A Randomized Phase II Trial of Bevacizumab (Avastin) and Temsirolimus (Torisel) in Combination with Intravenous Vinorelbine and Cyclophosphamide in Patients with Recurrent/Refractory Rhabdomyosarcoma
This randomized phase II trial is studying how well giving vinorelbine ditartrate and cyclophosphamide together works in combination with bevacizumab or temsirolimus in treating patients with recurrent or refractory rhabdomyosarcoma.
Ages Eligible for Study: up to 29 Years Genders Eligible for Study: Both Accepts Healthy Volunteers: No CriteriaDISEASE CHARACTERISTICS:Patients must have had a previous histological verification of rhabdomyosarcoma at original diagnosisPatients with first relapse or progression of rhabdomyosarcoma are eligible Patients with primary refractory disease are eligible Patients with botryoid histology, any stage or group, are ineligible Patients with embryonal histology, stage I or clinical group 1 at initial disease presentation, who present with local or regional recurrence, are ineligible Patients without measurable or evaluable disease are eligible Bone marrow disease involvement of tumor is allowed, however, peripheral blood count criteria must still be met Patients with known CNS disease, except for those with treated brain metastasis, are ineligibleTreated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 3 months, as ascertained by clinical examination and brain imaging (MRI or CT) Stable dose of anticonvulsants are allowed Treatment for brain metastases may include whole-brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent), or a combination as deemed appropriate by the treating physician Patients with CNS metastases treated within 3 months prior to enrollment by neurosurgical resection or brain biopsy are ineligible PATIENT CHARACTERISTICS:Patients must have a Karnofsky or Lansky performance status score of ï¿½?ï¿½ 50%, corresponding to ECOG categories of 0, 1, or 2Use Karnofsky for patients greater than 16 years of age and Lansky for patients ï¿½?ï¿½ 16 years of age Patients must have a life expectancy of ï¿½?ï¿½ 8 weeks Peripheral absolute neutrophil count (ANC) ï¿½?ï¿½ 750/Î¼L Platelet count ï¿½?ï¿½ 75,000/Î¼L (transfusion independent, defined as without transfusion for ï¿½?ï¿½ 1 week prior to enrollment) Hemoglobin ï¿½?ï¿½ 8.0 g/dL (may receive PRBC transfusions) Creatinine clearance or radioisotope GFR ï¿½?ï¿½ 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:ï¿½?ï¿½ 0.4 mg/dL (for patients aged 1 month to less than 6 months) ï¿½?ï¿½ 0.5 mg/dL (for patients aged 6 months to less than 1 year) ï¿½?ï¿½ 0.6 mg/dL (for patients aged 1 to less than 2 years) ï¿½?ï¿½ 0.8 mg/dL (for patients aged 2 to less than 6 years) ï¿½?ï¿½ 1 mg/dL (for patients aged 6 to less than 10 years) ï¿½?ï¿½ 1.2 mg/dL (for patients aged 10 to less than 13 years) ï¿½?ï¿½ 1.4 mg/dL (for female patients aged ï¿½?ï¿½ 13 years) ï¿½?ï¿½ 1.5 mg/dL (for male patients aged 13 to less than 16 years) ï¿½?ï¿½ 1.7 mg/dL (for male patients aged ï¿½?ï¿½ 16 years) Urine protein level:For patients aged ï¿½?ï¿½ 17 years, UPC ratio must be ï¿½?ï¿½ 1 for patient to be eligible For patients aged greater than 17 years, urine protein should be screened by urine analysis; if protein is 2+ or higher, 24-hour urine protein must be obtained and the level must be less than 1000 mg for patient enrollment Total bilirubin ï¿½?ï¿½ 1.5 x upper limit of normal (ULN) for age Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception for the duration of study participation Patients with a documented chronic non-healing wound, ulcer, or significant trauma injury (those with bone fractures, including pathological fractures, or requiring surgical intervention) within 28 days prior to beginning therapy are ineligible Patients with evidence of intratumoral hemorrhage, gastrointestinal bleeding, or on anticoagulation for thrombosis or history of thrombosis are ineligible Patients with uncontrolled hypertension are ineligible; uncontrolled hypertension is defined as follows:Patients aged ï¿½?ï¿½ 17 years: greater than 95th percentile systolic and diastolic blood pressure based on age and height that is not controlled by one antihypertensive medication Patients aged greater than 17 years: systolic blood pressure ï¿½?ï¿½ 160 mm Hg and/or diastolic blood pressure ï¿½?ï¿½ 90 mm Hg that is not controlled by one antihypertensive medication Patients with history of central venous catheter (CVC)-associated thrombosis requiring systemic anticoagulation are ineligibleNOTE: Patients with history of sluggish flow from CVC or CVC-associated thrombosis treated with tissue plasminogen activator (TPA) only are not excluded. Patients with clinically significant cardiovascular disease are excluded:History of cerebrovascular accident (CVA) within the prior 6 months Myocardial infarction or unstable angina within the prior 6 months New York Heart Association grade 2 or greater congestive heart failure Serious and inadequately controlled cardiac arrhythmia Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) Clinically significant peripheral vascular disease PRIOR CONCURRENT THERAPY:See Disease Characteristics Patients who previously received vinorelbine, bevacizumab, temsirolimus, or any other direct VEGF/VEGFR- or mTOR- targeting agents are ineligible Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study For autologous stem cell transplantation (SCT), ï¿½?ï¿½ 3 months must have elapsed For allogeneic SCT, ï¿½?ï¿½ 6 months must have elapsed and no evidence of active graft vs host disease 3 half-lives (or 6 weeks) must have elapsed since previous monoclonal antibody therapy prior to enrollment on this study At least 4 weeks must have elapsed between radiotherapy and study entryPatients who previously received craniospinal irradiation are ineligible Previously radiated lesions cannot be used to assess response unless those sites are the sites of disease progression No myelosuppressive chemotherapy within 3 weeks prior to entry onto this study (4 weeks if prior nitrosourea) Patients may have received prior therapy with oral tyrosine kinase inhibitors or other similar agentsAt least 7 days must have elapsed since the completion of therapy with a biologic agent and all toxicities must have resolved to less than grade 2 prior to enrollment No myeloid growth factor within 1 week prior to entry onto this study Patients must have recovered from any surgical procedure before enrolling on this studyMinor surgical procedures (e.g., biopsies involving core or fine-needle aspiration procedures, infusaport or Broviac line placement, paracentesis, or thoracocentesis) need to have fully healed and occurred greater than 7 days prior to enrollment Patients who have had a major surgical procedure (such as laparotomy, thoracotomy, open biopsy, or resection of tumor) can only be enrolled on study greater than 28 days from such procedure Patients currently taking anticoagulants or antiplatelet agents with the exception of aspirin (ï¿½?ï¿½ 81 mg/day) are ineligible Patients may not undergo surgery or radiotherapy during the first 2 courses (6 weeks) of therapy
This is a multicenter study. Patients are stratified according to histologic subtype at initial diagnosis. Patients are randomized to 1 of 2 treatment arms.Arm I: Patients receive vinorelbine ditartrate IV over 6-10 minutes on days 1 and 8 and cyclophosphamide IV over 30-60 minutes on day 1. Patients also receive bevacizumab IV over 30-90 minutes on day 1. Arm II: Patients receive vinorelbine ditartrate and cyclophosphamide as in arm I. Patients also receive temsirolimus IV over 30-60 minutes on days 1, 8, and 15. In both arms, treatment repeats every 21 days for 12 courses in the absence of disease progression or unacceptable toxicity.Blood and tissue samples may be collected for correlative studies.After completion of study treatment, patients are followed up annually for 5 years.
05/18/2013 04:02 AM