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

Phase 2

Completed

Conditions: Cervical Squamous Cell Carcinoma
Stage III Cervical Cancer
Cervical Small Cell Carcinoma
Cervical Adenocarcinoma
Cervical Adenosquamous Carcinoma
Recurrent Cervical Carcinoma
Stage IVA Cervical Cancer
Stage IVB Cervical Cancer

Interventions: Biological: Filgrastim
Other: Laboratory Biomarker Analysis
Biological: Pegfilgrastim
Drug: Topotecan Hydrochloride
Drug: Veliparib

Registration Number: NCT01266447

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II clinical trial is studying the how well veliparib, topotecan hydrochloride, and filgrastim or pegfilgrastim work in treating patients with persistent or recurrent cervical cancer. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as topotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by blocking them from dividing. Giving veliparib with chemotherapy may kill more tumor cells. Filgrastim or pegfilgrastim may cause the body to make more blood cells and help it recover from the side effects of chemotherapy.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 27

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (veliparib, topotecan hydrochloride, filgrastim)	Pegfilgrastim	Patients receive veliparib PO twice daily and topotecan hydrochloride IV over 30 minutes once daily on days 1-5. Patients also receive, according to institutional standard, filgrastim 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.
Treatment (veliparib, topotecan hydrochloride, filgrastim)	Filgrastim	Patients receive veliparib PO twice daily and topotecan hydrochloride IV over 30 minutes once daily on days 1-5. Patients also receive, according to institutional standard, filgrastim 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.
Treatment (veliparib, topotecan hydrochloride, filgrastim)	Laboratory Biomarker Analysis	Patients receive veliparib PO twice daily and topotecan hydrochloride IV over 30 minutes once daily on days 1-5. Patients also receive, according to institutional standard, filgrastim 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.
Treatment (veliparib, topotecan hydrochloride, filgrastim)	Topotecan Hydrochloride	Patients receive veliparib PO twice daily and topotecan hydrochloride IV over 30 minutes once daily on days 1-5. Patients also receive, according to institutional standard, filgrastim 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.
Treatment (veliparib, topotecan hydrochloride, filgrastim)	Veliparib	Patients receive veliparib PO twice daily and topotecan hydrochloride IV over 30 minutes once daily on days 1-5. Patients also receive, according to institutional standard, filgrastim 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.

Primary Outcome Measures

Name	Time	Method
Tumor Response	Every other cycle for first 6 months; then every 3 months thereafter until disease progression confirmed; and at any other time if clinically indicted based on symptoms or physical signs suggestive of progressive disease. The average time was 2.3 months	Complete and Partial Tumor Response as Assessed by RECIST 1.1. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), Complete Response (CR), disappearance of all target and non-target lesions without evidence of new lesion; Partial Response (PR), at least 30% decrease in the sum of the longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD with no unequivocal progression of non-target lesions and no evidence of new lesion. Complete or partial response requires confirmation at greater than or equal to 4 weeks from initial documentation.
Adverse Events (Grade 3 or Higher) During Treatment Period	During treatment period and up to 30 days after stopping the study treatment.The average of study treatment time was 2.3 months.	Number of participants with a maximum grade of 3 or higher during treatment period. Adverse events are graded and categorized using CTCAE v4.0.
Number of Patients With Dose-limiting Toxicities (in Safety lead-in)	Up to 21 days	A dose-limiting toxicity (DLT) is assessed by NCI CTCAE v4, occurring during cycle 1 of therapy.: A dose-limiting toxicity (DLT) is defined as either hematologic or non-hematologic toxicity assessed by NCI CTCAE v4, occurring during cycle 1 of therapy, which cause any of the following: For hematologic toxicity - dose delay of greater than 2 weeks due to failure to recover counts, Treatment related febrile neutropenia, grade 4 neutropenia lasting \>7 days, treatment related grade 4 thrombocytopenia or clinically significant bleeding with grade 3 thrombocytopenia. For non-hematologic toxicity; study treatment related grade 3 or 4 non-hematological toxicity (excluding anorexia, constipation, fatigue, hypersensitivity/allergic reaction to one of the study drugs, nausea \& vomiting, and grade 3 dehydration), grade 4 nausea and vomiting for \>48 hours despite maximum medical management, electrolyte imbalance of \> or equal to grade 3 that can be replaced within 48 hours; any drug related death

