Veliparib, Cyclophosphamide, and Doxorubicin Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors or Non-Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. Identify the maximally tolerated dose (MTD) and dose limiting toxicity (DLT) of
cyclophosphamide when combined with escalating doses of ABT-888 (veliparib).

II. Identify the maximally tolerated dose (MTD) and dose limiting toxicity (DLT) of
cyclophosphamide and doxorubicin (doxorubicin hydrochloride) when combined with escalating
doses of ABT-888.

SECONDARY OBJECTIVES:

I. Evaluate any effect of ABT-888 on the systemic clearance of parent cyclophosphamide and
the dose normalized area under the curve (AUC) of 4-hydroxy (4-OH) cyclophosphamide when used
in combination, using historical single-agent cyclophosphamide and 4-OH data.

II. Evaluate any effect of cyclophosphamide administration on the systemic pharmacokinetics
of ABT-888 and its primary metabolite A-925088 (M8), by comparing pharmacokinetic (PK)
parameters of ABT-888 on day 1 (before cyclophosphamide) and day 3 (with cyclophosphamide
administration); PK samples for analysis will not be collected from patients enrolled after
2/15/2012.

III. Evaluate inhibition of poly (adenosine diphosphate [ADP] ribose) polymerase (PARP) using
an immunoassay designed to measure PAR levels in baseline and on-study peripheral blood
mononuclear cells (PBMC) samples; PBMC samples for PAR analysis will not be collected from
patients enrolled after 2/15/2012.

IV. Evaluate gamma H2A histone family, member X (H2AX) at baseline and on-study circulating
tumor cell samples to evaluate the point of maximal deoxyribonucleic acid (DNA) damage from
the combination of cyclophosphamide and doxorubicin with ABT-888.

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

GROUP I: Patients receive veliparib orally (PO) every 12 hours on days 1-4 and
cyclophosphamide intravenously (IV) over 60 minutes on day 3.

GROUP II: Patients receive veliparib PO every 12 hours on days 1-4, cyclophosphamide IV over
60 minutes on day 3, and doxorubicin hydrochloride IV over 15 minutes on day 3.

GROUP III: Patients receive veliparib PO every 12 hours on days 1-7, cyclophosphamide IV over
60 minutes on day 1, and doxorubicin hydrochloride IV over 15 minutes on day 1.

GROUP IV: Patients receive veliparib PO every 12 hours on days 1-14, cyclophosphamide IV over
60 minutes on day 1, and doxorubicin hydrochloride over 15 minutes on day 1.

In all groups, courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Inclusion Criteria:

- Patients must have histologically confirmed malignancy that is metastatic or
unresectable and for which standard curative or palliative measures do not exist or
are no longer effective; patients with either solid tumors or non-Hodgkin's lymphoma
are eligible

- At the recommended Phase II dose level, an additional 6 to 12 patients in each
group with the following criteria will be enrolled: documented breast cancer
(BRCA)1/BRC2 mutation, triple-negative breast cancer defined as estrogen receptor
(ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth
factor receptor (HER)2-negative, or patients who would benefit from a
cyclophosphamide-based regimen

- On the schedule of ABT-888 given for 7 or 14 days, only patients with metastatic
breast cancer will be enrolled

- Patients must be >= 4 weeks since prior chemotherapy or radiation therapy (>= 6 weeks
if the last regimen included carmustine [BCNU] or mitomycin C); patients previously
treated with cyclophosphamide should not be necessarily excluded

- Patients with non-Hodgkin's lymphoma that is amenable to hematopoietic stem cell
transplantation with curative intent may participate only if stem cell transplant is
refused or is not indicated

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Life expectancy of greater than 2 months

- Hemoglobin >= 9.0 g/dL

- Absolute neutrophil count (ANC) >= 1,500/uL

- Platelets >= 100,000/uL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
institutional upper limit of normal (ULN), =< 5 x ULN if known hepatic metastases

- Creatinine within normal institutional limits OR creatinine clearance >= 60
ml/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time
(PTT) =< 1.2 X institutional ULN

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

- Patients enrolled in a group where the treatment is adriamycin and cycloblastin (AC):
ejection fraction >= 50% by multigated acquisition scan (MUGA) or echocardiogram

- Patients must sign informed consent

Exclusion Criteria:

- Concurrent administration of any other investigational agent(s)

- Prior high-dose therapy requiring hematopoietic stem cell transplantation

- Prior anti-cancer treatments involving radioactive pharmaceuticals

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ABT-888 and/or cyclophosphamide

- Patients receiving any medications or substances that are strong inhibitors or strong
inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP 3A4),
cytochrome P450, family 2, subfamily B, polypeptide 6 (2B6), cytochrome P450, family
2, subfamily C, polypeptide 9 (2C9) or cytochrome P450, family 2, subfamily C,
polypeptide 19 (2C19) are prohibited; at the time of screening, if the patient is
currently receiving any of the listed prohibited medication(s), the medication(s) must
be discontinued for a period of no less than 7 days prior to administration of the
first dose of study medication in order for the patient to meet study eligibility
except for the following substance where the washout should be 6 months: amiodarone

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements; New York Heart Association (NYHA) grade II or greater congestive
heart failure

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with ABT-888; these potential risks may also apply to other
agents used in this study

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible; appropriate studies will be undertaken in patients receiving
combination antiretroviral therapy when indicated; NOTE: HIV seropositive patients not
receiving combination antiretroviral therapy who have cluster of differentiation (CD)4
cells >= 350/mm^3, no opportunistic infections and meet all eligibility criteria may
participate in this study

- Any condition (e.g., gastrointestinal tract disease resulting in an inability to take
oral medication or a requirement for IV alimentation, prior surgical procedures
affecting absorption, or active peptic ulcer disease) that impairs their ability to
swallow and retain ABT-888 capsules

- Patients with gastrointestinal conditions that might predispose for drug
intolerability or poor drug absorption (e.g., inability to take oral medication or a
requirement for IV alimentation, prior surgical procedures affecting absorption,
malabsorption syndrome, active peptic ulcer disease) are excluded; subjects with
ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel
obstruction are also excluded

- Patients with active central nervous system (CNS) metastases are excluded

- Patients with CNS metastases that have been treated must be off steroid treatment
for > 3 months, be asymptomatic and off steroid treatment prior to study
enrollment

- Patients that have symptoms to suggest CNS metastases should have a brain
magnetic resonance imaging (MRI) within 28 days of enrollment to confirm the
absence of CNS metastases; contrast computed tomography (CT) is acceptable for
patients who are unable to undergo a brain MRI

- Patients with active seizure or a history of active seizure

- Any other medical, social, or psychological condition that may significantly affect
safety and/or compliance

- Patients enrolled in a group where treatment is AC: prior doxorubicin exposure of >
300 mg/m^2 or equivalent anthracycline exposure (i.e., epirubicin dose > 540 mg/m^2)