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.

Study Overview

• Status: Completed
• Conditions: Fallopian Tube Cancer; Uterine Carcinosarcoma; Stage IV Ovarian Epithelial Cancer; Ovarian Sarcoma; Recurrent Uterine Sarcoma; Stage III Uterine Sarcoma; Stage IV Uterine Sarcoma; Recurrent Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Ovarian Carcinosarcoma; Female Reproductive Cancer; Uterine Leiomyosarcoma
• Intervention / Treatment: Drug: ziv-aflibercept

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 Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BCCA-Vancouver Cancer Centre
    • Vancouver, British Columbia, Canada, V5C 1M9
      • Vancouver General Hospital
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Centre at Hamilton Health Sciences
    • Kingston, Ontario, Canada, K7L 5P9
      • Cancer Centre of Southeastern Ontario At Kingston General Hospital
    • London, Ontario, Canada, N6A 4L6
      • London Regional Cancer Program
    • Toronto, Ontario, Canada, M5G 2M9
      • University Health Network-Princess Margaret Hospital
    • Toronto, Ontario, Canada, M4N 3M5
      • Odette Cancer Centre- Sunnybrook Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada, H2W 1S6
      • McGill University Department of Oncology
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Los Angeles, California, United States, 90033-0804
      • University of Southern California
    • Sacramento, California, United States, 95817
      • UC Davis Comprehensive Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Comprehensive Cancer Center
    • Evanston, Illinois, United States, 60201
      • Evanston CCOP-NorthShore University HealthSystem
    • Peoria, Illinois, United States, 61603
      • Peoria Gynecologic Oncology
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan University Hospital
  • Pennsylvania
    • Rockledge, Pennsylvania, United States, 19046
      • Fox Chase Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment (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.	Drug: ziv-aflibercept; Given IV; Other Names: aflibercept; vascular endothelial growth factor trap; VEGF Trap; Zaltrap

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start: September 1, 2006
• Primary Completion (ACTUAL): September 1, 2011
• Study Completion (ACTUAL): August 1, 2013

Study Registration Dates

• First Submitted: October 18, 2006
• First Submitted That Met QC Criteria: October 18, 2006
• First Posted (ESTIMATE): October 19, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): December 7, 2015
• Last Update Submitted That Met QC Criteria: December 3, 2015
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Disease Attributes; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Fallopian Tube Diseases; Neoplasms, Complex and Mixed; Ovarian Neoplasms; Neoplasms, Muscle Tissue; Sarcoma; Recurrence; Fallopian Tube Neoplasms; Carcinosarcoma; Mixed Tumor, Mullerian; Carcinoma, Ovarian Epithelial; Leiomyosarcoma; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aflibercept; Endothelial Growth Factors
• Other Study ID Numbers: NCI-2009-00177; N01CM62201 (U.S. NIH Grant/Contract); N01CM62203 (U.S. NIH Grant/Contract); N01CM62209 (U.S. NIH Grant/Contract); PHL-051 (OTHER_GRANT: N01CM62209); CDR0000508798 (OTHER_GRANT: N01CM62209)