Paclitaxel, Cisplatin, and Veliparib in Treating Patients With Advanced, Persistent, or Recurrent Cervical Cancer

PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of ABT-888
(veliparib) when combined with cisplatin and paclitaxel in women with advanced, persistent,
or recurrent cervical cancer.

II. To examine the safety of administering ABT-888 when combined with cisplatin and
paclitaxel.

III. Once the recommended phase II dose is established, to estimate the efficacy of
cisplatin, paclitaxel, and ABT-888 with respect to objective tumor response in patients with
advanced, persistent, or recurrent carcinoma of the cervix.

SECONDARY OBJECTIVES:

I. To examine the effects of this regimen on progression-free survival and overall survival.

TERTIARY OBJECTIVES:

I. To determine the proportion of patients with advanced, persistent, or recurrent cancer of
the cervix whose tumors demonstrate loss of the Fanconi anemia group D2 (FancD2) foci
formation.

III. To determine the association between loss of FancD2 foci formation and progression-free
survival, overall survival, and response in this patient population.

OUTLINE: This is a phase I, dose-escalation study of veliparib followed by a phase II study.

Patients receive paclitaxel intravenously (IV) over 3 hours on day 1, cisplatin IV over 1
hour on day 2, and veliparib orally (PO) on days 1-7. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Note added May 22, 2017: This trial was intended to be a phase 1/2 trial, but the trial never
moved forward to phase 2.

Inclusion Criteria:

- Patients must have primary stage IVB, recurrent or persistent squamous cell carcinoma,
adenosquamous carcinoma, or adenocarcinoma of the cervix which is not amenable to
curative treatment with surgery and/or radiation therapy; histologic documentation of
the original primary tumor is required via the pathology report

- All patients in the phase II portion must have measurable disease as defined by
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; measureable disease is
defined as at least one lesion that can be accurately measured in at least one
dimension (longest dimension to be recorded); each lesion must be >= 10 mm when
measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper
measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes
must be >= 15 mm in short axis when measured by CT or MRI; measurable disease is not
required for participation in the phase I portion of this study

- Patients in the phase II portion must have at least one "target lesion" to be used to
assess response on this protocol as defined by RECIST 1.1; tumors within a previously
irradiated field will be designated as "non-target" lesions unless progression is
documented or a biopsy is obtained to confirm persistence at least 90 days following
completion of radiation therapy

- Patients must have a Gynecologic Oncology Group (GOG) Performance Status of 0, 1, or 2

- Recovery from effects of recent surgery, radiotherapy or other therapy

- Patients should be free of active infection requiring antibiotics (with the
exception of uncomplicated urinary tract infection [UTI])

- Any hormonal therapy directed at the malignant tumor must be discontinued at
least one week prior to registration; continuation of hormone replacement therapy
is permitted

- At least six weeks must have elapsed from the last administration of
chemoradiotherapy, and at least three weeks must have elapsed from the last
administration of radiation therapy alone; at least six weeks must have elapsed
from the time of any major surgical procedure prior to randomization

- Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl

- Platelets greater than or equal to100,000/mcl

- Hemoglobin >= 9 gm/dL

- Creatinine less than or equal to institutional upper limit normal (ULN) or calculated
creatinine clearance (Cockcroft-Gault) >= 60 ml/min

- Calcium, magnesium, phosphate, and potassium levels within institutional normal limits

- Bilirubin less than or equal to 1.5 x ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal
to 3 x ULN

- Alkaline phosphatase less than or equal to 2.5 x ULN

- Neuropathy (sensory and motor) less than or equal to grade 1

- Patients must have signed an approved informed consent and authorization permitting
release of personal health information

- Patients of childbearing potential must have a negative pregnancy test prior to the
study entry and be practicing an effective form of contraception; women of
child-bearing potential 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

- PHASE I: All patients must have received prior chemoradiation

- PHASE I: Patients do not need to have measurable disease

Exclusion Criteria:

- Patients with prior treatment with ABT-888 or other poly adenosine phosphate (ADP)
ribose polymerase (PARP) inhibitors

- Patients with a history of other invasive malignancies, with the exception of
non-melanoma skin cancer and other specific malignancies are excluded if there is any
evidence of the other malignancy being present within the last three years; patients
are also excluded if their previous cancer treatment contraindicates this protocol
therapy

- Patients who have received prior radiotherapy to any portion of the abdominal cavity
or pelvis OTHER THAN for the treatment of cervical cancer within the last three years
are excluded; prior radiation for localized cancer of the breast, head and neck, or
skin is permitted, provided that it was completed more than three years prior to
registration, and the patient remains free of recurrent or metastatic disease

- Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER
THAN for the treatment of cervical cancer within the last three years are excluded;
patients may have received prior adjuvant chemotherapy for localized breast cancer,
provided that it was completed more than three years prior to registration, and that
the patient remains free of recurrent or metastatic disease

- Patients previously treated with chemotherapy for cervical cancer except when used
concurrently with radiation therapy and/or as adjuvant therapy

- Chemotherapy administered concurrent with primary radiation (e.g., weekly
cisplatin) is allowed; adjuvant chemotherapy given following the completion of
radiation therapy (or concurrent chemotherapy and radiation therapy) is allowed
(e.g., paclitaxel and carboplatin for up to 4 cycles)

- Patients may not be receiving any other investigational agents

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to ABT-888 or other agents used in study

- Patients with 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

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

- Patients with history or evidence upon physical examination of central nervous system
(CNS) disease, including primary brain tumor, any brain metastases, or history of
cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or
subarachnoid hemorrhage within 6 months of the first date of treatment on this study

- Patients who are unable to swallow medication

- Patients who are breast feeding should be excluded