A Phase I Study of ABT-888 in Combination With Cyclophosphamide in Solid Tumors or Non-Hodgkins 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)