This is the first study to evaluate the safety and clinical activity of the combination of oral pazopanib, intravenous or oral irinotecan, and oral temozolomide in pediatric and young adult patients with relapsed or refractory sarcomas. This study will use a 3 + 3 design for dose escalation (Part 1), followed by an expansion cohort (Part 2) at the recommended phase 2 dose level.

The combination of irinotecan and temozolomide is well-tolerated and provides an active therapy option for heavily pre-treated patients with sarcoma. The toxicity profile and activity level suggest that this combination will provide a useful platform onto which novel compounds may be added. Pazopanib has been shown to demonstrate single-agent activity in sarcomas in the preclinical and clinical settings. Pazopanib has also been shown to have additive or synergistic effects in preclinical models of sarcomas when combined with cytotoxic chemotherapy. Pharmacokinetic studies of pazopanib and irinotecan as well as pharmacodynamic studies of pazopanib to assess anti-angiogenesis will be performed. Exploratory studies to assess non-invasive methods of monitoring tumor response [circulating tumor DNA and functional imaging by positron emission tomography (PET)/magnetic resonance imaging (MRI) will be performed].

Inclusion Criteria:

1. Age: Patients must be 6-30 years of age at the time of study enrollment.

2. Body Surface Area: Eligible patients have a body surface area >/= 0.7 m2 AND be able to swallow whole tablets at the time of study enrollment.

3. Diagnosis: 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.

4. Disease Status: Patients must have either measurable or evaluable disease

5. Therapeutic Options: 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.

6. Performance Level: 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.

7. Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy.

   Myelosuppressive chemotherapy: Patients must not have received myelosuppressive therapy within 2 weeks of enrollment onto this study (6 weeks 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 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.

   Immunotherapy: At least 4 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines.

   Monoclonal antibodies: >/= 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.

   External beam radiation therapy (XRT): >/= 2 weeks must have elapsed for local palliative 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.

   Stem Cell Transplant (SCT): No evidence of active graft-versus-host disease (GVHD) and >/= 2 months must have elapsed since transplant or rescue.

   Prior treatment with pazopanib, irinotecan, temozolomide: 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.

8. Organ Function Requirements:

Adequate Bone Marrow Function defined as:

• Peripheral absolute neutrophil count (ANC) >/= 750/μL
• Platelet count >/= 75,000/μl (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

Adequate Renal and Metabolic Function defined as:

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >/= 70 mL/min/1.73 m2 or
• A serum creatinine based on age/gender per protocol.

The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control and Prevention (CDC).

• 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).

Adequate Liver Function defined as:

• Total bilirubin </= 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate 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).
• No known positivity of hepatitis B surface antigen (HBsAg), or of positive hepatitis C antibody.

Adequate Cardiac Function defined as:

• 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.

Adequate Blood Pressure Control defined as: A blood pressure (BP) \