Patient case: 78-year-old female with sarcoma; genetic feature: MDM2

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

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: 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

Relevance to patient case: not relevant