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Pazopanib Paediatric Phase II Trial Children's Oncology Group (COG) in Solid Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 by Novartis
Children's Oncology Group
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals ) Identifier:
First received: August 1, 2013
Last updated: August 8, 2016
Last verified: August 2016
The purpose of this study is to find out what effects, good or bad, pazopanib (GW786034), National Service Center (NSC) # 737754, has on children, adolescents and young adults between 12 months and less than or equal to 18 years of age with relapsed or refractory rhabdomyosarcoma, non rhabdomyosarcomatous soft tissue sarcoma, Ewing sarcoma, relapsed or refractory osteosarcoma, neuroblastoma (measurable and/or evaluable), or hepatoblastoma. This is a two-stage open label phase II trial of pazopanib in children, adolescents and young adults with recurrent or refractory solid tumors. Eligible subjects will receive pazopanib daily as an oral tablet (450 mg/m^2/dose) or as a powder for suspension (225 mg/m^2/dose) in 28 day cycles. The maximum dose to be administered daily for tablets is 800 mg and for suspension 400 mg. Subjects will be closely monitored with clinical and laboratory observations for side effects. Response to treatment will be evaluated using appropriate imaging studies. In the absence of severe toxicity or progressive disease, subjects may continue receiving pazopanib.

Condition Intervention Phase
Solid Tumours
Drug: Pazopanib GW786034
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Pazopanib GW786034, NSC# 737754 in Children, Adolescents and Young Adults With Refractory Solid Tumors

Resource links provided by NLM:

Further study details as provided by Novartis:

Primary Outcome Measures:
  • The investigator assessed objective response rate (ORR) in subjects' with tumors of primary interest [ Time Frame: Up to 24 cycles from the start of treatment ] [ Designated as safety issue: No ]
    ORR is defined as the percentage of subjects with tumors of rhabdomyosarcoma, non-rhabdomyosarcomatous soft tissue sarcoma, or Ewing's sarcoma achieving either a complete or partial tumor response as per response criteria (RECIST1.1). The response rate will be calculated based on the investigator review.

Secondary Outcome Measures:
  • The investigator assessed ORR for the tumor types of secondary interest. [ Time Frame: Up to 2 years from the start of treatment ] [ Designated as safety issue: No ]
    The ORR will be computed for subjects with tumors of secondary interest which include the following 4 tumor types Osteosarcoma, Neuroblastoma (measurable), Neuroblastoma (evaluable), and Hepatoblastoma.

  • Incidence of toxicities of oral pazopanib [ Time Frame: Upto 2 years from the start of treatment ] [ Designated as safety issue: No ]
    All subjects who receive at least one dose of pazopanib will be considered in the evaluation of toxicity.

  • Progression free survival (PFS) as assessed by the Investigator in subjects with relapsed or refractory solid tumors [ Time Frame: Upto 2 years from the start of treatment ] [ Designated as safety issue: No ]
    PFS is defined as the interval of time between the date of study entry and the earliest date of disease progression or death due to any cause. Disease progression is based on radiographic evidence, and assessments made by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. For participants who do not progress or die, PFS will be censored at the time of initiation of alternative anticancer therapy or date of last adequate assessment.

  • The time to progression (TTP) in subjects with relapsed or refractory solid tumors [ Time Frame: Upto 2 years from the start of treatment ] [ Designated as safety issue: No ]
    The TTP is defined as the interval between the date of study entry and the earliest date of disease progression or death due to disease under study. Subjects are considered to have progressive disease if they have documented progression based on radiologic assessment as determined by investigator review

  • The therapeutic activity (a confirmed complete or partial response or stable disease for at least 4 cycles) per stratum [ Time Frame: Upto 2 years from the start of treatment ] [ Designated as safety issue: No ]
    Number of participants with a best overall response of confirmed complete response (CR) or confirmed partial response (PR) as assessed by the Investigator.

  • The relationship between tumor response and angiogenic cytokines. [ Time Frame: Upto 2 years from the start of treatment ] [ Designated as safety issue: No ]
    Examination of the relationship between tumor response and angiogenic cytokines will be conducted using a common logistic regression modeling strategy. Changes in blood levels of angiogenic cytokines will be measured. Tumor response will be measured by CT scan

  • Vascular endothelial growth factor (VEGF) and kinase insert domain receptor (KDR) genotype/phenotype relationships in subjects with cancer treated with pazopanib. [ Time Frame: Upto 2 years from the start of treatment ] [ Designated as safety issue: No ]
    KDR polymorphism and pazopanib-induced change in vascular endothelial growth factor receptor 2 (VEGFR2) will be assessed. KDR is the gene that encodes VEGFR2.

