Clinical trial NCT01281852: Paclitaxel, Cisplatin, and Veliparib in Treating Patients With Advanced, Persistent, or Recurrent Cervical Cancer
Official title: A Limited Access Phase I Trial of Paclitaxel, Cisplatin and CTEP Supplied Agent ABT-888 (Veliparib) (NSC#737664) in the Treatment of Advanced, Persistent, or Recurrent Carcinoma of the Cervix
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cervical Adenocarcinoma
Cervical Adenosquamous Carcinoma
Cervical Squamous Cell Carcinoma, Not Otherwise Specified
Recurrent Cervical Carcinoma
Stage IVB Cervical Cancer AJCC v6 and v7
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: NRG Oncology
First posted: 2011-01-24
Enrollment: 37
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I clinical trial studies the side effects and best dose of veliparib when given together with paclitaxel and cisplatin and to see how well they work in treating patients with cervical cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment or that has come back. Drugs used in chemotherapy, such as paclitaxel and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving more than one drug (combination chemotherapy) and giving chemotherapy together with veliparib may kill more tumor cells.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Dose-limiting toxicities in the first course of treatment (Phase I)
timeFrame: 21 days
measure: Frequency and severity of adverse effects as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events v. 4.0
timeFrame: Within 30 days of last protocol treatment
measure: Objective tumor response (complete or partial response) (Phase II)
timeFrame: Up to 5 years
Secondary outcomes:
measure: Progression-free survival (Phase II)
timeFrame: From study entry to time of progression or death, whichever occurs first, assessed up to 5 years
measure: Overall survival (Phase II)
timeFrame: From study entry to time of death or the date of last contact, assessed up to 5 years
Other outcomes:
measure: Proportion of patients with tumors that demonstrate loss of the FancD2 foci formation
timeFrame: Baseline
Locations:
city: Los Angeles
country: United States
facility: USC / Norris Comprehensive Cancer Center
state: California
city: Augusta
country: United States
facility: Augusta University Medical Center
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Pascagoula
country: United States
facility: Singing River Hospital
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Columbus
country: United States
facility: Riverside Methodist Hospital
state: Ohio
city: Mayfield Heights
country: United States
facility: Hillcrest Hospital Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Tulsa
country: United States
facility: Oklahoma Cancer Specialists and Research Institute-Tulsa
state: Oklahoma
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Women and Infants Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Houston
country: United States
facility: Lyndon Baines Johnson General Hospital
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
Study officials:
affiliation: NRG Oncology
name: Ritu Salani
role: PRINCIPAL_INVESTIGATOR
References:
citation: Thaker PH, Salani R, Brady WE, Lankes HA, Cohn DE, Mutch DG, Mannel RS, Bell-McGuinn KM, Di Silvestro PA, Jelovac D, Carter JS, Duan W, Resnick KE, Dizon DS, Aghajanian C, Fracasso PM. A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852). Ann Oncol. 2017 Mar 1;28(3):505-511. doi: 10.1093/annonc/mdw635.