Clinical Trials /

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

NCT01956669

Description:

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.

Related Conditions:
  • Desmoplastic Small Round Cell Tumor
  • Ewing Sarcoma
  • Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
  • Hepatoblastoma
  • Neuroblastoma
  • Osteosarcoma
  • Peripheral Primitive Neuroectodermal Tumor
  • Rhabdomyosarcoma
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pazopanib Paediatric Phase II Trial Children's Oncology Group (COG) in Solid Tumors
  • Official Title: A Phase II Study of Pazopanib GW786034, NSC# 737754 in Children, Adolescents and Young Adults With Refractory Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 116731
  • NCT ID: NCT01956669

Conditions

  • Solid Tumours

Interventions

DrugSynonymsArms
Pazopanib GW786034Pazopanib

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
PazopanibExperimentalSubjects 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 subjects receiving powder for oral suspension will have extended pharmacokinetic sampling and will be closely monitored for safety and for occurence of DLTs . 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.
  • Pazopanib GW786034

Eligibility Criteria

        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).

          -  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, 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.

        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.

          -  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 currently receiving aspirin, and/or ibuprofen, or other Nonsteroidal
             anti-inflammatory drugs (NSAIDs) are not eligible.

          -  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.
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The investigator assessed objective response rate (ORR) in subjects' with tumors of primary interest
Time Frame:Primary analysis perform 20 weeks after LPFV in the 3 cohorts of primary interest
Safety Issue:
Description: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

Measure:The investigator assessed ORR for the tumor types of secondary interest.
Time Frame:Primary analysis perform 20 weeks after LPFV in the 3 cohorts of primary interest
Safety Issue:
Description: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.
Measure:Incidence of toxicities of oral pazopanib
Time Frame:Primary analysis perform 20 weeks after LPFV in the 3 cohorts of primary interest
Safety Issue:
Description:All subjects who receive at least one dose of pazopanib will be considered in the evaluation of toxicity.
Measure:Progression free survival (PFS) as assessed by the Investigator in subjects with relapsed or refractory solid tumors
Time Frame:Primary analysis perform 20 weeks after LPFV in the 3 cohorts of primary interest
Safety Issue:
Description:PFS is defined as the interval of time between the date of first dose of protocol therapy 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 date of last adequate assessment or date of last adequate assessment prior to initiation of new anti-cancer therapy
Measure:The time to progression (TTP) in subjects with relapsed or refractory solid tumors
Time Frame:Primary analysis perform 20 weeks after LPFV in the 3 cohorts of primary interest
Safety Issue:
Description:The TTP is defined as the interval between the date of first dose of protocol therapy 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
Measure:To determine the therapeutic activity (a confirmed complete or partial response or stable disease for at least 4 cycles) per cohort
Time Frame:Primary analysis perform 20 weeks after LPFV in the 3 cohorts of primary interest
Safety Issue:
Description:Number of participants with a best overall response of confirmed complete response (CR) or confirmed partial response (PR) as assessed by the Investigator.
Measure:The relationship between tumor response and angiogenic cytokines.
Time Frame:Primary analysis perform 20 weeks after LPFV in the 3 cohorts of primary interest
Safety Issue:
Description: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
Measure:Vascular endothelial growth factor (VEGF-A) and kinase insert domain receptor (KDR) genotype plasma relationships in subjects with cancer treated with pazopanib.
Time Frame:Primary analysis perform 20 weeks after LPFV in the 3 cohorts of primary interest
Safety Issue:
Description:KDR polymorphism and pazopanib-induced change in vascular endothelial growth factor receptor 2 (VEGFR2) will be assessed. KDR is the gene that encodes VEGFR2.
Measure:Pazopanib pharmacokinetic/pharmacodynamic relationships with biomarkers and clinical outcomes
Time Frame:Primary analysis perform 20 weeks after LPFV in the 3 cohorts of primary interest
Safety Issue:
Description: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.
Measure:Composite of pharmacokinetic (PK) parameters of pazopanib after administration of the oral suspension
Time Frame:Primary analysis perform 20 weeks after LPFV in the 3 cohorts of primary interest
Safety Issue:
Description: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.
Measure:Overall Survival (OS)
Time Frame:Primary analysis perform 20 weeks after LPFV in the 3 cohorts of primary interest
Safety Issue:
Description:OS is defined as the time from first dose of study medication until death due to any cause

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • VEGF
  • Pazopanib
  • Sarcoma
  • GW786034
  • Refractory Solid Tumors

Last Updated

April 19, 2017