Secondary Outcome Measures

Name	Time	Method
Overall Survival	From study entry to death or last contact, up to 5 years of follow-up.	Overall survival is defined as the duration of time from study entry to time of death or the date of last contact.
Progression-free Survival	From study entry to disease progression, death or date of last contact, whichever occurs first, up to 5 years of follow-up.	Progression-free survival is the period of time from study entry to time of disease progression, death or date of last contact, whichever occurs first. Progression is defined as at least a 20% increase in the sum of the longest dimensions (LD) of target lesions taking as reference the smallest sum LD recorded since study entry, or unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions, or global deterioration in health status attributable to the disease requiring a change in therapy without objective evidence of progression, or death due to disease without prior objective documentation of progression.
Duration of Objective Response	Every other cycle for first 6 months; then every 3 months until disease progression confirmed; and at any other time if clinically indicated based on symptoms or signs suggestive of progressive disease.The average of study treatment time was 2.3 months.	Duration of objective response is defined as the duration from the time measurement criteria is met for partial or complete response by RECIST 1.1, whichever is first recorded, until the first date the recurrent or progressive disease is objectively documented. Per Response Evaluation Criteria in Solid Tumors (RECIST) criteria Complete Response (CR), disappearance of all target and non-target lesions without evidence of new lesion; Partial Response (PR), at least 30% decrease in the sum of the longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD with no unequivocal progression of non-target lesions and no evidence of new lesion. Complete or partial response requires confirmation at greater than or equal to 4 weeks from initial documentation.

