Vinorelbine Tartrate and Cyclophosphamide in Combination With Bevacizumab or Temsirolimus in Treating Patients With Recurrent or Refractory Rhabdomyosarcoma

PRIMARY OBJECTIVES:

l. To determine the feasibility of administering bevacizumab in combination with intravenous
vinorelbine (vinorelbine tartrate) and cyclophosphamide (VC) in patients with recurrent
rhabdomyosarcoma (RMS).

II. To determine the feasibility of administering temsirolimus in combination with VC in
patients with recurrent RMS.

III. To estimate the event-free survival (EFS) of patients with recurrent/refractory RMS
treated with bevacizumab and VC and compare with the EFS of those treated with temsirolimus
and VC.

SECONDARY OBJECTIVES:

I. To estimate the initial (2 cycle) response rate of patients with recurrent/refractory RMS
treated with bevacizumab and VC and compare with the response rate of those treated with
temsirolimus and VC, and to also compare the best response rate on each regimen of protocol
therapy.

II. To evaluate surrogate biological markers in patients with recurrent RMS and to estimate
differences in these markers following treatment with bevacizumab and temsirolimus.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive vinorelbine tartrate intravenously (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 tartrate 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.

After completion of study treatment, patients are followed up annually for 5 years.

Inclusion Criteria:

- 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)

- Note: Patients without measurable or evaluable disease are eligible

- Patients must have had a previous histological verification of rhabdomyosarcoma at
original diagnosis

- Patients must have a Karnofsky or Lansky performance status score of >= 50%,
corresponding to Eastern Cooperative Oncology Group (ECOG) categories of 0, 1, or 2;
use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of
age

- Patients must have a life expectancy of >= 8 weeks

- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study

- Myelosuppressive chemotherapy: Must not have received within 3 weeks prior to entry
onto this study (4 weeks if prior nitrosourea)

- Biologic (anti-neoplastic agent):

- Patients may have received prior therapy with oral tyrosine kinase inhibitors or
other similar agents; 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

- 3 half-lives (or 6 weeks) must have elapsed since previous monoclonal antibody
therapy prior to enrollment on this study

- Myeloid growth factor: Must not have received within 1 week prior to entry onto this
study

- 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

- 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 disease

- Patients must have recovered from any surgical procedure before enrolling on this
study

- Minor 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 > 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 >
28 days from such procedure

- Peripheral absolute neutrophil count (ANC) >= 750/μL

- Platelet count >= 75,000/μL (transfusion independent, defined as without transfusion
for >= 1 week prior to enrollment)

- Hemoglobin >= 8.0 g/dL (may receive packed red blood cells [PRBC] transfusions)

- Bone marrow disease involvement of tumor is allowed, however, peripheral blood count
criteria must still be met

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:

- =< 0.4 mg/dL (for patients aged 1 month to < 6 months)

- =< 0.5 mg/dL (for patients aged 6 months to < 1 year)

- =< 0.6 mg/dL (for patients aged 1 to < 2 years)

- =< 0.8 mg/dL (for patients aged 2 to < 6 years)

- =< 1 mg/dL (for patients aged 6 to < 10 years)

- =< 1.2 mg/dL (for patients aged 10 to < 13 years)

- =< 1.4 mg/dL (for female patients aged >= 13 years)

- =< 1.5 mg/dL (for male patients aged 13 to < 16 years)

- =< 1.7 mg/dL (for male patients aged >= 16 years)

- 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

- 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 < 1,000 mg for patient enrollment

- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

- Shortening fraction of >= 27% by echocardiogram or ejection fraction of >= 50% by
radionuclide angiogram

Exclusion Criteria:

- 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 who previously received craniospinal irradiation are ineligible

- Patients who previously received vinorelbine, bevacizumab, temsirolimus, or any other
direct vascular endothelial growth factor (VEGF)/vascular endothelial growth factor
receptor (VEGFR-) or mammalian target of rapamycin (mTOR-) targeting agents are
ineligible

- Patients with known central nervous system (CNS) disease (excluding
intracranial/intraspinal extension secondary to local progression of a parameningeal
or paraspinal primary), except for those with treated brain metastasis, are
ineligible

- Treated 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
(magnetic resonance imaging [MRI] or computed tomography [CT]); stable dose of
anticonvulsants are allowed; treatment for brain metastases may include
whole-brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear
accelerator [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

- Patients who receive radiation or chemotherapy (inclusive of palliative intent) for
first disease progression or relapse of rhabdomyosarcoma prior to enrollment are
ineligible

- Female patients who are pregnant are ineligible

- Lactating females are not eligible unless they have agreed to discontinue
breastfeeding

- Female patients of childbearing potential are not eligible unless a negative
pregnancy test result has been obtained

- Sexually active patients of reproductive potential are not eligible unless they have
agreed to use an effective contraceptive method for the duration of their 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 =< 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 > 17 years: systolic blood pressure >= 160 mm Hg and/or diastolic
blood pressure >= 90 mm Hg that is not controlled by one antihypertensive
medication

- Patients currently taking anticoagulants or antiplatelet agents with the exception of
aspirin (=< 81 mg/day) are ineligible

- Patients with history of central venous catheter (CVC)-associated thrombosis
requiring systemic anticoagulation are ineligible; Note: 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

- Patients diagnosed with rhabdomyosarcoma as a second malignant neoplasm are not
eligible

- Patients with history of any second malignant neoplasm who have received chemotherapy
or radiation for the treatment of that malignancy are not eligible