| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| relapsed solid tumours in children, adolescents and young adults. |
|
| E.1.1.1 | Medical condition in easily understood language |
| solid cancers in children, adolescents and young adults. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine the investigator assessed objective response rate of pazopanib in children, adolescents and young adults (subjects) with relapsed or refractory rhabdomyosarcoma, non-rhabdomyosarcomatous soft tissue sarcomas, and
Ewing sarcoma. |
|
| E.2.2 | Secondary objectives of the trial |
1.Determine the investigator assessed objective response rate of pazopanib in children, adolescents, and young adults with relapsed or refractory osteosarcoma, neuroblastoma (measurable and/or evaluable) and hepatoblastoma
2.Further define and describe the toxicities of oral pazopanib in subjects with recurrent/refractory solid tumors
3.Determine progression free survival in subjects with relapsed or refractory solid tumors
4.Determine the time to progression in subjects with relapsed or refractory solid tumors
5.Determine the therapeutic activity (a confirmed complete or partial response or stable disease for at least 4 cycles) per stratum
6.Further examine the biologic relationship between tumor response and angiogenic cytokines
7.Further assess VEGF and KDR genotype/phenotype relationships in subjects with cancer treated with pazopanib
8.Further explore pazopanib pharmacokinetic/ pharmacodynamic relationships with
biomarkers and clinical outcomes, including hypertension |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age: Patients must be at least 1 and less than or equal to 18 years of age at the time of study entry.
Diagnosis: 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 PNET
d) Osteosarcoma
e) Neuroblastoma (Measurable)
f) Neuroblastoma (Evaluable)
g) Hepatoblastoma
Body Surface Area (for subjects taking tablet formulation only): Patients who will be receiving the tablet formulation must have a BSA > 0.48 m2 at the time of study enrollment.
Disease Status: Patients must have radiographically measurable disease. Patients with neuroblastoma who do not have measurable disease but have MIBG+ evaluable disease are eliglble
Performance Level: Patients must have a Lansky or Karnofsky performance status score of ≥ 50,
corresponding to ECOG categories 0, 1 or 2. Use Karnofsky for patients >16 years of age and Lansky for patients ≤ 16 years of age
Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering
this study.
Organ Function Requirements:
Adequate Bone Marrow Function defined as; Peripheral absolute neutrophil count (ANC) >1000/uL; Platelet count >75,000/uL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment); and Hemoglobin >8.0 g/dL (may receive RBC transfusions).
Adequate Renal and Metabolic Function defined as:
a. Creatinine clearance or radioisotope GFR >70mL/min/1.73 m2 or
b. A serum creatinine based on age/gender.
c. Urine protein: creatinine ratio of <1 or a urinalysis that is negative for protein; or, 24-hour urine protein level < 1000 mg/dL
d. No more than Grade 1 abnormalities of potassium, calcium (confirmed by ionized calcium), magnesium and phosphorous (supplementation allowed).
Adequate Liver Function defined as:
a. Total bilirubin equal to less than 1.5 x upper limit of normal (ULN) for age;
b. SGPT (ALT) equal to less than 2.5 x ULN (for the purpose of this study, the ULN for SGPT is 45 U/L);
c. Serum albumin equal to more than 2 g/dL.
Adequate Cardiac Function defined as:
a. Shortening fraction of equal to more than 27% by echocardiogram (while not receiving medications for cardiac function), or
b. Ejection fraction of ≥ 50% by gated radionuclide study (while not receiving medications for cardiac function)
c. QTc < 450 msec
d. 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.
- Patients 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 Function defined as:
a. Patients with a known history of seizures must have well-controlled seizures and may not be receiving enzyme-inducing anti-convulsants
b. CNS toxicity ≤ Grade 2.
Adequate Coagulation defined as:
PT and PTT ≤ 1.2 x upper limit of normal and an INR ≤ 1.2. |
|
| E.4 | Principal exclusion criteria |
1.Pregnancy or Breast-Feeding:
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.
2.Concomitant Medications
Corticosteroids: 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.
Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible.
