| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10027105 | | E.1.2 | Term | Medullary thyroid cancer | |
| 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 demonstrate an improvement in progression-free survival (PFS) with ZD6474 as compared to placebo in subjects with unresectable locally advanced or metastatic MTC | |
| E.2.2 | Secondary objectives of the trial | 1.To demonstrate an improvement in the overall objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) with ZD6474 as compared to placebo
2.To demonstrate an improvement in the overall survival (OS) in subjects with MTC who have been treated with ZD6474 as compared to placebo
3.To demonstrate an improvement in biochemical response with ZD6474 as compared to placebo as measured by calcitonin (CTN) and carcinoembryonic antigen (CEA)
4.To demonstrate an increase in the time to opioid analgesic use (TTOU) in subjects who are not taking opioid analgesics at baseline, defined as <10 mg morphine sulfate (or equivalent), with ZD6474 as compared to placebo
5.To demonstrate a reduction in the use of opioid analgesic medication in subjects with MTC who have pain at baseline requiring ≥10mg/day morphine sulfate or equivalent after treatment with ZD6474 as compared to placebo
PLUS other secondary and exploratory objectives detailed in the protocol | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1.Provision of written informed consent
2.Female or male aged 18 years and over
3.Previously confirmed histological diagnosis of unresectable, locally advanced or metastatic hereditary or sporadic MTC. Documentation must be provided in subject’s medical chart.
4.Life expectancy of 12 weeks or longer
5.WHO Performance status 0-2
6.Able to swallow study medication
7.Presence of a measurable tumor as defined by:
a)a solitary lesion measuring ≥2 cm, OR
b)for multiple lesions, a sum of diameter ≥2cm (with no target lesion measuring <1cm and assuming 5 mm section), OR
c)for multiple lesions, a sum of diameter ≥3cm (with no target lesion measuring <1.5 cm assuming >5 mm section)
8.CTN ≥ 500 pg/ml
9.All subjects (other than those with hereditary MTC who have a documented germline RET mutation) must submit a suitable archived tumor collection sample. If an archived tumor sample is not available prior to 2 weeks of randomization, a fresh tumor sample must be obtained in its place. The tumor sample must be obtained by the investigative site and shipped to its destination prior to randomization.
10.Negative pregnancy test for female subjects of childbearing potential
| |
| E.4 | Principal exclusion criteria | 1.Brain metastases or spinal cord compression, unless treated at least 4 weeks before first dose and stable without steroid treatment for 10 days
2.Any concomitant medications that may affect QTc or induce CYP3A4 function (with the exception of somatostatin or somatostatin analog) and/or any prohibited medications referenced in the protocol3.Major surgery within 4 weeks before randomization
4.The last dose of prior chemotherapy is received less than 4 weeks prior to randomization
5.Radiation therapy within the last 4 weeks prior to randomization (with the exception of palliative radiotherapy)
6.Serum bilirubin greater than 1.5 x the upper limit of reference range (ULRR)
7.Serum creatinine >1.5 x ULRR or creatinine clearance ≤50 ml/minute (calculated by Cockcroft-Gault formula)
8.Potassium <4.0 mmol/L despite supplementation; serum calcium (ionized or adjusted for albumin), or magnesium out of normal range despite supplementation
9.Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) greater than 2.5 x ULRR, or greater than 5.0 x ULRR if judged by the investigator to be related to liver metastases
10.Significant cardiac event (eg myocardial infarction), superior vena cava [SVC] syndrome, New York Heart Association [NYHA] classification of heart disease ≥2 within 12 weeks before randomization, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia
11.History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted.
12.Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age
13.QT prolongation with other medications that required discontinuation of that medication
14.Presence of left bundle branch block (LBBB)
15.QTc with Bazett’s correction unmeasurable or ≥480 msec or greater on screening ECG (Note: If a subject has QTc interval ≥480 msec on screening ECG, the screening ECG may be repeated 2 times [at least 24 hours apart] for a total of 3 ECGs. The average QTc from the three screening ECGs must be <480 msec in order for the subject to be eligible for the study.)
16.Hypertension not controlled by medical therapy (systolic BP greater than 160 millimeter of mercury [mmHg] or diastolic blood pressure greater than 100 mmHg)
17.Previous or current malignancies of other histologies within the last 5 years, with the exception of tumors associated with MEN2a and MEN2b, in situ carcinoma of the cervix, and adequately treated basal cell or squamous cell carcinoma of the skin
18.Any unresolved chronic toxicity greater than CTCAE grade 2 from previous anticancer therapy
19.Participation in a clinical study and/or receipt of an investigational drug during the last 30 days (participation in the survival follow-up period of a study is not an exclusion)
20.Previous exposure to ZD6474
21.Currently pregnant or breast feeding
22.Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the investigational site)
23.Previous randomization or treatment in the present study
| |
| E.5 End points |
| E.5.1 | Primary end point(s) | | Progression free survival | |
| 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 | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions 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 | | Subjects who continue to receive ZD6474 study treatment will receive open label supplies for as long as the investigator determines they are obtaining clinical benefit, or until they are given another anti-cancer therapy other than the study medication. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
