Ziv-aflibercept in Treating Patients With Locally Advanced, Unresectable, or Metastatic Gynecologic Soft Tissue Sarcoma

• Objective response rate, evaluated according to the RECIST criteria [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
• Incidence of disease stabilization, as measured by progression-free survival at 6 months [ Time Frame: 6 months ] [ Designated as safety issue: No ]

• Survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  Survival statistics will be estimated using the Kaplan-Meier method. Standard descriptive statistics, such as the mean, median, range and proportion, will be used to summarize the patient sample and to estimate parameters of interest. 95% confidence intervals will be provided for estimates of interest where possible.
• Response as assessed by RECIST criteria [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  Standard descriptive statistics, such as the mean, median, range and proportion, will be used to summarize the patient sample and to estimate parameters of interest. 95% confidence intervals will be provided for estimates of interest where possible.

This phase II trial is studying how well ziv-aflibercept works in treating patients with locally advanced, unresectable or metastatic gynecologic soft tissue sarcoma. Ziv-aflibercept may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PRIMARY OBJECTIVES:

I. To assess the objective response of recurrent or metastatic gynecologic soft-tissue sarcomas to VEGF-Trap (ziv-aflibercept).

II. To assess the incidence of disease stabilization, as measured by 6-month progression-free survival, in patients with recurrent or metastatic gynecologic soft-tissue sarcomas treated with VEGF-Trap.

SECONDARY OBJECTIVES:

I. To assess time-to-progression and overall survival in patients with recurrent or metastatic gynecologic soft-tissue sarcoma treated with VEGF-Trap.

* As of 24 October 2012, overall survival follow-up is to be discontinued for the one remaining patient on long term follow-up, who has been off protocol therapy for at least 3 years. Time to progression and median survival times have been based on the currently available data.

II. To assess the toxicity associated with VEGF-Trap in patients with recurrent or metastatic gynecologic soft-tissue sarcoma.

III. To characterize the population pharmacokinetics of VEGF-Trap and to explore for demographic and clinical covariates

OUTLINE: This is an open-label, multicenter study.

Patients are stratified according to histology (uterine leiomyosarcoma vs malignant mixed mullerian tumor/carcinosarcoma). Patients receive ziv-aflibercept over 1 hour on day 1. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood collection at baseline, every 8 weeks during treatment, and 60 days after completion of study treatment for population pharmacokinetic analysis using enzyme-linked immunosorbent assay (ELISA).

After completion of study treatment, patients are followed at 4 weeks and then every 3 months thereafter.

• Fallopian Tube Cancer
• Female Reproductive Cancer
• Ovarian Carcinosarcoma
• Ovarian Sarcoma
• Recurrent Ovarian Epithelial Cancer
• Recurrent Uterine Sarcoma
• Stage III Ovarian Epithelial Cancer
• Stage III Uterine Sarcoma
• Stage IV Ovarian Epithelial Cancer
• Stage IV Uterine Sarcoma
• Uterine Carcinosarcoma
• Uterine Leiomyosarcoma

• Drug: ziv-aflibercept
  Given IV
  Other Names:

  • aflibercept
  • vascular endothelial growth factor trap
  • VEGF Trap
  • Zaltrap
• Other: laboratory biomarker analysis
  Correlative studies
• Other: pharmacological study
  Correlative studies
  Other Name: pharmacological studies

Inclusion Criteria:

• Histologically or cytologically confirmed soft tissue sarcoma of the gynecologic tract, including 1 of the following subtypes: uterine leiomyosarcoma, malignant mixed mullerian tumor/carcinosarcoma, disease originating in the ovary or fallopian tube allowed
• Locally advanced, unresectable, or metastatic disease
• Previously treated disease must have radiographic or clinical evidence of progressive disease
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan
• Indicator lesions may not have been previously treated with surgery, radiotherapy, or radiofrequency ablation unless progressive disease has been confirmed
• No evidence of CNS disease, including primary brain tumor or brain metastasis
• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Life expectancy >= 3 months
• WBC >= 3,000/mm^3
• Absolute neutrophil count >= 1,500/mm^3
• Platelet count >= 75,000/mm^3
• Bilirubin =< 1.5 times upper limit of normal (ULN)
• AST and ALT =< 3 times ULN
• INR =< 1.5 (unless on warfarin)
• Creatinine =< 1.5 times ULN OR creatinine clearance >= 60 mL/min
• Urine protein < 1+ by dipstick OR 24-hour urine protein < 500 mg OR urine protein:creatinine ratio < 1
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 6 months after completion of study treatment
• No other active malignancy within the past 5 years except adequately treated cervical carcinoma in situ or nonmelanoma skin cancer
• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
• No history of allergic reactions attributed to compounds of similar chemical or biological composition to study agents
• No serious or nonhealing wound, ulcer, or bone fracture
• No abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within the past 28 days
• No significant traumatic injuries within the past 28 days

• No clinically significant cardiovascular disease, including any of the following:

  • Cerebrovascular accident within the past 6 months,
  • Uncontrolled hypertension, defined as blood pressure (BP) > 150/100 mm Hg OR systolic BP > 180 mm Hg if diastolic BP < 90 mm Hg, on ≥ 2 repeated determinations on separate days within the past 3 months,
• OR; Antihypertensive medications allowed, as long as the dose and number of antihypertensive medications have not been increased within the past 2 weeks, Myocardial infarction, coronary artery bypass graft, or unstable angina within the past 6 months, OR;
• OR; New York Heart Association class III-IV congestive heart failure, serious cardiac arrhythmia requiring medication, or unstable angina pectoris within the past 6 months, Clinically significant peripheral vascular disease within the past 6 months (i.e., limiting activities of daily living or the presence of pain at rest),
• OR; pulmonary embolism, deep vein thrombosis, or other thromboembolic event within the past 6 months
• No evidence of bleeding diathesis or coagulopathy
• No uncontrolled intercurrent illness including, but not limited to, the following: Ongoing or active infection, psychiatric illness or social situations that would preclude study compliance
• No more than 2 prior cytotoxic chemotherapy regimen for recurrent, locally advanced, or metastatic disease
• Recovered from prior therapy
• No prior antiangiogenic agent
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas, carmustine, or mitomycin C)
• At least 4 weeks since prior investigational treatment
• At least 4 weeks since prior radiotherapy
• At least 4 weeks since prior major surgery or open biopsy
• At least 1 week since prior core biopsy
• At least 1 month since prior thrombolytic agents
• Concurrent full-dose anticoagulants (e.g., warfarin) with INR > 1.5 allowed provided all the following criteria are met:, In-range INR (usually between 2-3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin,
• OR; For patients on warfarin, the upper target for INR is ≤ 3 No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor invading major vessels or known varices)
• No other concurrent investigational agents
• No concurrent major surgery
• No concurrent combination antiretroviral therapy for HIV-positive patients