Trial Locations

Locations (78): Cooper Hospital University Medical Center
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Camden, New Jersey, United States
North Shore University Hospital
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Manhasset, New York, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
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Baltimore, Maryland, United States
UT Southwestern/Simmons Cancer Center-Dallas
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Dallas, Texas, United States
Case Western Reserve University
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Cleveland, Ohio, United States
Fox Chase Cancer Center
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Philadelphia, Pennsylvania, United States
Riverside Methodist Hospital
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Columbus, Ohio, United States
Zale Lipshy University Hospital
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Dallas, Texas, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
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Orange, California, United States
The Hospital of Central Connecticut
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New Britain, Connecticut, United States
Smilow Cancer Hospital Care Center at Saint Francis
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Hartford, Connecticut, United States
Saint Alphonsus Cancer Care Center-Boise
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Boise, Idaho, United States
Memorial University Medical Center
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Savannah, Georgia, United States
Decatur Memorial Hospital
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Decatur, Illinois, United States
Sudarshan K Sharma MD Limted-Gynecologic Oncology
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Hinsdale, Illinois, United States
Memorial Medical Center
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Springfield, Illinois, United States
University of Iowa/Holden Comprehensive Cancer Center
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Iowa City, Iowa, United States
Hurley Medical Center
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Flint, Michigan, United States
Oakwood Hospital and Medical Center
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Dearborn, Michigan, United States
Allegiance Health
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Jackson, Michigan, United States
Borgess Medical Center
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Kalamazoo, Michigan, United States
Bronson Methodist Hospital
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Kalamazoo, Michigan, United States
West Michigan Cancer Center
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Kalamazoo, Michigan, United States
Sparrow Hospital
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Lansing, Michigan, United States
Saint Mary Mercy Hospital
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Livonia, Michigan, United States
Saint Joseph Mercy Oakland
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Pontiac, Michigan, United States
Saint Joseph Mercy Port Huron
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Port Huron, Michigan, United States
Saint Mary's of Michigan
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Saginaw, Michigan, United States
University of Mississippi Medical Center
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Jackson, Mississippi, United States
Cancer Research for the Ozarks NCORP
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Springfield, Missouri, United States
Mercy Hospital Springfield
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Springfield, Missouri, United States
CoxHealth South Hospital
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Springfield, Missouri, United States
State University of New York Downstate Medical Center
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Brooklyn, New York, United States
Southwest Gynecologic Oncology Associates Inc
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Albuquerque, New Mexico, United States
North Shore-LIJ Health System/Center for Advanced Medicine
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New Hyde Park, New York, United States
Long Island Jewish Medical Center
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New Hyde Park, New York, United States
Lake University Ireland Cancer Center
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Mentor, Ohio, United States
Oklahoma Cancer Specialists and Research Institute-Tulsa
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Tulsa, Oklahoma, United States
Abington Memorial Hospital
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Abington, Pennsylvania, United States
Women and Infants Hospital
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Providence, Rhode Island, United States
Parkland Memorial Hospital
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Dallas, Texas, United States
Clements University Hospital
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Dallas, Texas, United States
Scott and White Memorial Hospital
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Temple, Texas, United States
Harrison HealthPartners Hematology and Oncology-Bremerton
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Bremerton, Washington, United States
Providence Regional Cancer Partnership
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Everett, Washington, United States
PeaceHealth Medical Group PC
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Bellingham, Washington, United States
Harrison Medical Center
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Bremerton, Washington, United States
Skagit Valley Hospital Regional Cancer Care Center
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Mount Vernon, Washington, United States
Harrison HealthPartners Hematology and Oncology-Poulsbo
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Poulsbo, Washington, United States
Cancer Care Northwest - Spokane South
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Spokane, Washington, United States
Olympic Medical Cancer Care Center
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Sequim, Washington, United States
MultiCare Tacoma General Hospital
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Tacoma, Washington, United States
Rockwood Cancer Treatment Center-DHEC-Downtown
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Spokane, Washington, United States
Providence Saint Mary Regional Cancer Center
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Walla Walla, Washington, United States
Saint Joseph Medical Center
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Tacoma, Washington, United States
Wenatchee Valley Hospital and Clinics
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Wenatchee, Washington, United States
D N Greenwald Center
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Mukwonago, Wisconsin, United States
Oconomowoc Memorial Hospital-ProHealth Care Inc
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Oconomowoc, Wisconsin, United States
Waukesha Memorial Hospital
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Waukesha, Wisconsin, United States
Pacific Gynecology Specialists
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Seattle, Washington, United States
Fred Hutchinson Cancer Research Center
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Seattle, Washington, United States
Seattle Cancer Care Alliance
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Seattle, Washington, United States
Group Health Cooperative-Seattle
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Seattle, Washington, United States
Swedish Medical Center-First Hill
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Seattle, Washington, United States
Northwest Hospital
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Seattle, Washington, United States
University of Washington Medical Center
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Seattle, Washington, United States
Indiana University/Melvin and Bren Simon Cancer Center
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Indianapolis, Indiana, United States
Women's Cancer Center of Nevada
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Las Vegas, Nevada, United States
Saint John Hospital and Medical Center
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Detroit, Michigan, United States
University of Oklahoma Health Sciences Center
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Oklahoma City, Oklahoma, United States
University of Colorado Cancer Center - Anschutz Cancer Pavilion
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Aurora, Colorado, United States
Florida Hospital Orlando
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Orlando, Florida, United States
Saint Joseph Mercy Hospital
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Ann Arbor, Michigan, United States
Michigan Cancer Research Consortium CCOP
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Ann Arbor, Michigan, United States
University Medical Center Brackenridge
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Austin, Texas, United States
Virginia Commonwealth University/Massey Cancer Center
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Richmond, Virginia, United States
University of New Mexico Cancer Center
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Albuquerque, New Mexico, United States
Genesys Regional Medical Center
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Grand Blanc, Michigan, United States