Vinorelbine Tartrate and Cyclophosphamide in Combination With Bevacizumab or Temsirolimus in Treating Patients With Recurrent or Refractory Rhabdomyosarcoma
Condition: Adult Rhabdomyosarcoma; Childhood Alveolar Rhabdomyosarcoma; Childhood Pleomorphic Rhabdomyosarcoma; Childhood Rhabdomyosarcoma With Mixed Embryonal and Alveolar Features; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Rhabdomyosarcoma
MeSH terms: Sarcoma; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Rhabdomyosarcoma, Alveolar; Recurrence
Intervention: Bevacizumab; Cyclophosphamide; Laboratory Biomarker Analysis; Temsirolimus; Vinorelbine Tartrate
Intervention description: Given IV; Given IV; Correlative studies; Given IV; Given IV
Intervention MeSH terms: Sirolimus; Cyclophosphamide; Bevacizumab; Temsirolimus; Vinorelbine; Antineoplastic Agents, Immunological; MTOR Inhibitors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G; Endothelial Growth Factors
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 87.0
Sex: All
Maximum age: 29 Years
Healthy volunteers: No

Summary:

      This randomized phase II trial studies how well vinorelbine tartrate and cyclophosphamide
      work in combination with bevacizumab or temsirolimus in treating patients with recurrent or
      refractory rhabdomyosarcoma. Drugs used in chemotherapy, such as vinorelbine tartrate and
      cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing
      the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can
      block tumor growth in different ways. Some block the ability of tumor cells to grow and
      spread. Others find tumor cells and help kill them or carry tumor-killing substances to them.
      Bevacizumab may also stop the growth of rhabdomyosarcoma by blocking blood flow to the tumor.
      Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for
      cell growth. It is not yet known whether combination chemotherapy is more effective when
      given together with bevacizumab or temsirolimus in treating rhabdomyosarcoma.
    

Eligibility criteria:

        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