Clinical trial NCT00390234: Ziv-aflibercept in Treating Patients With Locally Advanced, Unresectable, or Metastatic Gynecologic Soft Tissue Sarcoma
Official title: A Phase II Study of VEGF-Trap in Recurrent or Metastatic Gynecologic Soft-Tissue Sarcomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-10-19
Enrollment: 63
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Objective Response Rate, Evaluated According to the RECIST Criteria
timeFrame: Up to 3 years
measure: Incidence of Disease Stabilization, as Measured by Progression-free Survival at 6 Months (Leiomyosaroma Group)
timeFrame: 6 months
measure: Incidence of Disease Stabilization, as Measured by Progression-free Survival at 6 Months (Carcinosarcoma Group)
timeFrame: 6 months
Secondary outcomes:
measure: Survival (Leiomyosarcoma Group)
timeFrame: Up to 3 years
measure: Survival (Carcinosarcoma Group)
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Sacramento
country: United States
facility: UC Davis Comprehensive Cancer Center
state: California
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Evanston
country: United States
facility: Evanston CCOP-NorthShore University HealthSystem
state: Illinois
city: Peoria
country: United States
facility: Peoria Gynecologic Oncology
state: Illinois
city: Ann Arbor
country: United States
facility: University of Michigan University Hospital
state: Michigan
city: Rockledge
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: BCCA-Vancouver Cancer Centre
state: British Columbia
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: Kingston
country: Canada
facility: Cancer Centre of Southeastern Ontario at Kingston General Hospital
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Toronto
country: Canada
facility: Odette Cancer Centre- Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: University Health Network-Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: McGill University Department of Oncology
state: Quebec
Study officials:
affiliation: University Health Network-Princess Margaret Hospital
name: Amit Oza
role: PRINCIPAL_INVESTIGATOR
References: