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

Phase 2

Completed

• Conditions: Fallopian Tube Cancer; Female Reproductive Cancer; Ovarian Sarcoma; Stage IV Uterine Sarcoma; Uterine Carcinosarcoma; Uterine Leiomyosarcoma; Stage III Uterine Sarcoma; Stage IV Ovarian Epithelial Cancer; Ovarian Carcinosarcoma; Recurrent Ovarian Epithelial Cancer
• Interventions: Drug: ziv-aflibercept

• Registration Number: NCT00390234
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

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

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.

Study Timeline

• Study Start: 2006-09
• Study First Submitted: 2006-10-18
• Study First Submitted QC: 2006-10-18
• Study First Posted: 2006-10-19
• Primary Completion: 2011-09
• Status Verified: 2013-05
• Study Completion: 2013-08
• Results First Submitted: 2014-11-14
• Results First Submitted QC: 2014-11-14
• Results First Posted: 2014-11-21
• Last Update Submitted: 2015-12-03
• Last Update Posted: 2015-12-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 63

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (ziv-aflibercept)	ziv-aflibercept	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Survival (Leiomyosarcoma Group)	Up to 3 years	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.
Survival (Carcinosarcoma Group)	Up to 3 years	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.

Trial Locations

Locations (16)

Juravinski Cancer Centre at Hamilton Health Sciences; 🇨🇦 Hamilton, Ontario, Canada

Vancouver General Hospital; 🇨🇦 Vancouver, British Columbia, Canada

McGill University Department of Oncology; 🇨🇦 Montreal, Quebec, Canada

University of Southern California; 🇺🇸 Los Angeles, California, United States

UC Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

University of Chicago Comprehensive Cancer Center; 🇺🇸 Chicago, Illinois, United States

Evanston CCOP-NorthShore University HealthSystem; 🇺🇸 Evanston, Illinois, United States

University of Michigan University Hospital; 🇺🇸 Ann Arbor, Michigan, United States

Cancer Centre of Southeastern Ontario at Kingston General Hospital; 🇨🇦 Kingston, Ontario, Canada

Odette Cancer Centre- Sunnybrook Health Sciences Centre; 🇨🇦 Toronto, Ontario, Canada

University Health Network-Princess Margaret Hospital; 🇨🇦 Toronto, Ontario, Canada

City of Hope; 🇺🇸 Duarte, California, United States

Peoria Gynecologic Oncology; 🇺🇸 Peoria, Illinois, United States

BCCA-Vancouver Cancer Centre; 🇨🇦 Vancouver, British Columbia, Canada

London Regional Cancer Program; 🇨🇦 London, Ontario, Canada

Fox Chase Cancer Center; 🇺🇸 Rockledge, Pennsylvania, United States