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

• ClinicalTrials.gov Identifier: NCT00390234
• Recruitment Status: Completed
• First Posted: October 19, 2006
• Results First Posted: November 21, 2014
• Last Update Posted: December 7, 2015
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
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	Drug: ziv-aflibercept	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 63 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of VEGF-Trap in Recurrent or Metastatic Gynecologic Soft-Tissue Sarcomas
• Study Start Date: September 2006
• Actual Primary Completion Date: September 2011
• Actual Study Completion Date: August 2013

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate, Evaluated According to the RECIST Criteria [ Time Frame: Up to 3 years ]
2. Incidence of Disease Stabilization, as Measured by Progression-free Survival at 6 Months (Leiomyosaroma Group) [ Time Frame: 6 months ]
3. Incidence of Disease Stabilization, as Measured by Progression-free Survival at 6 Months (Carcinosarcoma Group) [ Time Frame: 6 months ]

Secondary Outcome Measures :

1. Survival (Leiomyosarcoma Group) [ Time Frame: 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.
2. Survival (Carcinosarcoma Group) [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

City of Hope

Duarte, California, United States, 91010

University of Southern California

Los Angeles, California, United States, 90033-0804

UC Davis Comprehensive Cancer Center

Sacramento, California, United States, 95817

United States, Illinois

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, United States, 60637-1470

Evanston CCOP-NorthShore University HealthSystem

Evanston, Illinois, United States, 60201

Peoria Gynecologic Oncology

Peoria, Illinois, United States, 61603

United States, Michigan

University of Michigan University Hospital

Ann Arbor, Michigan, United States, 48109

United States, Pennsylvania

Fox Chase Cancer Center

Rockledge, Pennsylvania, United States, 19046

Canada, British Columbia

Vancouver General Hospital

Vancouver, British Columbia, Canada, V5C 1M9

BCCA-Vancouver Cancer Centre

Vancouver, British Columbia, Canada, V5Z 4E6

Canada, Ontario

Juravinski Cancer Centre at Hamilton Health Sciences

Hamilton, Ontario, Canada, L8V 5C2

Cancer Centre of Southeastern Ontario at Kingston General Hospital

Kingston, Ontario, Canada, K7L 5P9

London Regional Cancer Program

London, Ontario, Canada, N6A 4L6

Odette Cancer Centre- Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada, M4N 3M5

University Health Network-Princess Margaret Hospital

Toronto, Ontario, Canada, M5G 2M9

Canada, Quebec

McGill University Department of Oncology

Montreal, Quebec, Canada, H2W 1S6

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Amit Oza; University Health Network-Princess Margaret Hospital

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00390234
• Other Study ID Numbers: NCI-2009-00177; PHL-051 ( Other Grant/Funding Number: N01CM62209 ); CDR0000508798 ( Other Grant/Funding Number: N01CM62209 ); N01CM62209 ( U.S. NIH Grant/Contract ); N01CM62203 ( U.S. NIH Grant/Contract ); N01CM62201 ( U.S. NIH Grant/Contract )
• First Posted: October 19, 2006
• Results First Posted: November 21, 2014
• Last Update Posted: December 7, 2015
• Last Verified: May 2013

Additional relevant MeSH terms:

Sarcoma; Fallopian Tube Neoplasms; Carcinoma, Ovarian Epithelial; Leiomyosarcoma; Carcinosarcoma; Mixed Tumor, Mullerian; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Fallopian Tube Diseases; Adnexal Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Endocrine Gland Neoplasms; Ovarian Diseases; Endocrine System Diseases; Gonadal Disorders; Neoplasms, Muscle Tissue; Neoplasms, Complex and Mixed; Aflibercept; Endothelial Growth Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors