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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Active, not recruiting

CT.gov ID

NCT00588991

Collaborator

(none)

Enrollment

Locations

Arm

Patients Per Site

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
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-MLL Adult Acute Myeloid Leukemia Without Maturation Adult Acute Myelomonocytic Leukemia Adult Erythroleukemia Adult Pure Erythroid Leukemia Chronic Myelomonocytic Leukemia de Novo Myelodysplastic Syndrome Essential Thrombocythemia Hematopoietic and Lymphoid Cell Neoplasm Myelodysplastic Syndrome Philadelphia Chromosome Negative, BCR-ABL1 Positive Chronic Myelogenous Leukemia Polycythemia Vera Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Secondary Myelodysplastic Syndrome	Drug: Carboplatin Other: Laboratory Biomarker Analysis Drug: Topotecan Hydrochloride Drug: Veliparib	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

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.
To determine the maximum tolerated dose of ABT-888 when administered with topotecan hydrochloride and carboplatin in these patients.
To determine if ABT-888 when administered with topotecan hydrochloride and carboplatin can induce clinical responses in these patients.

SECONDARY OBJECTIVES:

To determine the pharmacokinetics of ABT-888 when administered alone and in combination with topotecan hydrochloride with or without carboplatin in these patients.
To obtain pharmacodynamic data regarding the ability of ABT-888 to inhibit poly (ADP-ribose) levels in leukemic blasts.
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.

Study Design

Study Type:

Interventional

Actual Enrollment :

12 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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

Actual Study Start Date :

Nov 28, 2007

Actual Primary Completion Date :

Feb 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
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: Carboplatin Given IV Other Names: Blastocarb Carboplat Carboplatin Hexal Carboplatino Carboplatinum Carbosin Carbosol Carbotec CBDCA Displata Ercar JM-8 Nealorin Novoplatinum Paraplatin Paraplatin AQ Paraplatine Platinwas Ribocarbo Other: Laboratory Biomarker Analysis Correlative study Drug: Topotecan Hydrochloride Given IV Other Names: Hycamptamine Hycamtin SKF S-104864-A Topotecan HCl topotecan hydrochloride (oral) Drug: Veliparib Given orally Other Names: ABT-888 PARP-1 inhibitor ABT-888

Arm

Intervention/Treatment

Experimental: Treatment (veliparib, topotecan hydrochloride, carboplatin)

Drug: Carboplatin

Given IV

Other Names:

Blastocarb

Carboplat

Carboplatin Hexal

Carboplatino

Carboplatinum

Carbosin

Carbosol

Carbotec

CBDCA

Displata

Ercar

JM-8

Nealorin

Novoplatinum

Paraplatin

Paraplatin AQ

Paraplatine

Platinwas

Ribocarbo

Other: Laboratory Biomarker Analysis

Correlative study

Drug: Topotecan Hydrochloride

Given IV

Other Names:

Hycamptamine

Hycamtin

SKF S-104864-A

Topotecan HCl

topotecan hydrochloride (oral)

Drug: Veliparib

Given orally

Other Names:

ABT-888

PARP-1 inhibitor ABT-888

Outcome Measures

Primary Outcome Measures

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

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]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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