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

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