when administered with topotecan hydrochloride and carboplatin can induce clinical responses in these patients. SECONDARY OBJECTIVES: I. To determine the pharmacokinetics of ABT-888 when administered alone and in combination with topotecan hydrochloride with or without carboplatin in these patients. II. To obtain pharmacodynamic data regarding the ability of ABT-888 to inhibit poly (ADP-ribose) levels in leukemic blasts. III. To obtain descriptive data regarding the mutational status and/or methylation status of key genes in selected DNA repair pathways (Fanconi complementation groups A-F, Blooms, and ataxia-telangiectasia) in leukemic blasts. OUTLINE: This is a multicenter, dose-escalation study of veliparib. Patients receive veliparib orally twice daily on days 1-8, 1-14, or 1-21 and topotecan hydrochloride with or without carboplatin IV continuously over 120 hours on days 3-7. Treatment repeats every 28-63 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection periodically for pharmacokinetic studies. After completion of study therapy, patients are followed for 30 days.

Official Title
-----------------
A Phase I Study of ABT-888 in Combination With Topotecan Plus Carboplatin for High-Risk Myeloproliferative Disorders and AML Out of Myeloproliferative Disorders

Conditions
-----------------
Adult Acute Megakaryoblastic Leukemia, Adult Acute Monoblastic Leukemia, Adult Acute Monocytic Leukemia, Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With Maturation, Adult Acute Myeloid Leukemia With Minimal Differentiation, Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1, Adult Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); MLLT3-KMT2A, Adult Acute Myeloid Leukemia Without Maturation, Adult Acute Myelomonocytic Leukemia, Adult Erythroleukemia, Adult Pure Erythroid Leukemia, Chronic Myeloid Leukemia, Philadelphia Chromosome Negative, BCR-ABL1 Positive, Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndrome, Essential Thrombocythemia, Hematopoietic and Lymphoid Cell Neoplasm, Myelodysplastic Syndrome, Polycythemia Vera, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Secondary Myelodysplastic Syndrome

Intervention / Treatment
-----------------
* Drug: Carboplatin
* Other: Laboratory Biomarker Analysis
* Drug: Topotecan Hydrochloride
* Drug: Veliparib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pathologically confirmed diagnosis of 1 of aggressive MPD or AML out of MPD Aggressive phase high-risk myeloproliferative disorders (i.e., polycythemia vera, essential thrombocythemia, or Ph-negative chronic myelogenous leukemia) meeting ≥ 1 of the following criteria: Marrow blasts > 5% Peripheral blood blasts plus progranulocytes > 10% New onset or increasing myelofibrosis OR; New onset or > 25% increase in hepatomegaly or splenomegaly New onset constitutional symptoms (i.e., fever, weight loss, splenic pain, or bone pain) Patients who failed primary induction therapy or relapsed after achieving complete remission are eligible No active CNS leukemia; patients with a history of CNS disease must be stable for > 3 months after treatment and off steroid treatment prior to study enrollment Chronic myelomonocytic leukemia meeting either of the following criteria: 5-19% bone marrow blasts (aggressive) At least 20% marrow blasts (transformation) ECOG performance status 0-2 No hyperleukocytosis with >= 50,000 blasts/uL AST, ALT, and alkaline phosphatase =< 5 times upper limit of normal Bilirubin =< 2.0 mg/dL Creatinine normal OR creatinine clearance >= 60 mL/min LVEF >= 45% by MUGA or ECHO Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 30 days after completion of study therapy No active disseminated intravascular coagulation No active uncontrolled infection Patients with infection that is under active treatment and controlled with antibiotics are eligible No other life-threatening illness No mental deficits and/or psychiatric history that would preclude giving informed consent or following protocol No prior or current seizure disorder or a history of seizure No more than 3 prior cytotoxic regimens At least 3 weeks since prior cytotoxic chemotherapy At least 2 weeks since prior radiotherapy At least 4 weeks since prior autologous or allogeneic stem cell transplantation No active graft-versus-host disease At least 1 week since prior biologic therapies, including hematopoietic growth factors At least 24 hours since prior hydroxyurea, steroids, imatinib mesylate, arsenic trioxide, interferon, or other noncytotoxic agents for blast count control No prior ABT-888 No other concurrent chemotherapy, radiotherapy, or immunotherapy No concurrent antiretroviral therapy for HIV-positive patients No other concurrent investigational or commercial agents or therapies for this cancer

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (veliparib, topotecan hydrochloride, carboplatin)<br>Patients receive veliparib orally twice daily on days 1-8, 1-14, or 1-21 and topotecan hydrochloride with or without carboplatin IV continuously over 120 hours on days 3-7. Treatment repeats every 28-63 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Other: Laboratory Biomarker Analysis<br>* Correlative study<br>Drug: Topotecan Hydrochloride<br>* Given IV<br>* Other names: topotecan hydrochloride (oral);Drug: Veliparib<br>* Given orally<br>* Other names: PARP-1 inhibitor ABT-888;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of veliparib, determined as the highest dose level where 0/3 or 1/6 experience DLT, measured according to NCI-CTCAE 4.0 |  | Up to 63 days | 
| Clinical response (CR, CRi, PR) |  | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics and pharmacodynamics of veliparib | Relevant individual PK parameters will be estimated using non-compartmental PK methods. PK parameters will be compared when administered alone or in combination by a paired student's t-test. Comparison of PK parameters among dose levels will be performed using non-parametric statistical methods for K-independent samples. Associations between exposure parameters (Cmax and AUC) and pharmacodynamic endpoints (cellular PAR levels, mutation and/or altered expression of selected DNA repair genes) will be assessed using the appropriate non-parametric statistical tests. | Day 1 at pre-treatment, .25, .5, 1, 2, 4, 6, and 8 hours after veliparib and day 4 at pre-veliparib, .25, .5, 1, 2, 4, 6, and 8 hours after the first dose of veliparib |