Pazopanib Hydrochloride, Irinotecan, and Temozolomide in Treating Children and Young Adults with Relapsed or Refractory Sarcoma

Inclusion Criteria

• Eligible patients have a body surface area >= 0.7 m^2 AND be able to swallow whole tablets at the time of study enrollment
• Patients must have had histologic verification of one of the malignancies listed below at original diagnosis or at time of relapse * Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET) * Osteosarcoma * Rhabdomyosarcoma * Non-rhabdomyosarcoma soft tissue sarcoma * Desmoplastic small round cell tumor Note: Patients with known involvement of the central nervous system (CNS) by malignancy will be included if there is no evidence of active bleeding or intratumoral hemorrhage on radiographic imaging
• Patients must have either measurable or evaluable disease
• Patient’s current disease state must be one for which there is not known curative therapy or therapy proven to prolong survival with an acceptable quality of life
• Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50% for patients =< 16 years of age; Note: Neurologic deficits in patients with metastatic CNS tumors must have been relatively stable for a minimum of 1 week 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
• Patients must not have received myelosuppressive therapy within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea)
• 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
• At least 7 days must have passed after the last treatment with a biologic agent; for agents that have known adverse events occurring beyond 7 days from 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
• At least 4 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines
• >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
• >= 2 weeks must have elapsed for local palliative radiation therapy (XRT) (small port) and enrollment on study; at least 24 weeks must have elapsed since prior total body irradiation (TBI), radiation to >= 50% of pelvis, or craniospinal radiation; >= 6 weeks must have elapsed if the patient has received other substantial bone marrow radiation
• No evidence of active graft versus host disease (GVHD) and >= 2 months must have elapsed since transplant or rescue
• Patients may not have previously received pazopanib; however patients may have received other vascular endothelial growth factor (VEGF) blocking tyrosine kinase inhibitors, patients must have recovered from any VEGF blocking drug-related toxicity (e.g., proteinuria); patients previously treated with irinotecan and/or temozolomide will be eligible for this study provided they did not progress while receiving one of these agents
• Peripheral absolute neutrophil count (ANC) >= 750/uL
• Platelet count >= 75,000/ul (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment)
• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions)
• 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: * Age: 1 to < 2 years; maximum serum creatinine (mg/dl): 0.6 * Age: 2 to < 6 years; maximum serum creatinine (mg/dl): 0.8 * Age: 6 to < 10 years; maximum serum creatinine (mg/dl): 1.0 * Age: 10 to < 13 years; maximum serum creatinine (mg/dl): 1.2 * Age: 13 to < 16 years; maximum serum creatinine (mg/dl): 1.5 (male) 1.4 (female) * Age: >= 16 years; maximum serum creatinine (mg/dl): 1.7 (male) 1.4 (female)
• Urine protein to creatinine ratio of < 1, a urinalysis that is negative for protein, or a 24-hour urine protein level < 1000 mg/dL
• No more than grade 1 abnormalities of potassium, calcium (confirmed by ionized calcium), magnesium, and phosphorus (supplementation allowed)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x ULN (for the purpose of this study, the ULN for SGPT is 45 U/L)
• Serum albumin >= 2 g/dL
• Must not have active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per investigator assessment); * Note: Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis
• No known positivity of hepatitis B surface antigen (HBsAg), or of positive hepatitis C antibody
• Shortening fraction of >= 27% by echocardiogram (while not receiving medications for cardiac function), or
• Ejection fraction of >= 50% by gated radionuclide study (while not receiving medications for cardiac function)
• Corrected QT interval (QTc) < 480 msec
• Must not have a history of myocardial infarction, severe or unstable angina, peripheral vascular disease or familial QT prolongation
• A blood pressure (BP) =< 95% percentile for age, height, and gender; patients on stable doses of no more than one anti-hypertensive medication, with a baseline BP =< 95% percentile for age, height, and gender will be eligible
• Patients with a known history of seizures must have well-controlled seizures and may not be receiving enzyme-inducing anti-convulsants
• CNS toxicity =< grade 2
• No evidence of dyspnea at rest
• No exercise intolerance
• Prothrombin time (PT) and partial thromboplastin time (PTT) =< 1.5 x ULN
• International normalized ratio (INR) =< 1.2

Exclusion Criteria

• Pregnant or breastfeeding women will not be entered on this study; negative 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 an effective contraceptive method; the definition of adequate contraception will be based on the judgment of the principal investigator or designated associate; breastfeeding women are excluded
• Patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 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 or radiation therapy are not eligible
• Patients who are currently receiving more than one anti-hypertensive medication (grade 3) or whose blood pressure is not controlled are not eligible for study enrollment
• Patients must not be on therapeutic anti-coagulation; prophylactic anti-coagulation (i.e., intraluminal heparin) of venous or arterial access devices is allowed
• Patients currently receiving aspirin, and/or ibuprofen, or other non-steroidal anti-inflammatory drugs (NSAIDs) are not eligible
• Patients who are currently receiving enzyme-inducing anti-convulsants are not eligible
• Patients receiving drugs with a known risk of torsades de pointes are not eligible; Note: This list includes the prohibition of grapefruit for 14 days prior to enrollment
• Patients who require thyroid replacement therapy are not eligible if they have not been receiving a stable replacement dose for at least 4 weeks prior to study enrollment
• Patients who are unable to swallow whole tablets are not eligible
• Patients who have an active or uncontrolled infection are not eligible
• Patients will be excluded if any of the following are present: * Evidence of active bleeding, intratumoral hemorrhage, or bleeding diathesis * History (within 6 months prior to study enrollment) of pulmonary embolism, deep vein thrombosis (DVT), or other venous thromboembolic event * History of hemoptysis within 6 weeks prior to study enrollment
• Patients with known involvement of the CNS by malignancy will be included if there is no evidence of active bleeding or intratumoral hemorrhage on radiographic imaging
• Patients who have had or are planning to have the following invasive procedures will be excluded: * Major surgical procedures, laparoscopic procedure, open biopsy, or significant traumatic injury within 28 days prior to day 1 therapy; subcutaneous port placement or central line placement is not considered major surgery, but must be placed greater than 48 hours from planned day 1 of therapy * Core biopsy within 7 days prior to day 1 therapy * Fine needle aspirate or central line placement within 48 hours prior to day 1 therapy Note: Routine bone marrow aspirate and biopsy for the purposes of disease staging are not part of these exclusion guidelines
• Patients with serious or non-healing wound, ulcer, or bone fracture
• History of abdominal fistula, gastrointestinal perforation, pneumothorax, or intra-abdominal abscess within 28 days of study enrollment
• 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
• Patients with history of allergic reactions attributed to compounds of similar composition to pazopanib, irinotecan, or temozolomide are not eligible