E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic melanoma with brain metastases. |
|
E.1.1.1 | Medical condition in easily understood language |
Melanoma skin cancer which has spread to the brain. |
|
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 | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006128 |
E.1.2 | Term | Brain metastases |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The principal objective of this study is to evaluate how long whole brain radiotherapy plus vandetanib is able to control the progression of melanoma brain metastases, compared with radiotherapy alone. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to further evaluate the effectiveness of whole brain radiotherapy plus vandetanib compared with radiotherapy alone in patients with melanoma brain metastases in terms of: 1. maintenance of cognitive function. 2. control of disease at 6 months following start of treatment. 3. duration of survival of patients on study. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A patient will be eligible for inclusion in this study if all of the following criteria apply: 1. Age ≥ 18 years. 2. Able to give written informed consent. 3. Histologically/cytologically proven malignant melanoma. 4. Unresectable stage III or IV metastatic melanoma with brain metastases. 5. Karnofsky performance score ≥70% (see appendix 1 of trial protocol). 6. RTOG RPA score 1 or 2 (see appendix 6 of trial protocol). 7. Measurable disease as defined by RECIST version 1.1. 8. Life expectancy of at least 12 weeks. 9. Haematological and biochemical indices within the ranges shown below: Haemoglobin (Hb) ≥ 10 g/dL White Blood Count (WBC) ≥ 3 x 109/L Platelet count ≥ 100,000/μL Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L Serum bilirubin ≤ 1.5 x ULN AST or ALT ≤ 2.5 x ULN ALP ≤ 2.5 x ULN Creatinine clearance (Cockcroft-Gault) > 30 ml/min or Serum creatinine ≤ 1.5 x ULN Serum potassium ≥ LLN and < 5.5 mmol/L Serum magnesium ≥ LLN and < 1.23 mmol/L Serum calcium ≥ LLN and < 2.9 mmol/L 10. Adequate cardiac function (NHYA 0-1). 11. QTc <480 msec on screening ECG. 12. The patient is willing and able to comply with the protocol for the duration of the study, and scheduled follow-up visits and examinations. |
|
E.4 | Principal exclusion criteria |
A patient will not be eligible for the trial if any of the following apply: 1. Any radiotherapy or systemic melanoma therapy within 28 days prior to starting trial treatment, except palliative radiotherapy. 2. Prior whole brain irradiation. 3. CNS melanoma where all detectable disease has been treated by neurosurgery or stereotactic irradiation. 4. Presence of leptomeningeal disease. 5. More than 3 extra-cranial organ sites involved with melanoma. 6. Pregnant or breast-feeding women. Female patients must have a negative urinary or serum pregnancy test or have evidence of post-menopausal status (defined as absence of menstruation for >12 months, bilateral oophrectomy or hysterectomy). 7. Patients (both male and female) of reproductive potential who are not willing to use adequate contraceptive measures for the duration of the study (as detailed in the study protocol). 8. Clinically significant cardiovascular event (e.g. myocardial infarction, superior vena cava syndrome) within 3 months before study entry (defined as signing of consent form), heart failure (NYHA class 2 or above), presence of cardiac disease that, in the opinion of the Investigator, increases the risk of ventricular arrhythmia. 9. Uncontrolled hypertension (systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg, despite treatment). 10. History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia or uncontrolled atrial fibrillation), which is symptomatic or requires treatment (CTCAE version 4.0 grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on medication is not excluded. 11. History of QT prolongation with other medications that required discontinuation of that medication. 12. Congenital long QT syndrome, or 1st degree relative with unexplained sudden death under 40 years of age. 13. Presence of left bundle branch block (LBBB) on screening ECG. 14. Serum calcium, magnesium or potassium below the normal range despite supplementation. 15. Concomitant medications that are potent inducers of CYP3A4 function (see appendix 5 of protocol). 16. Concomitant medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes (see appendix 4 of protocol). If the patient is on any such medications, they need to be stopped at least 14 days prior to day 1 dosing. If they cannot be stopped, the patient is excluded. 17. Ocular malignant melanoma. 18. Another active malignancy within the past five years, with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin. 19. Any clinically significant and uncontrolled major medical condition(s). 20. Any unresolved toxicity greater than CTCAE version 4.0 grade 1 from previous anti-cancer therapy. 21. Inability to swallow tablets, refractory nausea and vomiting, chronic gastrointestinal disease (eg: inflammatory bowel disease), significant bowel resection, or any other condition that would preclude adequate absorption of vandetanib. 22. Currently active diarrhoea that may affect the ability of the patient to absorb vandetanib or tolerate treatment-induced diarrhoea. 23. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV. 24. Major surgery within 4 weeks, or incompletely healed surgical incision before starting study therapy. 25. Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results. 26. Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to enrolment. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Progression free survival in the brain (as assessed by MRI scan and/or clinical symptoms) |
|
E.5.2 | Secondary end point(s) |
1. Maintenance of cognitive function 2. PFS in brain at 6 months 3. Overall Survival |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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 | 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.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
Protocol defined as when the last patient has completed six months follow up or relapsed. |
|
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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |