ARST0921, A Randomized Phase II Trial of Bevacizumab (IND# 7921, Avastin) and Temsirolimus (IND# 61010, Torisel) in Combination with Intravenous Vinorelbine and Cyclophosphamide in Patients with Recurrent/Refractory Rhabdomyosarcoma
Patients will be randomized at study entry to 1 of 2 study arms: vinorelbine/cyclophosphamide (VC) + bevacizumab (Regimen A) or VC+ temsirolimus (Regimen B). Therapy may continue for a maximum of 12 cycles in the absence of disease progression if off protocol therapy criteria have not yet been satisfied.
Each cycle will last 21 days. On Regimen A, bevacizumab will be administered at 15 mg/kg/dose on Day 1 of each cycle (ie, every 3 weeks). On Regimen B, temsirolimus will be administered at 15 mg/m2/dose on Days 1, 8 and 15 of each cycle (ie, weekly). The dose of temsirolimus is capped at 30 mg. Myeloid growth factor support (such as filgrastim) is required on this study.
Patients may not have surgery or radiation during the first 2 cycles of therapy (6 weeks). If surgery or radiation is indicated during that period, the patient will go off protocol therapy.
Surgery: Of note, bevacizumab must be held for 4 weeks prior to a major surgical procedure and also must be held following a surgical procedure (the length of time will depend upon the type of surgery performed). Vinorelbine, cyclophosphamide and temsirolimus therapy may be reinitiated after a surgical procedure at the discretion of the treating physician/surgeon.
Radiation therapy: If indicated, it is recommended that RT be administered at the completion of all chemotherapy (12 cycles) or at the time of disease progression. Patients will remain on protocol therapy if radiation is used for local control following the first 2 cycles of therapy but prior to the completion of protocol therapy or disease progression. Both bevacizumab and temsirolimus will be held during radiation therapy.
* Age: Patient must be < 30 years of age at the time of study enrollment.
* Diagnosis: Patients with first relapse or progression of rhabdomyosarcoma are eligible. Patients with primary refractory disease are eligible. Primary refractory disease is defined as first progression after receiving at least one course of cyclophosphamide or ifosfamide containing chemotherapy without prior demonstration of a radiographic response to chemotherapy (progression on irinotecan-containing chemotherapy without cyclophosphamide or ifosfamide containing chemotherapy will not be considered a first progression). Patients without measurable or evaluable disease are eligible. Patients must have had a previous histological verification of rhabdomyosarcoma at original diagnosis.
* Performance Level: Patients must have a Karnofsky or Lansky performance status score of >= 50%, corresponding to ECOG categories of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients <= 16 years of age.
* Life Expectancy: Patients must have a life expectancy of >= 8 weeks.
* Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
a. Myelosuppressive chemotherapy: Must not have received within 3 weeks prior to entry onto this study (4 weeks if prior nitrosourea).
b. Biologic (anti-neoplastic agent):
i) Patients may have received prior therapy with oral tyrosine kinase inhibitors or other similar agents. Given variable half-lives for such compounds (sorafenib = 36 hours, sunitinib = up to 110 hours), at least 7 days must have elapsed since the completion of therapy with a biologic agent and all toxicities must have resolved to < Grade 2 prior to enrollment.
ii) Anti-IGFR-1R and other monoclonal antibodies have variable half-lives depending on the type of antibody; therefore, 3 half-lives (or 6 weeks) must have elapsed since previous monoclonal antibody therapy prior to enrollment on this study.
c. Myeloid Growth Factor: Must not have received within 1 week prior to entry onto this
d. Radiation therapy (RT): At least 4 weeks must have elapsed between RT and study entry. Previously radiated lesions cannot be used to assess response unless those sites are the sites of disease progression.
e. Stem Cell Transplant (SCT): For autologous SCT, >= 3 months must have elapsed. For allogeneic SCT, >= 6 months must have elapsed and no evidence of active graft vs. host
* Patients must have recovered from any surgical procedure before enrolling on this study.
a. Minor surgical procedures (eg, biopsies involving core or fine needle aspiration procedures, infusaport or Broviac line placement, paracentesis or thoracocentesis) need to have fully healed and occurred > 7 days prior to enrollment.
b. Patients who have had a major surgical procedure (such as laparotomy, thoracotomy, open biopsy or resection of tumor) can only be enrolled on study > 28 days from such procedure.
* Organ Function Requirements: All patients must have:
* Adequate Bone Marrow Function defined as:
- Peripheral absolute neutrophil count (ANC) >= 750/uL
- Platelet count >= 75,000/uL (transfusion independent, defined as without transfusion for >= 1 week prior to enrollment)
- Hemoglobin >= 8.0 g/dL (may receive PRBC transfusions)
Note: Bone marrow disease involvement of tumor is allowed. However, peripheral blood count criteria as defined above must still be met.
* Adequate Renal Function defined as
- Creatinine clearance or radioisotope GFR >= 70 mL/min/1.73 m2 or
- A serum creatinine based on age/gender as listed in the protocol.
* Urine Protein Level
Patients aged <= 17 years:
Urine Protein to Creatinine (UPC) ratio should be calculated. UPC ratio must be <= 1 for patient to
be eligible. Note: UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion - a
UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1000 mg. UPC ratio is calculated using one of the following formulae:
- [urine protein]/[urine creatinine] - if both protein and creatinine are reported in mg/dL
- [(urine protein) x 0.088]/[urine creatinine] - if urine creatinine is reported in mmol/L
Patients aged > 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 < 1000 mg for patient enrollment.
* Adequate Liver Function defined as:
- Total bilirubin <= 1.5 x upper limit of normal (ULN) for age.
* Adequate Cardiac Function defined as:
- Shortening fraction of >= 27% by echocardiogram, or
- Ejection fraction of >= 50% by radionuclide angiogram.
* All patients and/or their parents or legal guardians must sign a written informed consent.
* All institutional, FDA, and NCI requirements for human studies must be met.