| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| melanoma brain metastases |
|
| E.1.1.1 | Medical condition in easily understood language |
| melanoma brain metastases |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006128 |
| E.1.2 | Term | Brain metastases |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 measure the incidence of neurological-specific death at 1 year |
|
| E.2.2 | Secondary objectives of the trial |
1. To assess the best intracranial response rate
2. To assess the best extracranial response rate
3. To assess the overall response rate
4. To measure the overall progression free survival
5. To measure the incidence of non-neurological-specific death at 1 year
6. To measure overall survival
7. To assess the incidence of radionecrosis within 5 years from the commencement of radiotherapy
8. To assess the requirement for salvage radiotherapy
Incidence of salvage radiotherapy to intracranial brain metastases in each cohort.
9. To assess the requirement for salvage intracranial surgery.
10. To assess researcher-rated and patient-rated neurocognitive function
11. To assess the patient-rated quality of life
12. To assess functional performance status |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Female or male patients, ≥18 years of age.
2. Signed, written, informed consent.
3. AJCC Stage IV [any T, any N, M1d, M1d(0) or M1d(1)] histologically confirmed cutaneous, acral or mucosal melanoma or unknown primary melanoma with metastases to the brain that are considered unresectable.
Patients must have at least 1 radiological definitive brain metastasis that is ≥ 5mm and ≤40mm, measurable per RECIST version 1.1 guidelines (modified for brain metastases, in which up to five lesions can be selected as target lesions in addition to extracranial lesions).
There is no upper limit restriction to the number of brain metastases, provided the remaining eligibility criteria are met.
4. The BRAF mutation status must be available prior to randomisation.
5. The radiation oncologist should consider ALL intracranial melanoma lesions amenable to stereotactic radiosurgery/therapy over whole brain including the SRS treatment of intracranial lesions ≤5mm in diameter.
Patients for whom there is a definite and immediate indication for radiotherapy (e.g. rapidly progressing disease with associated clinical signs and /or symptoms) should not be considered for enrolment.
The presence of small brain metastases - ≤5mm in diameter – in addition to a qualifying lesion ≥ 5mm and ≤40mm must be considered treatable with SRS. If there is a clinical reason or MDT recommendation or a technical reason for not treating these lesions, the patient is NOT eligible for this study.
6. Brain metastases must be untreated with any modality of radiotherapy.
Previous surgery for melanoma brain metastases is permitted.
Prior radiotherapy to any extracranial lesions is permitted
7. Brain metastases must be untreated with any form of systemic treatment.
Systemic treatment for extracranial disease is permitted if given in the neoadjuvant or adjuvant settings and only if brain metastases were confirmed absent with radiological evidence throughout systemic treatment.
The presenting diagnosis of brain metastases at the time of enrolment in this study must have occurred a minimum of 6 months after stopping neoadjuvant or adjuvant systemic therapy for extracranial disease
Prior anti-PD1, anti PD-L1, anti-CTLA-4, BRAF / MEK inhibitors or clinical trial agents are acceptable in the setting of neoadjuvant or adjuvant treatment for extracranial disease.
8. Asymptomatic from brain metastases at the time of study enrolment without corticosteroids, analgesia or any other treatment for the management of neurological symptoms or as prophylactic treatment (except for antiepileptics prescribed for any reason, provided the patient is asymptomatic).
Resolved neurological symptoms are permitted if complete resolution, without any intervention, has been sustained for a minimum of 7 days prior to randomisation.
9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
10. A life expectancy of > 30 days.
11. Able to undergo MRI with Gadolinium contrast agent. CT of the brain is not an acceptable alternative should patients be unable to safely undergo a contrast MRI.
12. Adequate haematological, hepatic and renal organ function as defined by:
a. White cell count ≥ 2.0 × 109/L
b. Neutrophil count ≥ 1.5 × 109/L
c. Haemoglobin ≥ 90 g/L
d. Platelet count ≥ 100 x 109/L
e. Total bilirubin ≤ 1.5 x ULN
f. Alanine transaminase ≤ 3.0 x ULN
g. Aspartate aminotransferase ≤ 3.0 x ULN
h. Serum creatinine ≤ 1.5 x the upper limit of normal (ULN). If serum creatinine is > 1.5 x ULN, calculate creatinine clearance using standard Cockcroft-Gault formula. Creatinine clearance must be 40ml/min to be eligible.
13. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of the first dose of study drug and agree to use effective contraception from 14 days prior to commencing study drug, throughout the treatment period and for 23 weeks* after the last dose of study drug. Effective contraception includes:
a. Intrauterine device with a documented failure rate of less than 1% per year.
b. Vasectomised partner who is sterile prior to the female partner patient’s commencement of study drug and is the sole sexual partner for that female.
c. Combined (oestrogen and progestogen) hormonal contraception associated with inhibition of ovulation or progestogen only hormonal contraception associated with inhibition of ovulation.
