This phase I clinical trial is studies the side effects and best dose of giving veliparib together with temozolomide in treating patients with acute leukemia. Veliparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, 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 temozolomide may kill more cancer cells.
PRIMARY OBJECTIVES: I. To define the maximum-tolerated dose (MTD) and recommended phase II dose of ABT-888 (veliparib) administered in combination with temozolomide in patients with acute leukemias. II. To evaluate the feasibility, safety, and toxicity of administering ABT-888 in combination with temozolomide in patients with acute leukemias. SECONDARY OBJECTIVES: I. To document response in acute leukemias. II. To observe the pharmacokinetics of both ABT-888 and temozolomide when administered alone and in combination. III. To study the pharmacodynamics to determine the levels of poly(ADP-ribose) (PAR) before and after administration of ABT-888 and temozolomide in patient leukemia blasts, to analyze methyl-guanine methyl-transferase (MGMT) protein levels in primary leukemia blasts, and to quantify the induction of gamma-H2A histone family, member X (y-H2AX) and RAD51 recombinase (RAD51) foci in patient leukemia blasts after treatment. OUTLINE: This is a dose-escalation study of veliparib. Patients receive veliparib orally (PO) once daily (QD) on day 1 and twice daily on days 4-12 and temozolomide PO QD on days 3-9 of course 1. Beginning at least 30 days after the start of treatment, patients receive veliparib PO twice daily (BID) on days 1-8 and temozolomide PO QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients achieving complete remission receive 5 more courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
66
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States
MTD of veliparib, determined according to incidence of dose limiting toxicity, graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time frame: 28 days
Response rate at the MTD, assessed using revised International Working Group response criteria
The proportion of responders will be estimated and reported with the corresponding 90% confidence interval.
Time frame: Up to 30 days
Changes in levels of poly(ADP-ribose) (PAR)
The proportion of subjects with significant inhibition will be estimated for each dose level. Summary statistics and results of the statistical tests for contingency tables will be reported.
Time frame: From baseline to 6 hours after drug administration on day 1 of course 1
Average expression of MGMT
Average expression of MGMT will be measured and classified as positive versus negative (less than 20% of mean value) for all patients regardless of the administered drug dose. We will use the Fisher's exact test for 2 x 2 tables to assess whether the lack of MGMT expression correlates with the response.
Time frame: Up to 30 days
Average change from baseline level in y-H2AX foci
The average change from baseline level in γ-H2AX and RAD51 foci will be estimated for all patients to assess whether increase in foci and response to treatment are associated. Assessed using a single group repeated measures analysis of variance (ANOVA) with 0.05 significance level.
Time frame: From baseline to 30 days
Average change from baseline level in RAD51 foci
The average change from baseline level in γ-H2AX and RAD51 foci will be estimated for all patients to assess whether increase in foci and response to treatment are associated. Assessed using a single group repeated measures ANOVA with 0.05 significance level.
Time frame: From baseline to 30 days
Non-homologous end joining repair
Repeated measures data structure will provide adequate power to estimate intra- and inter-patient variability.
Time frame: Up to 30 days
Double strand break (DSB) repair
The plausible relationship between change in DSB repair and clinical response will be examined using the Fisher's exact test.
Time frame: Up to 30 days
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