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

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

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.

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