Veliparib and Topotecan With or Without Carboplatin in Treating Patients With Relapsed or Refractory Acute Leukemia, High-Risk Myelodysplasia, or Aggressive Myeloproliferative Disorders
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Adult Acute Megakaryoblastic Leukemia (M7) Adult Acute Minimally Differentiated Myeloid Leukemia (M0) Adult Acute Monoblastic Leukemia (M5a) Adult Acute Monocytic Leukemia (M5b) Adult Acute Myeloblastic Leukemia With Maturation (M2) Adult Acute Myeloblastic Leukemia Without Maturation (M1) Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) Adult Acute Myeloid Leukemia With t(16;16)(p13;q22) Adult Acute Myeloid Leukemia With t(8;21)(q22;q22) Adult Acute Myelomonocytic Leukemia (M4) Adult Erythroleukemia (M6a) Adult Pure Erythroid Leukemia (M6b) Chronic Myelomonocytic Leukemia de Novo Myelodysplastic Syndromes Essential Thrombocythemia Hematopoietic/Lymphoid Cancer Philadelphia Chromosome Negative Chronic Myelogenous Leukemia Polycythemia Vera Previously Treated Myelodysplastic Syndromes Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Relapsing Chronic Myelogenous Leukemia Secondary Myelodysplastic Syndromes |
Drug: veliparib Drug: topotecan hydrochloride Drug: carboplatin Other: laboratory biomarker analysis |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| 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 |
- 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 ] [ Designated as safety issue: Yes ]
- Clinical response (CR, CRi, PR) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
- Pharmacokinetics and pharmacodynamics of veliparib [ Time Frame: 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 ] [ Designated as safety issue: No ]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.
| Estimated Enrollment: | 12 |
| Study Start Date: | November 2007 |
| Primary Completion Date: | December 2012 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: 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.
|
Drug: veliparib
Given orally
Other Name: ABT-888
Drug: topotecan hydrochloride
Given IV
Other Names:
Drug: carboplatin
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative study
|
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.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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
Contacts and Locations| United States, Maryland | |
| Johns Hopkins University | Recruiting |
| Baltimore, Maryland, United States, 21287-8936 | |
| Contact: Keith W. Pratz 410-502-7726 kpratz1@jhmi.edu | |
| Principal Investigator: Keith W. Pratz | |
| United States, Minnesota | |
| Mayo Clinic | Recruiting |
| Rochester, Minnesota, United States, 55905 | |
| Contact: Mark R. Litzow 507-284-5362 Litzow.Mark@Mayo.edu | |
| Principal Investigator: Mark R. Litzow | |
| Principal Investigator: | Keith Pratz | Johns Hopkins University |
More Information
No publications provided
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT00588991 History of Changes |
| Other Study ID Numbers: | NCI-2009-00259, J0783, CDR0000579626, U01CA062491, U01CA070095, U01CA069912 |
| Study First Received: | December 20, 2007 |
| Last Updated: | March 28, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Congenital Abnormalities Leukemia Leukemia, Erythroblastic, Acute Leukemia, Lymphoid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Megakaryoblastic, Acute Leukemia, Monocytic, Acute Leukemia, Myeloid, Acute Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myelomonocytic, Acute Leukemia, Myelomonocytic, Chronic Myelodysplastic Syndromes Preleukemia Myeloproliferative Disorders |
Philadelphia Chromosome Polycythemia Polycythemia Vera Thrombocythemia, Essential Thrombocytosis Neoplasms by Histologic Type Neoplasms Bone Marrow Diseases Hematologic Diseases Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Myelodysplastic-Myeloproliferative Diseases Precancerous Conditions |
ClinicalTrials.gov processed this record on May 23, 2013