Resumen

El propósito del estudio Columbus-AD es evaluar la eficacia y la seguridad de 12 meses de encorafenib en combinación con binimetinib en el contexto adyuvante del melanoma en estadio IIB/C con mutación BRAF V600E/K, frente al estándar de atención actual (vigilancia).

Descripción detallada

Se trata de un ensayo clínico internacional, multicéntrico, de fase III, aleatorizado, triple ciego, controlado con placebo y de superioridad. Los participantes con melanoma cutáneo completamente resecado y estado documentado de BRAF V600E/K por determinación centralizada serán aleatorizados 1:1 para recibir tratamiento con encorafenib y binimetinib o sus dos placebos durante 12 meses. Los pacientes serán estratificados según el estadio de la enfermedad conforme a la versión 8 de la AJCC entre: * estadio IIB (es decir, pT3b o pT4a) * estadio IIC (es decir, pT4b). La evaluación a largo plazo de todos los criterios de valoración (incluida información sobre la aparición de nuevos eventos adversos relacionados con el tratamiento, si los hubiere) tendrá lugar 10 años después de la aleatorización del último paciente.

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

Pre-Screening
Male or female ≥ 18 years of age;
Surgically resected, with tumour free margins, and histologically/pathologically confirmed new diagnosis of stage II (pT3b-pT4bN0) cutaneous melanomaa;
Sentinel node (SN) biopsy within 14 weeks from initial diagnosis of melanoma.
Sentinel node (SN) staged node negative (pN0);
Available tumour sample for central determination of the BRAF V600E/K mutation.
Screening
Melanoma confirmed centrally to be BRAF V600E/K mutation-positive;
Participant still free of disease as evidenced by the required baseline imaging and physical/dermatological assessments performed respectively within 6 weeks and 2 weeks before randomization (Day 1);
No more than 12 weeks elapsed between full surgical resection (including SLNB) and randomization;
Recovered from definitive surgery (e.g., complete wound healing, no uncontrolled wound infections or indwelling drains);
ECOG performance status of 0 or 1;
Adequate haematological function as defined as Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L and Hemoglobin
≥ 9.0 g/dL;
Adequate renal function as defined as Serum creatinine ≤ 1.5 × ULN; or calculated creatinine clearance ≥ 50 mL/min;
Adequate electrolytes, defined as serum potassium and magnesium levels within institutional normal limits;
Adequate hepatic function as defined as Serum total bilirubin ≤ 1.5 x ULN and \< 2 mg/dL, Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x ULN;
Adequate cardiac function as defined as LVEF ≥ 50% as determined by MUGA scan or echocardiogram and Mean triplicate QTcF value ≤ 480 msec and no history of QT syndrome;
Adequate coagulation function, defined as INR ≤1.5× ULN unless the patient is receiving anticoagulant therapy as long as PT or aPTT is within the therapeutic range;
Negative serum β-HCG test (female patient of childbearing potential only) performed within 3 days prior to Day 1;
Female patients of child-bearing potential and male patients must agree to follow the protocol's contraception guidance during the treatment period and for ≥30 days after last administration.

Criterios de exclusión

Pre-screening
Unknown ulceration status;
Uveal and mucosal melanoma;
Clinically apparent metastases (N+/M1);
Microsatellites, satellites and/or in-transit metastases,
Local (scar) recurrences.
Screening
Breast feeding women;
Pregnant women;
History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO;
History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to randomization;
History of previous or concurrent malignancy within preceding 3 years or any condition with a life expectancy of less than 5 years;
Participants with a prior cancer associated with RAS mutation;
Prior systemic anticancer therapy for melanoma or radiotherapy for melanoma;
Hypersensitivity to the study drugs or to any of the excipients;
Participants with severe lactose intolerance (e.g., Rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption);
Impaired cardiovascular function or clinically significant cardiovascular diseases;
Neuromuscular disorders that are associated with CK \> ULN (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy);
Non-infectious pneumonitis and Interstitial Lung Disease;
Positive SARs-CoV-2 or variants of SARs-CoV2 RT-PCR test at screening or suspected to be infected with SARs-CoV2 or variants of SARsCoV2 with confirmation pending;
Active bacterial, fungal, or viral infection, including, but not limited to HBV, HCV, and known HIV or AIDS-related illness, or an infection requiring systemic therapeutic treatment within 2 weeks prior to randomization.

Intervenciones

drug

Encorafenib and Binimetinib

Encorafenib 450 mg (6 × 75 mg capsules) once daily (QD) and binimetinib 45 mg (3 x 15 mg tablets) twice daily (BID) orally for a maximum of 12 months.

drug

Placebo to match Encorafenib ; Placebo to match Binimetinib

Encorafenib (6 × 75 mg placebo capsules) QD and binimetinib (3 × 15 mg placebo tablets) BID placebos orally for a maximum of 12 months.

Ubicaciones

Centro Oncologico Korben

CABA, Buenos Aires, Argentina

Centro de Investigaciones Medicas Mar del Plata

Mar del Plata, Buenos Aires, Argentina

Fundacion CIDEA

Ciudad Autonoma Bs As, Ciudad Autonoma Buenos Aires, Argentina

Sanatorio Britanico S.A.

Rosario, Santa Fe Province, Argentina

Instituto de Oncologia de Rosario

Rosario, Santa Fe Province, Argentina

Hospital Aleman

Ciudad Autonoma Buenos Aires, Argentina

Instituto Medico Especializado Alexander Fleming

Ciudad Autonoma Buenos Aires, Argentina

Clinica Adventista Belgrano

Ciudad Autonoma Buenos Aires, Argentina

Encorafenib y binimetinib adyuvantes versus placebo en melanoma en estadio IIB/C completamente resecado con mutación BRAF V600E/K: estudio de fase III, triple ciego, aleatorizado, en colaboración con el Grupo de Melanoma de la EORTC

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

Encorafenib and Binimetinib

Placebo to match Encorafenib ; Placebo to match Binimetinib

Ubicaciones

Centro Oncologico Korben

Centro de Investigaciones Medicas Mar del Plata

Fundacion CIDEA

Sanatorio Britanico S.A.

Instituto de Oncologia de Rosario

Hospital Aleman

Instituto Medico Especializado Alexander Fleming

Clinica Adventista Belgrano

Patrocinadores