The study design was an open-label Phase II pediatric clinical study. The purpose of Study X2203 was to identify any efficacy signal in subjects with the disease subtypes under study, when treated with pazopanib monotherapy. Furthermore, it was to define the toxicities of pazopanib in children, as well as examine biological markers, e.g. cytokines and angiogenic factors, that could help further characterize any response of pazopanib in children. Pazopanib was administered as monotherapy in tablet and powder suspension formulations at daily doses of 450 mg/m2/dose or 225 mg/m2/dose, respectively. The first 6 enrolled subjects receiving oral suspension formulation were assessed for tolerability and extended PK sampling; and, only if pazopanib was tolerated, subsequent subjects were enrolled at the same starting dose with the suspension. Dose escalation was not permitted. For the tablet, a dosing nomogram was used based on the subject's BSA. Dose reduction was dependent upon the toxicity of pazopanib and disease status of the infants, toddlers, children, adolescents, and young adults. Subjects could be as young as 1 year-old infants to screen for enrollment. Subjects were assessed for initial response after 8 weeks of treatment prior to Cycle 3. A cycle was defined as 28 days of pazopanib treatment with no rest period between cycles. Treatment was administered continuously once daily. Treatment was to be discontinued if there was evidence of disease progression, unacceptable treatment-related toxicity, pregnancy. Histological classification was an important diagnostic inclusion in these subjects with a wide variety of refractory solid tumors, i.e. 7 different tumor types and each being a cohort.

The study design included a hierarchical 2-stage tumor response assessment with each cohort independent from one other. First, an initial 10 subjects were enrolled into each cohort. In the event of ≥ 1 response in any of these initial subjects, an additional 10 subjects may be enrolled in that cohort to proceed. In the event of ≥ 3 responses, the agent was considered effective. However after end of-stage 1, study enrollment stopped due to insufficient antitumor activity. Subjects who discontinued study treatment were followed for survival status. The study was to continue accruing data and thus, remained open for approximately 1 year from Last Subject Last Visit (LSLV).

Key Inclusion Criteria:

