| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Children with solid tumors which resistant to treatment |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065143 |
| E.1.2 | Term | Malignant solid tumour |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. To estimate the maximum tolerated dose (MTD) and/or recommended Phase II dose of oral pazopanib administered on a once daily schedule to children with refractory solid tumors.
2. To define and describe the toxicities of oral pazopanib administered as either a tablet or suspension.
3. To characterize the pharmacokinetics of oral pazopanib in children with refractory solid tumors. |
|
| E.2.2 | Secondary objectives of the trial |
1. To preliminarily define the antitumor activity of oral pazopanib within the confines of a Phase I study.
2. To assess the biologic activity of oral pazopanib including changes in peripheral blood monocyte counts, circulating endothelial cells, and plasma angiogenic factors.
3. To explore changes in tumor vascular permeability following initiation of pazopanib therapy and to correlate these changes with clinical outcome, as applicable. Specifically, to evaluate changes in dynamic contrast enhanced MRI (DCE-MRI) scans obtained within 15 ± 2 days after initiation of pazopanib
therapy as compared to baseline within a soft tissue sarcoma cohort.
4. To preliminarily assess VEGF haplotype/phenotype relationships in a pediatric cancer patient population.
5. To explore pazopanib concentration-effect relationships with biomarkers and with clinical outcomes, including hypertension.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age: Patients must be > than 2 years and < 21 years of age at the time of study enrollment.
2. Body Surface Area (Part 1 and 2b only): Patients participating in Part 1 (Phase 1 Dose Escalation) and Part 2b (Expanded Imaging Cohort) must have a BSA ≥ 0.48 m2 at the time of study enrollment.
3. Diagnosis:
a. Part 1 (Phase I Dose Escalation) and Part 2a (Suspension Formulation Component): Patients with relapsed or refractory solid tumors including CNS tumors are eligible. Patients must have had histological verification of malignancy at original diagnosis or relapse except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of CSF or serum tumor markers including alpha-fetoprotein or beta-HCG.
b. Part 2b (Expanded Imaging Cohort):
i. Patients must have had histological verification of a soft tissue sarcoma at original diagnosis.
ii. Patients must have a tumor in the head, neck, extremity or fixed within the abdomen or pelvis such that it is not sensitive to motion artifact. (Patients with isolated pulmonary metastases are not eligible for Part 2b).
iii. Slides or tissue blocks from either initial diagnosis or relapse must be available for central review.
4. Disease Status:
a. Part 1 and Part 2a: Patients must have either measurable or evaluable disease.
b. Part 2b:
Patients must have a measurable tumor that is at least 2 cm in its longest diameter.
5. Therapeutic Options: Patient’s current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life.
4.1.6 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 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
7.1 Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
a. Myelosuppressive chemotherapy: Must not have received within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea).
b. Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor that supports platelet or white cell number or function.
c. Biologic (anti-neoplastic agent):
- Patients may have received bevacizumab, VEGF-Trap, or other VEGF blocking tyrosine kinase inhibitors, but may not have 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. Patients must have recovered from any VEGF blocking drug-related toxicity.
- At least 7 days must have elapsed since the completion of therapy with other biologic agents.
- For other biologic 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.
d. Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a monoclonal antibody.
e. XRT: > 2 wks for local palliative XRT (small port); > 3 months must have elapsed if prior TBI, craniospinal XRT or if 50% radiation of pelvis; > 6 wks must have elapsed if other substantial BM radiation.
f. Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease and > 2 months must have elapsed since transplant.
8. Organ Function Requirements
8.1 Adequate Bone Marrow Function defined as:
a. Peripheral absolute neutrophil count (ANC) > 1000/uL;
b. Platelet count > 100,000/uL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment); and
c. Hemoglobin > 8.0 g/dL (may receive RBC transfusions)
8.2 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 (see protocol for maximum serum creatinine (mg/dL) defined per age group)
c. Urine protein:creatinine ratio of <1 or a urinalysis that is negative for protein; or, 24-hour urine protein level < 1 gram (See Appendix III).
d. No more than Grade 1 abnormalities of potassium, calcium, magnesium and phosphorous.
8.3 Adequate Liver Function as defined in the protocol.
8.4 Adequate Cardiac Function as defined in the protocol.
8.5 Adequate Blood Pressure Control as defined in the protocol.
8.6 Central Nervous System Function as defined in the protocol
8.7 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 will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies.
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.
Note: Oral contraceptives are not considered reliable or effective due to potential drug-drug interactions.
2. Concomitant Medications
2.1 Growth factors(s): Growth factors that support platelet or white cellnumber or function must not have been administered within the 7 days prior to study enrollment.
2.2 Corticosteroids:
a. Part 1 and Part 2a: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the prior 7 days are not eligible for study enrollment.
b. Part 2b: Patients receiving corticosteroids are not eligible to enroll on part 2b.
2.3 Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible.
2.4 Anti-Cancer Agents or Radiation Therapy: Patients who are currently receiving other anti-cancer agents or radiation therapy are not eligible.
2.5 Antihypertensives: Patients who are currently receiving medication(s) for blood pressure control are not eligible for study enrollment.
2.6 Anticoagulation: Patients must not be on therapeutic anticoagulation. (Warfarin (coumadin®) and/or low molecular weight heparin are prohibited.) Prophylactic anticoagulation (i.e. intralumenal heparin) of venous or arterial access devices is allowed.
2.7 Anti-inflammatory and anti-platelet agents: Patients currently receiving aspirin, and/or ibuprofen, or other NSAIDs are not eligible.
2.8 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. See Appendices IIA and IIB for a list of enzyme inducing, enzyme inhibiting and other adversely interacting
drugs and the appropriate washout periods required prior to study enrollment.
2.9 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.
3. Infection: Patients who have an uncontrolled infection are not eligible.
4. Bleeding and Thrombosis:
4.1 Evidence of active bleeding, intratumoral hemorrhage, or bleeding diathesis.
4.2 History (within 6 months prior to study enrollment) of arterial thromboembolic events, including transient ischemic attack (TIA) or cerebrovascular accident (CVA).
4.3 History (within 6 months prior to study enrollment) of pulmonary embolism, DVT, or other venous thromboembolic event.
4.4 History of hemoptysis within 6 weeks prior to study enrollment.
4.5 In patients with CNS tumors or known CNS metastases, evidence of new CNS hemorrhage of more than punctate size and/or more than three foci of punctate hemorrhage on baseline MRI obtained within 14 days prior to study enrollment are not eligible. Note: ECHO gradient MRI sequences per institutional guidelines are required for evaluation of CNS hemorrhage in patients with CNS tumors or known CNS metastases.
5. Surgery:
Patients who have had or are planning to have the following invasive procedures:
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.
c. Fine needle aspirate or central line placement within 48 hours prior to Day 1 therapy.
6. Patients with QTc >450 msec on baseline EKG obtained within 7 days prior to study enrollment or history of familial prolonged QTc syndrome.
7. Patients with serious or non-healing wound, ulcer, or bone fracture.
8. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days of study enrollment.
9. 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) |
| The primary endpoint is the Maximum tolerated dose (MTD) of daily administered pazopanib. The MTD will be determined by the evaluation of AEs and changes in laboratory values. The MTD is defined as the highest dose level that results in dose limiting toxicity in no more than 1 0f 6 patients. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Patients will attend clinic visits every 28 days (1 Cycle). AEs and SAEs will be reported on a continuous basis, routine laboratory tests will be performed at baseline, weekly during Cycle 1 and prior to each subsequent Cycle. |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Multi Centre, Interventional |
|
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 months | 36 |
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