  • Pazopanib pharmacokinetic/pharmacodynamic relationships with biomarkers and clinical outcomes [ Time Frame: Upto 2 years from the start of treatment ] [ Designated as safety issue: No ]
    The relationship between toxicity (including hypertension) and pharmacokinetic parameters (pazopanib trough concentration, Cmax and/or AUC) will be investigated as data permit. Data initially will be analyzed graphically. Models such as a simple linear or maximum effect (Emax) model may be fit to the data if the data warrant.

  • Composite of pharmacokinetic (PK) parameters of pazopanib after administration of the oral suspension [ Time Frame: Upto 2 years from the start of treatment ] [ Designated as safety issue: No ]
    The following PK parameters will be calculated : Maximum plasma pazopanib concentration (Cmax), the time to Cmax (tmax), and the area under the curve (AUC) from zero to the time of the last quantifiable concentration (AUC[0-t]). Blood samples will be collected at the following time points on Day 1 of Cycle 1: pre-dose, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours after the dose; Day 15 ± 1 day of Cycle 1: pre-dose, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours after the dose; and also prior to every odd cycle.

Estimated Enrollment: 154
Study Start Date: October 2014
Estimated Study Completion Date: February 2019
Estimated Primary Completion Date: February 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pazopanib
Subjects will be treated with pazopanib GW786034 tablets at a dose of 450 mg/m^2/dose or as a powder in suspension at a dose of 225 mg/m^2/dose. The first 6 subjects who require suspension will have extended pharmacokinetic sampling and safety data. These data will be reviewed prior to further enrollment of subjects requiring suspension to determine if 225 mg/m^2/dose is tolerated and PK exposure is similar to exposure in adults associated with clinical efficacy. Two isolated and reversible laboratory-defined dose limiting toxicities (DLTs) were observed at 225 mg/m^2/dose. The maximum dose to be administered daily for tablets is 800 mg and for suspension is 400 mg. If 225 mg/m^2/dose is not tolerated (>=2 DLTs in 6 evaluable subjects), the dose for subjects who require suspension may be reduced to 160 mg/m^2/dose. A cycle will be defined as 28 days with no rest periods between cycles.
Drug: Pazopanib GW786034
Pazopanib is supplied as a series of aqueous film-coated tablets containing 200 mg (oval-shaped, white, packaged in bottles containing 34 tablets each), and 400 mg (oval-shaped, white, packaged in bottles containing 68 tablets each). Pazopanib Powder for Oral Suspension is a white to slightly colour powder supplied to the clinical sites in amber glass (United State Pharmacopeia (USP) Type III) bottles with child-resistant closures. Each bottle contains 5 g of pazopanib.


Ages Eligible for Study:   1 Year to 18 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Subjects must be at least 1 and less than or equal to 18 years of age at the time of study entry.
  • Subjects 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. Note: Investigators are encouraged to enroll hepatoblastoma subjects on the appropriate COG biology study (eg: ABTR01B1) if they haven't already been enrolled and send available relapse tumor and/or blood samples in order to allow for future correlative biology studies in these subjects.
  • Subjects who will be receiving the tablet formulation must have a body surface area (BSA) >= 0.84 m^2 (square meter) at the time of study enrollment.
  • Subjects 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).
  • Subjects with neuroblastoma who do not have measurable disease but have iodine-131 - meta-iodobenzylguanidine positive (MIBG+) evaluable disease are eligible.
  • Subjects 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.
  • Subjects must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
  • Subjects 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).
  • At least 3 half-lives of the antibody must have elapsed since prior therapy that included a monoclonal antibody.
  • 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, 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.

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 30 days 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.
  • Subjects requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible.
  • Subjects who are currently receiving another investigational drug are not eligible.
  • Subjects who are currently receiving other anti-cancer agents or radiation therapy are not eligible.
  • Subjects 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.
  • Subjects 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.
  • Subjects currently receiving aspirin, and/or ibuprofen, or other Nonsteroidal anti-inflammatory drugs (NSAIDs) are not eligible.
  • Subjects receiving drugs with a known risk of torsades de pointes are not eligible.
  • Subjects 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.
  • Subjects who are unable to swallow tablets or liquid are not eligible.
  • Subjects who have an uncontrolled infection are not eligible.
  • Subjects 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 hemoptysis within 6 weeks prior to study enrollment.
  • Subjects with known involvement of the CNS by malignancy will be excluded.
  • Subjects 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.
  • Subjects 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.
  • Subjects who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01956669

Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals

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Sponsors and Collaborators
Novartis Pharmaceuticals
Children's Oncology Group
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals Identifier: NCT01956669     History of Changes
Other Study ID Numbers: 116731 
Study First Received: August 1, 2013
Last Updated: August 8, 2016
Health Authority: Canada: Health Canada
United States: Food and Drug Administration

Keywords provided by Novartis:
Refractory Solid Tumors processed this record on October 21, 2016