Anti-Cancer Agents or Radiation Therapy: Patients who are currently receiving other anti-cancer agents or radiation therapy are not eligible.
Anti-hypertensives: 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.
Anticoagulation: Patients must not be on therapeutic anticoagulation (Warfarin (coumadin®) and/or low molecular weight heparin are prohibited.) Prophylactic anticoagulation (ie intralumenal heparin) of venous or arterial access devices is allowed.
Anti-inflammatory and anti-platelet agents: Patients currently receiving aspirin, and/or ibuprofen, or other NSAIDs are not eligible.
CYP3A4 Substrates and drugs causing QTc prolongation: Patients receiving drugs metabolized through several of the specific P450 cytochrome isoforms and those receiving drugs with a known risk of torsades de pointes are not eligible. List includes grapefruit juice for 14 days prior to enrollment.
3.Thyroid Replacement Therapy: 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.
4.Infection: Patients who have an uncontrolled infection are not eligible.
5.Bleeding and Thrombosis: 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, DVT, or other venous thromboembolic event.
History of hemoptysis within 6 weeks prior to study enrollment.
6.Patients with known involvement of the CNS by malignancy will be excluded.
7.Surgery: Patients who have had or are planning to have the following invasive procedures will be excluded:
a. 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.)
b. Core biopsy within 7 days 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.
c. Fine needle aspirate or central line placement within 48 hours prior to Day 1 therapy.
8.Patients with serious or non-healing wound, ulcer, or bone fracture.
9.History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days of study enrollment.
10.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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint: Objective response rate in subjects with rhabdomyosarcoma, non-rhabdomyosarcomatous soft tissue sarcomas and Ewing sarcoma:
This is defined as the percentage of subjects achieving either a confirmed complete or partial tumor response determined by the investigator as per response criteria (dependent upon tumor type). Subjects with unknown or missing response will be treated as non-responders, i.e. they will be included in the denominator when calculating the percentage. 90% confidence intervals will be provided and the data will be presented for each stratum. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From randomization until the time of the first documented evidence of a confirmed complete response or partial response. It is estimated that the analysis will occur in November 2015. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
1) Objective response rate in subjects with osteosarcoma, neuroblastoma and hepatoblastoma:
The analysis method will be the same as that described for the primary endpoint. If recruitment is stopped in a non-primary histology group(s) and it has less than 10 subjects, the response data will display summary statistics. The analysis method will be the same as that described for PFS.
2) Define and describe toxicities of oral pazopanib:
Analyses will include evaluations of the frequency of adverse events (AEs), serious adverse events (SAEs) and AEs that results in a pazopanib dose modification or discontinuation, along with evaluations of clinical laboratory parameters and vital signs. AEs and hematology, coagulation parameters and clinical chemistry will be summarized using NCI-CTCAE v4.0.
3) Progression free survival (PFS):
This is defined as the interval between the date of study entry and the earliest date of disease progression or death due to any cause. Subjects are considered to have progressive disease if they have documented progression based on radiologic assessment as determined by investigator review. For subjects 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.
PFS will be summarized using a Kaplan-Meier survival curve. For the pazopanib treatment group, the Kaplan-Meier estimate for the median progression-free survival time and the first and third quartiles will be presented, along with a naive approximate 93% confidence interval if there are a sufficient number of progressions or deaths.
4) Time to progression (TTP):
This 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.
5) Therapeutic activity (clinical benefit):
This is defined as the percentage of subjects achieving either a complete or partial tumor response or stable disease for at least 16 weeks. 90% confidence intervals will be produced to characterize the variability around the point estimate. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For the secondary objectives listed above, the timepoints are:
1) From randomization until the time of the first documented evidence of a confirmed complete response or partial response. It is estimated that the analysis will occur in Nov 2015.
2) From randomization until the end of the treatment period (up to cycle 24). It is estimated that the analysis will occur in Nov 2015.
3) and 4) From randomization until the first documented sign of investigator-assessed disease progression or death. It is estimated that the analysis will occur in Nov 2015.
5) From randomization until the time of the first documented evidence of a confirmed complete response, partial response or stable disease. It is estimated that the analysis will occur in Nov 2015. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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