Ramucirumab in Treating Younger Patients with Recurrent or Refractory Solid Tumors, Including CNS Tumors

Inclusion Criteria

• Part A: Patients with recurrent or refractory non-CNS solid tumors are eligible; patients must have had histologic verification of malignancy at original diagnosis or relapse except patients with extra-cranial germ-cell tumors who have elevations of serum tumor markers including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG); patients in part A cannot have CNS metastases
• Part B: Patients with recurrent or refractory CNS tumors will be eligible and must have a histological verification of malignancy at original diagnosis or relapse except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with CNS-germ cell tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or beta-HCG
• Patients must have either measurable or evaluable disease
• Patient’s current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
• Karnofsky performance status >= 50% for patients > 16 years of age and Lansky >= 50 for patients =<16 years of age; Note: neurologic deficits in patients with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy * Myelosuppressive chemotherapy: at least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea) * Hematopoietic growth factors: at least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair * Biologic (anti-neoplastic agent): at least 7 days after the last dose of a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair * Immunotherapy: at least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines * Monoclonal antibodies: at least 3 half-lives of the antibody after the last dose of a monoclonal antibody * Radiation therapy (XRT): at least 14 days after local palliative XRT (small port); at least 150 days must have elapsed if prior total body irradiation (TBI), craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial bone marrow (BM) radiation * Stem cell infusion without TBI: no evidence of active graft vs host disease and at least 84 days must have elapsed after transplant or stem cell infusion * Patients must not have received prior exposure to ramucirumab
• For patients with solid tumors without known bone marrow involvement:
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions)
• Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts specified above (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity; at least 5 of every cohort of 6 patients must be evaluable for hematologic toxicity for the dose-escalation part of the study; if dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity.
• Urine protein: =< 30 mg/dl in urinalysis or =< 1+ on dipstick, unless quantitative protein is < 1000 mg in a 24 hour (h) urine sample
• 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: * 1 to < 2 years: 0.6 mg/dL (male), 0.6 mg/dL (female) * 2 to < 6 years: 0.8 mg/dL (male), 0.8 mg/dL (female) * 6 to < 10 years: 1 mg/dL (male), 1 mg/dL (female) * 10 to < 13 years: 1.2 mg/dL (male), 1.2 mg/dL (female) * 13 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female) * >= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)
• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
• Serum albumin >= 2 g/dL
• Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by gated radionuclide study
• A blood pressure (BP) =< the 95th percentile for age, height, and gender, and not receiving medication for treatment of hypertension; please note that 3 serial blood pressures should be obtained and averaged to determine baseline BP
• International normalized ratio (INR) =< 1.5
• All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
• Tissue blocks or slides must be sent; if tissue blocks or slides are unavailable, the study chair must be notified prior to enrollment

Exclusion Criteria

• Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use a highly effective method of contraception during protocol therapy and for at least 3 months after the last dose of ramucirumab; a highly effective method of contraception is defined as one that results in a low failure rate (that is, <1% per year) when used consistently and correctly; barrier methods used alone are not highly effective methods of contraception; for female patients, if a barrier method is used, a hormonal method must be used with it to ensure that pregnancy does not occur; abstinence is an acceptable method of birth control; those who become pregnant while on treatment with ramucirumab must discontinue immediately and consult their treating physician
• Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible
• Patients who are currently receiving another investigational drug are not eligible
• Patients who are currently receiving other anti-cancer agents are not eligible
• Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
• Patients who are chronically receiving aspirin, ibuprofen or other non-steroidal anti-inflammatory drugs are not eligible
• Patients who are currently receiving anti-platelet agents are not eligible
• Patients who are receiving anti-hypertensive medications for control of blood pressure at the time of enrollment are not eligible for this trial
• Patients who are currently receiving therapeutic anti-coagulation with heparin, low-molecular weight heparin or Coumadin are not eligible for this trial
• Patients who are currently receiving belimumab (a monoclonal antibody for systemic lupus erythematosus) are not eligible
• Patients who are currently receiving bisphosphonate derivatives are not eligible
• Patients who have had or are planning to have the following invasive procedures are not eligible: * Major surgical procedure, laparoscopic procedure, open biopsy or significant traumatic injury within 28 days prior to enrollment * Central line placement or subcutaneous port placement is not considered major surgery; external central lines must be placed at least 3 days prior to enrollment and subcutaneous ports must be placed at least 7 days prior to enrollment * Core biopsy within 7 days prior to enrollment * Fine needle aspirate within 7 days prior to enrollment * Surgical or other wounds must be adequately healed prior to enrollment; Note: for purposes of this study, bone marrow aspirate and biopsy are not considered surgical procedures and therefore are permitted within 14 days prior to start of protocol therapy
• Bleeding and thrombosis: * Patients with evidence of active bleeding: intratumoral hemorrhage by current imaging, or bleeding diathesis are not eligible * Patients with known or prior history in prior 3 months of esophageal varices are not eligible * Patients with a history of CNS arterial/venous thromboembolic events including transient ischemic attack (TIA) or cerebrovascular accident (CVA) within 6 months prior to study enrollment are not eligible * Patients with a history of deep vein thrombosis (including pulmonary embolism) within 3 months prior to study enrollment are not eligible * Patients with a history of hemoptysis or other signs of pulmonary hemorrhage within 3 months prior to study enrollment are not eligible * Patients with a history of >= grade 3 bleeding disorders, vasculitis, or had a significant (>= grade 3) episode from the gastrointestinal bleeding, within 6 months prior to enrollment are not eligible * For part B: patients with CNS tumors and evidence of new CNS hemorrhage of more than punctate size and/or more than three foci of punctate hemorrhage on baseline magnetic resonance imaging (MRI) obtained within 14 days prior to study enrollment are not eligible; Note: echocardiogram (ECHO) gradient MRI sequences per institutional guidelines are required for patients with CNS tumors
• Patients with known cardiac disease per the New York Heart Association definition such as myocardial infarction, severe or unstable angina, peripheral vascular disease, or congestive heart failure or peripheral vascular disease are not eligible
• Patients who have a history of fistula, gastrointestinal ulcer or perforation, or intra-abdominal abscess within 3 months of study enrollment are not eligible
• Patients with a history of hypertensive crisis or hypertensive encephalopathy within 6 months of study enrollment are not eligible
• Patients who have non-healing wound, unhealed or incompletely healed fracture, or a compound (open) bone fracture at the time of enrollment are not eligible
• Immunocompromised patients (other than that related to the primary oncologic diagnosis or to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive are not eligible
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible