E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable or metastatic BRAF V600-mutant melanoma |
|
E.1.1.1 | Medical condition in easily understood language |
Melanoma (a type of cancer), that cannot be completely removed by surgery or that has spread to other areas of the body |
|
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 | SOC |
E.1.2 | Classification code | 10029104 |
E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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 |
Characterize the pharmacokinetics of binimetinib, its active metabolite (AR00426032), encorafenib and its metabolite (LHY746) in adolescent patients with unresectable or metastatic BRAF V600-mutant melanoma |
|
E.2.2 | Secondary objectives of the trial |
- Assess the safety and tolerability of the binimetinib/encorafenib treatment combination - Identify the recommended doses in expansion of binimetinib and encorafenib - Assess the palatability of pediatric formulations of binimetinib and encorafenib - Assess the efficacy of the binimetinib/encorafenib treatment combination - Assess the impact of the binimetinib/encorafenib treatment on bone growth and soft tissue mineralization |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female 12 to < 18 years of age at the time of consent/assent. - Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer Stage IIIB, IIIC, or IV. - Presence of BRAF V600E or V600K mutation in tumor tissue as determined by a local or central laboratory. - Evidence of at least one evaluable lesion (measurable or non-measurable) as detected by radiological or photographic methods based on RECIST v1.1. - Adequate cardiac function: a. Left ventricular ejection fraction ≥ 50% as determined by ECHO or MUGA scan and above the institutional lower limit of normal; b. Triplicate average baseline QTcF value ≤ 450 ms. - Adequate bone marrow, organ function, and laboratory parameters: a. Absolute neutrophil count ≥ 1.5 × 109/L; b. Hemoglobin ≥ 9 g/dL with or without transfusions; c. Platelets ≥ 75 × 109/L without transfusions; d. Aspartate aminotransferase and/or alanine aminotransferase ≤ 2.5 × upper limit of normal (ULN); in patients with liver metastases ≤ 5 × ULN; e. Total bilirubin ≤ 1.5 × ULN. Patients with documented Gilbert syndrome or hyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled following discussion and agreement with the Sponsor; f. Creatinine ≤ 1.5 × institutional ULN for age, or calculated creatinine clearance ≥ 70 mL/min/1.73 m2 (following Schwartz formula). - Adequate performance status at Screening: a. Patients < 16 years old: Lansky Performance Scale score ≥ 80 b. Patients 16 to 17 years old: Karnofsky Performance Scale score ≥ 80 - Female patients of childbearing potential must agree to take appropriate precautions to avoid pregnancy from screening through 8 weeks following end of therapy and must have a negative pregnancy test at Screening and predose at Day 1. - Males must agree to take appropriate precautions to avoid fathering a child from Screening through 90 days following end of therapy. |
|
E.4 | Principal exclusion criteria |
- Presence of BRAFwt or indeterminate melanoma in tumor tissue as determined by local and central laboratory. - Known sensitivity or contraindication to any component of study treatment (binimetinib and encorafenib), or their excipients. - Uveal or mucosal melanoma. - Brain metastases that are uncontrolled or symptomatic, require steroids, are potentially life-threatening or have required radiation within 28 days prior to starting study drug. - History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO. - Prior therapy with a BRAF inhibitor and/or a MEK inhibitor - Impaired cardiovascular function or clinically significant cardiovascular disease, including any of the following: a. History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6 months prior to screening, b. Symptomatic chronic heart failure, history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality < 6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia. - Concurrent neuromuscular disorder associated with elevated creatine kinase. - Impairment of gastrointestinal function. - Uncontrolled arterial hypertension despite medical treatment. - Known history of positive test for human immunodeficiency virus or known acquired immunodeficiency syndrome. - Known active hepatitis B and/or active hepatitis C infection. - Patients who have undergone major surgery or radiotherapy ≤ 2 weeks prior to starting study treatment or who have not recovered from side effects of such procedure. - Pregnant or lactating females. - History of Gilbert’s syndrome. - Receipt of non-topical medication known to be a strong inhibitor or strong inducer of cytochrome P450 3A4 within 3 days prior to Screening. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Plasma concentration-time profiles and PK parameter estimates for binimetinib, its active metabolite (AR00426032), encorafenib and its metabolite (LHY746) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
- Incidence and severity of adverse events, including ophthalmologic events, and changes in clinical laboratory tests, vital signs, 12-lead electrocardiograms, echocardiogram/multi-gated acquisition scans and ophthalmic evaluations - Incidence of dose-limiting toxicities - Palatability score for the pediatric formulations as assessed by an age-appropriate questionnaire - Objective response rate as assessed by the investigator, based on Response Criteria Evaluation in Solid Tumors (RECIST) v1.1 - Duration of response - Time to response - Progression-free survival - One-year survival rate - Change from baseline bone age and the difference in bone age and chronological age - Change from Baseline in bone densitometry based on dual-energy X-ray absorptiometry (DEXA) scan - Change from Baseline in calcium-phosphorus product (Ca × P) |
|
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 | 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 | Yes |
E.6.13.1 | Other scope of the trial description |
Palatability of paediatric formulation |
|
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 |
Phase IB to assess PK, safety and efficacy |
|
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 | 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 | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
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 |
Australia |
Czechia |
Germany |
Italy |
New Zealand |
Switzerland |
United States |
|
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
|
End of study will be defined as the point when all patients have had the opportunity to be followed for at least 2 years after the start of study treatment. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 48 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 48 |