ABT-888 With Cyclophosphamide and Doxorubicin in Treating Patients With Metastatic or Unresectable Solid Tumors or Non-Hodgkin Lymphoma

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-Hodgkins 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 BCNU or mitomycin C); Patients previously treated with cyclophosphamide should not be necessarily excluded
• Patients with non-Hodgkins 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 0-2
• Life expectancy > 2 months
• Hemoglobin >= 9.0 g/dL
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count >= 100,00/mm^3
• Total bilirubin normal
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 times upper limit of normal (ULN) (=< 5 times ULN if hepatic metastases are present)
• Creatinine normal OR creatinine clearance >= 60 mL/min
• Prothrombin time (PT)/International normalized ratio (INR) or partial thromboplastin time (PTT) =< 1.2 times ULN
• The effects of ABT-888 on the developing human fetus are unknown; For this reason and because other therapeutic agents or modalities used in this trial are known to be teratogenic, 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 AC: Ejection fraction ≥ 50% by 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 CYP 3A4, 2B6, 2C9 or 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, 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 because ABT-888 is a PARP inhibitor with the potential for teratogenic or abortifacient effects; In addition, cyclophosphamide, an alkylating agent, also has potential for teratogenic or abortifacient effects; Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ABT-888, 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 because of the potential for pharmacokinetic interactions with cyclophosphamide and ABT-888; In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated; NOTE: HIV seropositive patients not receiving combination antiretroviral therapy who have CD4 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/m2 or equivalent anthracycline exposure (i.e., epirubicin dose > 540 mg/m^2)