Veliparib and Temozolomide in Treating Patients With Acute Leukemia

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.

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) must have failed tretinoin (ATRA), arsenic, and
gemtuzumab ozogamycin to be eligible (patients should be refractory to all three
agents-absence of durable hematologic response or relapse with complete remission
[CR] duration of less than 6 months)

- Relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL);
patients with Philadelphia chromosome-positive (Ph+) ALL [t(9;22)] will be
eligible provided that they have failed (intolerance/resistance) at least 2
different tyrosine kinase inhibitors (TKIs) or have a mutation associated with
resistance to TKIs (T315I)

- Chronic myelogenous leukemia (CML) in accelerated or blastic phase; patients
failed (resistance/intolerance) at least 2 different TKIs or have a mutation
associated with resistance to TKIs (T315I)

- Chronic myelomonocytic leukemia-2 (CMML-2) defined as having > 10% blasts
(including promonocytes) in the bone marrow or > 5-19% blasts (including
promonocytes) in the peripheral blood

- AML arising in the setting of antecedent myelodysplasia (MDS) or
myeloproliferative disorder (MPD)

- Therapy-related AML

- Untreated AML in adults 60 years of age and older who are not candidates for
induction chemotherapy due to poor-risk features including adverse cytogenetics
or molecular markers (fms-related tyrosine kinase 3 [FLT3] internal tandem
duplication [ ITD]+), or are unwilling to receive intensive induction
chemotherapy; adverse cytogenetics: 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

- Untreated ALL in adults 60 years of age and older who are not candidates for
induction chemotherapy due to poor-risk features including adverse cytogenetics
[t(4;11); t(1;19), hypodyploidy] or are unwilling to receive intensive induction
chemotherapy; patients with Ph+ ALL [t(9;22)] will be eligible provided that they
have failed (intolerance/resistance) at least 2 different TKIs or have a mutation
associated with resistance to TKIs (T315I)

- Previous therapy

- Only patients who have received or are ineligible for established curative
regimens, including stem cell transplantation when applicable, can be enrolled on
this study

- Patients may have received any number of prior chemotherapy regimens, which may
include allogeneic or autologous transplantation, provided that performance
status and organ function are maintained

- Previous cytotoxic chemotherapy should have been completed at least 3 weeks and
radiotherapy at least 2 weeks prior to treatment on the study (6 weeks if the
last regimen included carmustine [BCNU] or mitomycin C) and all adverse events
(excluding alopecia, acne, rash) due to agents administered more than 3 weeks
earlier should recover to =< grade 1; patients with hematologic malignancies are
expected to have hematologic abnormalities at study entry; these abnormalities
which are thought to be primarily related to the underlying leukemia, are not
considered to be toxicities (AE) and do not need to resolve to =< grade 1

- Patients should stop taking all biologic agents including hematopoietic growth
factors, imatinib or similar TKIs, at least 1 week prior to treatment on the
study and all adverse events (excluding alopecia, acne, rash) due to agents
administered more than 1 week earlier should recover to =< grade 1; since only
patients with advanced Ph+ ALL and CML in accelerated/blast phase are eligible
for this study, this short period off TKIs was selected to avoid rapid leukemia
progression; if using hydroxyurea, corticosteroids, or leukopheresis for blast
count control, patients must be off >= 24 hrs before starting treatment on the
study

- Patients who have undergone autologous stem cell transplantation (ASCT) are
eligible provided that they are >= 4 weeks from stem cell infusion and meet other
eligibility criteria

- Patients who have undergone allogeneic SCT (alloSCT) are eligible if they are >=
60 days post stem cell infusion, have no evidence of graft vs. host disease, and
are >= 2 weeks off all immunosuppressive therapy

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Patients have to be able to swallow pills

- Total or direct bilirubin < 2 mg/dl

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 5 X institutional upper limit of normal

- Creatinine < 2 mg/dl

- Female patients of childbearing potential must have a negative pregnancy test

- Female patients of childbearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry, for the duration of study participation, and for 30 days afterward; should a
woman become pregnant or suspect she is pregnant while participating in this study,
she should inform her treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients may not be receiving any other investigational agents, or concurrent
chemotherapy, radiation therapy, or immunotherapy

- Any previous treatment with temozolomide

- Patients with active central nervous system leukemia are excluded from this clinical
trial because they may develop progressive neurologic dysfunction that would confound
the evaluation of neurologic and other adverse events; patients with a history of
central nervous system (CNS) leukemia but no active disease at the time of enrollment
are eligible

- Hyperleukocytosis with > 30,000 blasts/ul; (if using hydroxyurea, corticosteroids, or
leukopheresis for blast count control, patients must be off >= 24 hrs before starting
treatment on the study); once patient starts treatment on the study the hydroxyurea
use should be avoided, however, for patients with rapidly proliferating disease use of
hydroxyurea is allowed on treatment days 1 through 12 if it becomes necessary to
control a rising white blood cell (WBC) or leukostasis; the WBC need not reach
30,000/ul to start hydroxyurea during protocol days 1-12; the decision to start
hydroxyurea during this time is at the discretion of the treating physician

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ABT-888 or temozolomide used in this study

- Active, uncontrolled infection; patients with infection under active treatment and
controlled with antibiotics are eligible

- Uncontrolled intercurrent illness including, but not limited to, symptomatic
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with ABT-888

- Known human immunodeficiency virus (HIV) infected patients (HIV testing will not be
performed as a part of screening) on combination antiretroviral therapy, exclusive of
zidovudine or starvudine, or HIV infected patients not on or willing to suspend
antiretroviral therapy will be eligible provided that their cluster of differentiation
(CD)4 cell count is greater than 250/mm3; HIV infected patients with CD4 count equal
or less than 250/mm3 will be excluded