A Phase I Study of ABT-888 in Combination With Topotecan Plus Carboplatin for High-Risk Myeloproliferative Disorders and AML Out of Myeloproliferative Disorders
Overview
- Phase
- Phase 1
- Intervention
- Carboplatin
- Conditions
- Adult Acute Megakaryoblastic Leukemia
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 12
- Locations
- 2
- Primary Endpoint
- 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
- Status
- Completed
- Last Updated
- last year
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.
Investigators
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:
Exclusion Criteria
- Not provided
Arms & Interventions
Treatment (veliparib, topotecan hydrochloride, carboplatin)
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.
Intervention: Carboplatin
Treatment (veliparib, topotecan hydrochloride, carboplatin)
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.
Intervention: Laboratory Biomarker Analysis
Treatment (veliparib, topotecan hydrochloride, carboplatin)
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.
Intervention: Topotecan Hydrochloride
Treatment (veliparib, topotecan hydrochloride, carboplatin)
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.
Intervention: Veliparib
Outcomes
Primary Outcomes
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
Time Frame: Up to 63 days
Clinical response (CR, CRi, PR)
Time Frame: Up to 3 years
Secondary Outcomes
- Pharmacokinetics and pharmacodynamics of veliparib(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)