Veliparib, Topotecan Hydrochloride, and Filgrastim or Pegfilgrastim in Treating Patients With Persistent or Recurrent Cervical Cancer

PRIMARY OBJECTIVES:

I. To estimate the antitumor activity (objective response rate by RECIST 1.1) of ABT-888
(veliparib) 10 mg administered orally twice a day on days 1 to 5 with topotecan (topotecan
hydrochloride) 0.6 mg/m^2 administered IV once daily on days 1 to 5 of each cycle in
patients with persistent or recurrent carcinoma of the cervix.

II. To determine the nature and degree of toxicity of ABT-888 and topotecan in patients with
persistent or recurrent carcinoma of the cervix.

SECONDARY OBJECTIVES:

I. To determine the duration of progression-free survival and overall survival.

TERTIARY OBJECTIVES:

I. To determine whether evidence of an interaction exists between study treatments and tumor
expression of poly(ADP-ribos)ylation of E2 protein, E6/E7 proteins, and p53R2 in relation to
progression-free and overall survival or metastasis. (Translational) II. To explore the
association between methylation of FanCF and BRCA in pre-treatment tumor samples and pre-
and post-treatment biopsy samples and response, progression-free and overall survival of
patients, and/or metastasis. (Translational)

OUTLINE:

Patients receive veliparib orally (PO) twice daily and topotecan hydrochloride intravenously
(IV) over 30 minutes once daily on days 1-5. Patients also receive, according to
institutional standard, filgrastim subcutaneously (SC) beginning on day 6, 7, or 8 and
continuing until hematopoietic recovery or pegfilgrastim SC on day 6, 7, or 8. Courses
repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Tumor tissue samples may be collected periodically for translational studies.

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

Inclusion Criteria:

- Patients must have persistent or recurrent squamous cell carcinoma, adenosquamous
carcinoma, adenocarcinoma or non-squamous cell carcinoma of the cervix with
documented disease progression; histological documentation of the original primary
tumor is required via the pathology report

- All patients must have measurable disease as defined by RECIST 1.1; measurable
disease is defined as at least one lesion that can be accurately measured in at least
one dimension (longest diameter 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

- Patient 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 not be eligible for a higher priority Gynecologic Oncology Group (GOG)
protocol, if one exists; in general, this would refer to any active GOG Phase III
protocol or Rare Tumor protocol for the same patient population

- Patients must have a GOG performance status of 0, 1, or 2

- Recovery from effects of recent surgery, radiotherapy, or chemotherapy

- Patients should be free of active infection requiring antibiotics

- 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

- Any other prior therapy directed at the malignant tumor, including chemotherapy,
biologic/targeted (non-cytotoxic) therapy and immunologic agents must be discontinued
at least three weeks prior to registration; all side effects must have resolved to =<
grade 1 or stabilized, prior to enrolling on this study

- Any prior radiation therapy must be completed at least 4 weeks prior to registration

- Patients MUST have had one prior systemic chemotherapeutic regimen for management of
advanced, metastatic, or recurrent squamous or non-squamous cell carcinoma of the
cervix; chemotherapy administered concurrent with primary radiation is not counted as
a systemic chemotherapy regimen (e.g.; weekly cisplatin); adjuvant chemotherapy given
following the completion of radiation therapy (or concurrent chemotherapy and
radiation therapy) is not counted as a systemic chemotherapy regimen (e.g.;
paclitaxel and carboplatin for up to 4 cycles)

- Patients who are registered during the safety lead-in portion of this protocol are
required to have prior pelvic radiation

- Patients must have NOT received more than one previous cytotoxic chemotherapy regimen
(either with single or combination cytotoxic drug therapy)

- Patients are allowed to receive, but are not required to receive, biologic/targeted
(non-cytotoxic) therapy as part of their one prior systemic chemotherapeutic regimen;
patients are allowed to receive, but are not required to receive, biologic/targeted
(non-cytotoxic) therapy for management of recurrent or persistent disease

- Patients MUST not be eligible for further curative intent surgical or pelvic
radiation treatment for management of recurrent or persistent disease as determined
by treating physicians

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

- Platelets greater than or equal to 100,000/mcl

- Creatinine less than or equal to 1.5 x institutional upper limit normal (ULN)

- 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 must meet pre-entry requirements

- 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 must have the ability to swallow pills whole

Exclusion Criteria:

- Patients are excluded who have had prior therapy with ABT-888 (veliparib), poly
(ADP)-ribose polymerase inhibitors, or topotecan

- Patient 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 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 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 with seizures or history of seizures are ineligible

- Patients with history or evidence upon physical examination of central nervous system
(CNS) disease, including primary brain tumor, any CNS metastases, or history of
cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or
subarachnoid hemorrhage within six months of the first date of treatment on this
study, are ineligible; patients with CNS metastases must be stable for > 3 months
after treatment and off steroid treatment prior to study enrollment