Women who are not of childbearing potential are defined as any female who has had a documented hysterectomy, bilateral oopherectomy or bilateral tubal ligation or any female who is post-menopausal (≥ one year without menses and >50 years of age in the absence of hormone replacement therapy and confirmed with FSH testing). |
|
| E.4 | Principal exclusion criteria |
1. Patients whose intracranial disease changes between the diagnostic MRI scan and the baseline / SRS planning MRI scan and who are no longer suitable for SRS and / or require a specific alternative treatment outside of this protocol.
2. Any melanoma brain metastasis greater than 40mm diameter.
3. Evidence of leptomeningeal disease, with the exception of pathological findings seen at a previous resection of brain disease, but with no evidence of leptomeningeal disease elsewhere at the time of resection or at study entry.
4. History of, or current ocular (both uveal and conjunctival) melanoma (patients with mucosal and acral melanoma are eligible).
5. Symptoms from brain metastases at the time of study enrolment or a requirement for corticosteroids, analgesia or any other treatment for the management of neurological symptoms.
6. Prior radiotherapy to the brain (prior surgery permitted).
7. Prior systemic drug therapy for melanoma, unless given in the neoadjuvant or adjuvant setting for extracranial disease only, completed ≥ 6 months before enrolment in this study and if administered with radiological proof of the absence of brain metastases.
8. Patients with active, known or suspected autoimmune disease. Patients with the following conditions are permitted to enrol:
a. Vitiligo
b. Type I diabetes mellitus
c. Residual hypothyroidism due to an autoimmune condition only requiring hormone replacement
d. Psoriasis that does not require systemic treatment
e. Autoimmune conditions not expected to recur in the absence of an external trigger.
9. Current systemic treatment with corticosteroids, or within 7 days of randomisation, with the exception of prednisone at non-immunosuppressive doses of ≤ 10 mg/day (or equivalent, e.g. prednisone 10mg ≡ dexamethasone 1.6mg ≡ hydrocortisone 40mg). Patients with the following circumstances are permitted to enrol:
a. Past treatment for non-neurological symptoms allowed, if this was ceased 7 days prior to randomisation
b. Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if the patient is on a stable dose
c. Non-absorbed intra-articular steroid injections.
During the study, treatment with systemic corticosteroids is permitted during radiotherapy if the patient experiences radiation related symptoms but this should be tapered per standard clinical practice as soon as possible to ≤ 10mg/day and before the next infusion of study drug(s) is due. This also refers to steroids for drug related signs or symptoms.
10. Any active infection requiring treatment.
11. A history of interstitial lung disease.
12. A known history of another malignancy or concurrent malignancy unless the patient is disease-free for a minimum of 1 year, is completely treated and is at low-risk of recurrence. The time requirement does not apply for patients with successful definitive resection or curative treatment of:
a. Non-melanoma skin cancer (e.g. basal cell or squamous cell carcinoma of the skin),
b. Superficial bladder cancer,
c. In situ carcinoma of the cervix,
d. In situ breast cancer,
e. Atypical melanocytic hyperplasia or melanoma in situ
f. Other in situ carcinomas,
13. Serious or unstable pre-existing medical conditions or other conditions that could interfere with the patient’s safety, consent, or compliance.
14. Pregnant or breastfeeding females.
15. Administration of any form of live vaccine within 30 days of starting the trial and during the trial. Administration of any other vaccine is cautionary within 30 days of starting the trial and for the duration of the treatment phase of the trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The incidence of neurological-specific death in the whole patient population. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1 year, from start of nivolumab and ipilimumab, where the immediate cause of death is due to brain metastases. |
|
| E.5.2 | Secondary end point(s) |
1. The best response in intracranial metastases as measured using brain modified (bm) RECIST, following at least ONE dose of nivolumab and ipilimumab and based on imaging
2. The best response in extracranial disease for each patient measured using bm RECIST, following at least ONE dose of nivolumab and ipilimumab and based on imaging
3. Proportion of patients with an overall complete or partial response as measured using bm RECIST following at least ONE dose of nivolumab and ipilimumab and based on imaging.
4. Overall progressionfree survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. from week 12 onwards and confirmed a minimum of 4 weeks later.
2. from week 12 onwards and confirmed a minimum of 4 weeks later.
3. from week 12 onwards and confirmed a minimum of 4 weeks later.
4. a. Time from the start of nivolumab and ipilimumab to the date of any progression of disease as measured using bm RECIST with confirmation of response a minimum of 4 weeks later.
b. Patients dying from causes other than melanoma or treatment related toxicity will be censored at the date of death.
c. Patients alive without progression will be censored at the date of their last assessment.
d. A diagnosis of a second primary melanoma is not considered a progression event. |
|
| 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 | 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 | No |
| E.8.1.1 | Randomised | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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