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