• Subjects must be at least 1 and less than or equal to 18 years of age at the time of study entry.
• Patients must have had histologic verification of one of the malignancies listed below at original diagnosis or at relapse - a) Rhabdomyosarcoma, b) Non-rhabdomyosarcomatous Soft Tissue Sarcoma (including desmoplastic small round cell tumor), c) Ewing Sarcoma / Peripheral Primitive Neuroectodermal Tumor (PNET), d) Osteosarcoma, e) Neuroblastoma (Measurable), f) Neuroblastoma (Evaluable), g) Hepatoblastoma.
• Patient must have disease that has either relapsed or is refractory to prior therap
• Patients who will be receiving the tablet formulation must have a body surface area (BSA) >= 0.84 m^2 (square meter) at baseline.
• Patients must have radiographically measurable disease (with the exception of neuroblastoma), Measurable disease is defined as the presence of at least one lesion on magnetic resonance imaging (MRI) or computed tomography (CT) scan that can be accurately measured with the longest diameter a minimum of 10 mm in at least one dimension (CT scan slice thickness no greater than 5 mm).
• Patients with neuroblastoma who do not have measurable disease but have iodine-131 - meta-iodobenzylguanidine positive (MIBG+) evaluable disease are eligible.
• Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2. Use Karnofsky for subjects >= 16 years of age and Lansky for subjects <= 16 years of age.
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
• Patients must not have received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea).
• At least 7 days must have elapsed since the completion of therapy with a growth factor that supports platelet or white cell number or function. At least 14 days must have elapsed after receiving peg-filgrastim.
• At least 7 days must have elapsed since the completion of therapy with a biologic agent. For biologic agents that have known adverse events occurring beyond 7 days after administration, the period prior to enrollment must be extended beyond the time during which adverse events are known to occur.
• Subjects may have received bevacizumab, VEGF-Trap, or other VEGF blocking tyrosine kinase inhibitors, provided that they did not progress while receiving one of these agents. Subjects may not have previously received pazopanib.
• At least 21 days must have elapsed since the completion of the last dose of VEGF-Trap, and at least 7 days since a VEGF blocking tyrosine kinase inhibitor. Subjects must have recovered from any VEGF blocking drug-related toxicity (e.g., proteinuria).
• > = 21 days must have elapsed from infusion of last dose of antibody and toxicity related to prior antibody therapy must have recovered to Grade <= 1.
• Radiotherapy: >=2 weeks must have elapsed since local palliative radiotherapy (XRT) (small port); >=3 months must have elapsed if prior Traumatic Brain Injury (TBI), craniospinal XRT or if >=50% radiation of pelvis; >=6 weeks must have elapsed if other substantial bone marrow irradiation was given.
• No evidence of active graft versus host disease and >=2 months must have elapsed since transplant or rescue
• Adequate Bone Marrow Function defined as peripheral absolute neutrophil count (ANC) >=1000/ microlitre (µL), platelet count >= 75,000/µL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment); and hemoglobin >= 8.0 grams (g)/decilitre (dL), may receive red blood cell (RBC) transfusions. Subjects with bone marrow involvement will be eligible for study (provided they meet the criteria) but will not be evaluable for hematologic toxicity.
• Adequate Renal and Metabolic Function defined as creatinine clearance or radioisotope Glomerular filtration rate (GFR) >= 70 millilitre (mL)/ (min)/1.73 meter (m)^2 or A serum creatinine based on age/gender as follows, age 1 to < 2 years (male-0.6 milligrams (mg)/dL, female-0.6 mg/dL), age 2 to < 6 years (male-0.8 mg/dL, female-0.8 mg/dL), age 6 to < 10 years (male-1 mg/dL, female-1 mg/dL), age 10 to < 13 years (male-1.2 mg/dL, female-1.2 mg/dL), age 13 to < 16 years (male-1.5 mg/dL, female-1.4 mg/dL), age >= 16 years (male-1.7 mg/dL, female-1.4 mg/dL), urine creatinine ratio of <1 or a urinalysis that is negative for protein; or, 24-hour urine protein level < 1000 mg/dL, adequate thyroid function ,no more than Grade 1 abnormalities of potassium, calcium (confirmed by ionized calcium), magnesium and phosphorous.
• Adequate Liver Function defined as total bilirubin <=1.5 x upper limit of normal (ULN) for age, serum glutamic-pyruvic transaminase (SGPT) Alanine transaminase (ALT) <=2.5 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, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice, or cirrhosis. 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), the corrected QTc interval by Bazett's formula (QTcB) <450 milliseconds (msec), and must not have a history of myocardial infarction, severe or unstable angina, peripheral vascular disease or familial QTc prolongation.
• Adequate Blood Pressure Control defined as a blood pressure (BP) <= the 95th percentile for age, height, and gender measured, subjects on stable doses of no more than one anti-hypertensive medication, with a baseline BP <= 95th percentile for age, height and gender, will be eligible.
• Central Nervous System (CNS) Function defined as subjects with a known history of seizures must have well-controlled seizures and may not be receiving enzyme-inducing anti-convulsants, CNS toxicity <= Grade 2.
• Adequate Coagulation defined as prothrombin time (PT) and partial thromboplastin time (PTT) <= 1.2 x upper limit of normal and an international normalized ratio (INR) <= 1.2.

Key Exclusion Criteria:

• Pregnant or breast-feeding women are not eligible for this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. 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 beginning at the signing of the informed consent until at least 2 weeks after the last dose of the study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate. Study drug may also potentially be secreted in milk and therefore breastfeeding women are excluded.

Males (including those who have had vasectomies) with partners who can become pregnant will need to use birth control while on this study, as will their partner. Men are advised to use condoms during sexual intercourse while on study drug and continue to use adequate contraception for at least 2 weeks after the last dose of protocol therapy.

• 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 well controlled are not eligible for study enrollment.
• Patients must not be on therapeutic anticoagulation (Warfarin [coumadin] and/or low molecular weight heparin are prohibited). Prophylactic anticoagulation (i.e. intraluminal heparin) of venous or arterial access devices is allowed.
• Patients receiving drugs with a known risk of torsades de pointes are not eligible.
• 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 tablets or liquid are not eligible.
• Patients who have an 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 arterial thromboembolic events, including transient ischemic attack (TIA) or cerebrovascular accident (CVA); history (within 6 months prior to study enrollment) of pulmonary embolism, deep venous thrombosis (DVT), or other venous thromboembolic event; history of clinically significant bleeding within 6 weeks prior to study enrollment.
• Patients with known involvement of the CNS by malignancy will be excluded.
• Patients who have had or are planning to have the following invasive procedures will be excluded- Major surgical procedure, 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 1therapy.
• Patients with serious or non-healing wound, ulcer, or bone fracture.
• History of abdominal fistula, gastrointestinal perforation, 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.

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com