| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hereditary medullary thyroid cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 10027105 |
| E.1.2 | Term | Medullary thyroid cancer |
| 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 |
| To assess the activity of vandetanib using RECIST |
|
| E.2.2 | Secondary objectives of the trial |
To assess the activity of vandetanib using tumour biomarkers and tumour related diarrhoea
To assess the safety and tolerance of vandetanib at a adose equivalent to the adult recommended dose
To assess the PK at steady state
To assess PFS and OS
Other secondary objectives
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants must be 5 to 18 years of age, inclusive.
Diagnosis: Hereditary (MEN 2A or MEN 2B) medullary thyroid carcinoma (histologically confirmed) that is unresectable, recurrent or metastatic. Participants must have previously had a characteristic germline mutation in the RET proto-oncogene documented. Results of the germline mutation testing will be obtained from the referring institution.
Participants must have measurable disease as defined in RECIST as the presence of at least one lesion that can be accurately measured in at least one dimension with longest diameter of at least 20 mm using conventional techniques or at least 10 mm with spiral CT scan. Superficial (easily palpable) lymph nodes will be considered measurable.
Participants must be able to take one of the oral formulations of vandetanib.
Prior therapy: There are no standard chemotherapy regimens known to be effective for MTC. Therefore, previously untreated partipants are eligible if their tumor(s) are not surgically resectable.
Participants must be at least 4 weeks from prior surgical procedures and surgical incisions must be healed.
Participants must have had their last fraction of external beam radiation therapy at least 4 weeks prior to enrollment.
Participants must have had their last dose of cytotoxic chemotherapy at least 28 days prior to enrollment, their last dose of biological therapy, such as biological response modifiers (e.g., cytokines), immunomodulatory agents, vaccines, differentiating agents, used to treat their cancer at least 7 days prior to enrollment, their last dose of a monoclonal antibody at least 30 days prior to enrollment, and their last dose of any investigational agent at least 30 days prior to enrollment.
Participants must have received their last dose of short acting colony stimulating factor, such as filgrastim or sargramostim at least 72 hours prior to enrollment and their last dose of long-acting colony stimulating factors, such as PEG-filgrastim at least 7 days prior to enrollment.
Participants must have recovered from the acute toxic effects of prior therapy to a grade 1 (CTCAE v.3.0) level prior to enrollment.
Performance Status: Lansky (for participants 10 years of age or younger) or Karnofsky (for participants older than 10 years) performance score greater than 50
Participants who have previously had a thyroidectomy should be on thyroid hormone replacement therapy.
The peripheral absolute neutrophil count must be at least 1500 micro liters and the platelet count must be at least 1000 micro liters within 72 hours prior to enrollment.
PT and PTT must not be more than 1.5 x ULN within 72 hours prior to enrollment. PT and PTT should drawn by venipuncture, rather than from a central venous catheter when feasible.
Bilirubin must not be more than 1.5 x ULN and the AST and ALT must not be more than 2.5 x ULN within 72 hours prior to enrollment. AST and ALT may be up to 5 x ULN within 72 hours prior to enrollment in participants with hepatic metastases.
Participants must have an age-adjusted normal serum creatinine or a creatinine clearance of at least 60 ml/min/1.73 m2.
Participants of child-bearing or child-fathering potential must be willing to use a medically effective form of birth control, which includes abstinence, while taking vandetanib and for 2 months after the last dose.
Negative pregnancy test for women of childbearing potential.
Participants who are 18 years of age or legal guardians of participants who are younger than 18 years must sign an informed consent for the POB Screening Protocol prior to participating in studies required to determine eligibility for this trial. After confirmation of eligibility, participants or legal guardians of minor participants must sign an informed consent document for this trial, indicating that they are aware of the investigational nature of the proposed treatment, the risks and benefits of participating and the alternatives to participating. |
|
| E.4 | Principal exclusion criteria |
Pregnant or breast feeding females because the anti-angiogenic properties of vandetanib may be harmful to the developing fetus or nursing infant.
Participants with pheochromocytoma as evidenced by elevated plasma free metanephrines.
Participants with a serum potassium less than 3.5 mmol/L or a serum calcium or magnesium below the lower limits of normal. Correction of these electrolyte abnormalities with supplements is allowed.
Participants with a history of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia, uncontrolled atrial fibrillation, left bundle branch block) that is symptomatic or requires treatment (except for controlled atrial fibrillation)
Participants with a history of congenitally prolonged QTc, a first degree relative with unexplained sudden death under 40 years of age, or a measured QTc (Bazett's correction) longer than 480 msec on ECG. ECGs should be performed after correction of electrolyte abnormalities. Participants with a prolonged QTc should have a repeat ECG at least 24 hour after the first, and the mean of the 2 QTcs should not exceed 480 msec.
Participants who experienced QTc prolongation with other medications requiring discontinuation of that medication.
Participants receiving a medication that has a known risk of QTc prolongation within 14 days (28 days for levomethadyl) of enrollment.
Diastolic blood pressure above the 95% for age on at least 2 of 3 measurements with an appropriate-size cuff or patients who are currently taking anti-hypertensive therapy.
Other clinically severe or uncontrolled systemic illness that could compromise the participants ability to tolerate vandetanib or could compromise study procedures or endpoints. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Change in tumour size compared to baseline using RECIST
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After every 2 cycles for 4 cycles and then every 4 cycles |
|
| E.5.2 | Secondary end point(s) |
Change in tumour biomarkers (CEA and CTN) compared to baseline
Change in tumour related diarrhoea (frequency and consistency) compared to baseline
Safety and tolerance of vandetanib at a dose that is equivalent to the recommended dose in adults with limited intra-patient dose escalation
Progression-free survival
Overall survival
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the duration of the study |
|
| 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 | No |
| 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 | No |
| 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?
| Yes |
| E.8.4 | Will this trial be conducted at multiple sites globally? | No |
| 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
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|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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