Veliparib and Temozolomide in Treating Patients With Acute Leukemia

• Toxicity [ Designated as safety issue: Yes ]
• Maximum-tolerated dose (MTD) of veliparib and temozolomide [ Designated as safety issue: Yes ]

• Response rate at the MTD, assessed using revised International Working Group (IWG) response criteria [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
  The proportion of responders will be estimated and reported with the corresponding 90% confidence interval.
• Changes in levels of poly(ADP-ribose) (PAR) [ Time Frame: From baseline to 6 hours after drug administration on day 1 of course 1 ] [ Designated as safety issue: No ]
  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.
• Average expression of MGMT [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
  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.
• Average change from baseline level in γ-H2AX and RAD51 foci [ Time Frame: From baseline to 30 days ] [ Designated as safety issue: No ]
  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.
• NHEJ repair [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
  Repeated measures data structure will provide adequate power to estimate intra- and inter-patient variability.
• DSB repair [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
  The plausible relationship between change in DSB repair and clinical response will be examined using the Fisher's exact test.

• Response rate at the MTD [ Designated as safety issue: No ]
• Levels of poly(ADP-ribose) before and during treatment [ Designated as safety issue: No ]
• Average expression of methyl-guanine methyl-transferase [ Designated as safety issue: No ]
• Average change from baseline level in γ-H2AX and RAD51 foci [ Designated as safety issue: No ]

This phase I clinical trial is studying 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. 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. Evaluate the feasibility, safety, and toxicity of administering ABT-888 in combination with temozolomide in patients with acute leukemias.

SECONDARY OBJECTIVES:

I. Document response in acute leukemias. II. Observe the pharmacokinetics of both ABT-888 and temozolomide when administered alone and in combination.

III. 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 γ-H2AX and RAD51 foci in patient leukemia blasts after treatment.

OUTLINE: This is a dose-escalation study of veliparib.

Patients receive oral veliparib once daily on day 1 and twice daily on days 4-12 and oral temozolomide once daily on days 3-9 of course 1.

Beginning at least 30 days after the start of treatment, patients receive oral veliparib twice daily on days 1-8 and oral temozolomide once daily 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.

• Accelerated Phase Chronic Myelogenous Leukemia
• Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
• Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
• Adult Acute Myeloid Leukemia With Del(5q)
• Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
• Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
• Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
• Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
• B-cell Adult Acute Lymphoblastic Leukemia
• Blastic Phase Chronic Myelogenous Leukemia
• Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia
• Recurrent Adult Acute Lymphoblastic Leukemia
• Recurrent Adult Acute Myeloid Leukemia
• Relapsing Chronic Myelogenous Leukemia
• Secondary Acute Myeloid Leukemia
• T-cell Adult Acute Lymphoblastic Leukemia
• Untreated Adult Acute Lymphoblastic Leukemia
• Untreated Adult Acute Myeloid Leukemia

• Drug: temozolomide
  Given orally
  Other Names:

  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
• Drug: veliparib
  Given orally
  Other Name: ABT-888
• Other: pharmacological study
  Correlative studies
  Other Name: pharmacological studies
• Other: laboratory biomarker analysis
  Correlative studies

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of one of the following:

  • Relapsed or refractory acute myeloid leukemia (AML)

    • Patients with acute promyelocytic leukemia [t(15;17)] are eligible provided they have failed tretinoin, arsenic, and gemtuzumab ozogamicin (patients should be refractory to all three agents, defined as the absence of durable hematologic response or relapse with complete remission duration of < 6 months)

  • Relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL)

    • Patients with Philadelphia chromosome-positive (Ph+) ALL [t(9;22)] are eligible provided that they have failed (intolerance/resistance) ≥ 2 different tyrosine kinase inhibitors (TKIs) or have a mutation associated with resistance to TKIs (T315I)

  • Chronic myelogenous leukemia in accelerated or blastic phase

    • Patients failed (resistance/intolerance) ≥ 2 different TKIs or have a mutation associated with resistance to TKIs (T315I)
  • AML arising in the setting of antecedent myelodysplasia or myeloproliferative disorder
  • Therapy-related AML

  • Untreated AML in patients meeting the following criteria:

    • Adults 60 years of age and older
    • Not a candidate for induction chemotherapy due to poor-risk features including adverse cytogenetics [i.e., complex karyotype (≥ 3 chromosomal abnormalities), 5q-, 7q-, 9q-, 20q-, abn12p, +21, +8, t(6;9), t(6;11), t(11;19), -7, -5, inv3/t(3;3), abn11q23, abn17p, abn21q) or molecular markers (FLT3 ITD^+) OR unwilling to receive intensive induction chemotherapy

  • Untreated ALL in patients meeting the following criteria:

    • Adults 60 years of age and older
    • Not a candidate for induction chemotherapy due to poor-risk features including adverse cytogenetics [i.e., t[(4;11), t(1;19), hypodiploidy] OR unwilling to receive intensive induction chemotherapy
    • Patients with Ph+ ALL [t(9;22)] are eligible provided that they have failed (intolerance/resistance) ≥ 2 different TKIs or have a mutation associated with resistance to TKIs (T315I)
• Received or are ineligible for established curative regimens, including stem cell transplantation, when applicable
• No hyperleukocytosis with > 30,000 blast/μL

• No active CNS leukemia

  • Patients with a history of CNS leukemia must be stable for > 3 months off treatment and off steroid treatment prior to study entry
• See Disease Characteristics
• ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)
• Total or direct bilirubin ≤ 2 mg/dL
• AST/ALT < 5 times upper limit of normal
• Creatinine ≤ 2 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use adequate contraception before, during, and for 30 days after completion of study treatment
• Able to swallow pills

• No active, uncontrolled infection

  • Patients with infection under active treatment and controlled with antibiotics are eligible

• No uncontrolled concurrent illness including, but not limited to, any of the following:

  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness or social situations that would limit compliance with study requirements

• No known HIV-infected patients on combination antiretroviral therapy (except for zidovudine or stavudine)

  • HIV testing will not be performed as part of screening
  • HIV patients not on or willing to suspend antiretroviral therapy are eligible provided that their CD4 cell count is > 250/mm^3
• No uncontrolled, active seizure disorder or a history of seizure
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to veliparib or temozolomide
• See Disease Characteristics
• No prior veliparib or temozolomide
• Any number of prior chemotherapy regimens allowed
• Recovered to ≤ grade 1 from all adverse events (excluding alopecia, acne, and rash)

• Prior allogeneic stem cell transplantation allowed provided patients meet all of the following criteria:

  • At least 60 days since stem cell infusion
  • No evidence of graft-vs-host disease
  • At least 2 weeks since prior immunosuppressive therapy
• At least 4 weeks since prior autologous stem cell transplantation
• At least 3 weeks since prior cytotoxic chemotherapy (6 weeks since carmustine or mitomycin C)
• At least 2 weeks since prior radiotherapy
• At least 1 week since prior and no concurrent biologic agents including hematopoietic growth factors, imatinib, or similar tyrosine kinase inhibitors

• At least 24 hours since prior hydroxyurea, corticosteroids, or leukapheresis for blast count control

  • Concurrent hydroxyurea for patient with rapidly proliferating disease allowed on treatment days 1 through 12 at the discretion of treating physician
• No other concurrent investigational agents, chemotherapy, radiotherapy, or immunotherapy
• No other concurrent anticancer therapies or agents