A Phase I Study of the PARP Inhibitor ABT-888 in Combination With Temozolomide in Acute Leukemias

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