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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Study of VEGF-Trap in Recurrent or Metastatic Gynecologic Soft-Tissue Sarcomas

Conditions
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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

Intervention / Treatment
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* Drug: ziv-aflibercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically/cytologically confirmed soft tissue sarcoma of gynecologic tract including 1 of the following subtypes: uterine leiomyosarcoma, malignant mixed mullerian tumor/carcinosarcoma, disease originating in ovary/fallopian tube allowed Locally advanced/unresectable/metastatic disease Previously treated disease must have radiographic/clinical evidence of PD Measurable disease-at least 1 lesion in at least 1 dimension (longest diameter) as >=20mm with conventional techniques or as >=10mm with spiral CT scan Indicator lesions may not have been previously treated with surgery/radiotherapy/radiofrequency ablation unless PD has been confirmed ECOG 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=<1.5xULN AST and ALT=<3xULN INR=<1.5 (unless on warfarin) Creatinine=<1.5xULN 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/nursing Negative pregnancy test Fertile patients must use effective contraception during and for ≥6 months after treatment - No other active malignancy within past 5 years except adequately treated cervical carcinoma in situ/nonmelanoma skin cancer No known hypersensitivity to Chinese hamster ovary cell products/other recombinant human antibodies No history of allergic reactions attributed to compounds of similar chemical/biological composition to study agents No serious/nonhealing wound/ulcer/bone fracture No abdominal fistula/gastrointestinal perforation/bowel obstruction/intraabdominal abscess within past 28 days No significant traumatic injuries within past 28 days No evidence of bleeding diathesis/coagulopathy No uncontrolled intercurrent illness including but not limited to: Ongoing/active infection, psychiatric illness or social situations that would preclude study compliance <=2 prior cytotoxic chemotherapy regimen for recurrent, locally advanced or metastatic disease Recovered from prior therapy No prior antiangiogenic agent Exclusion Criteria: < 4weeks since prior chemotherapy (<6 weeks for nitrosoureas/carmustine/mitomycin C), prior investigational treatment, radiotherapy and major surgery/open biopsy 1 week since prior core biopsy 1 month since prior thrombolytic agents Concurrent full-dose anticoagulants with INR>1.5 allowed if: In-range INR (usually between 2-3) on stable dose of oral anticoagulant or low molecular weight heparin, OR; For patients on warfarin, the upper target for INR is ≤3 No active bleeding/pathological condition that carries a high risk of bleeding (e.g. tumor invading major vessels/known varices) No evidence of CNS disease including primary brain tumor/brain metastasis No other concurrent investigational agents - No concurrent major surgery No concurrent combination antiretroviral therapy for HIV-positive patients Clinically significant cardiovascular disease including: Cerebrovascular accident within past 6 months, Uncontrolled hypertension defined as BP>150/100mmHg OR systolic BP>180mmHg if diastolic BP<90 mmHg, on ≥2 repeated determinations on separate days within past 3 months, OR; Antihypertensive medications allowed as long as dose and number of antihypertensive medications have not increased within past 2 weeks, Myocardial infarction, coronary artery bypass graft, or unstable angina within past 6 months, OR; OR; NYHA class III-IV congestive heart failure, serious cardiac arrhythmia requiring medication, or unstable angina pectoris within past 6 months, Clinically significant peripheral vascular disease within past 6 months OR; pulmonary embolism, deep vein thrombosis, or other thromboembolic event within past 6 months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ziv-aflibercept)<br>Patients receive ziv-aflibercept IV over 1 hour on day 1. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity. | Drug: ziv-aflibercept<br>* Given IV<br>* Other names: Zaltrap;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate, Evaluated According to the RECIST Criteria |  | Up to 3 years | 
| Incidence of Disease Stabilization, as Measured by Progression-free Survival at 6 Months (Leiomyosaroma Group) |  | 6 months | 
| Incidence of Disease Stabilization, as Measured by Progression-free Survival at 6 Months (Carcinosarcoma Group) |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival (Leiomyosarcoma Group) | 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. | Up to 3 years | 
| Survival (Carcinosarcoma Group) | 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. | Up to 3 years |