Resumen

El propósito de este estudio es evaluar la eficacia y la seguridad de lenvatinib (E7080/MK-7902) más pembrolizumab (MK-3475) más quimioterapia en comparación con quimioterapia sola en participantes con cáncer gastroesofágico avanzado/metastásico. Las hipótesis primarias del estudio son que lenvatinib más pembrolizumab más quimioterapia es superior a quimioterapia sola tanto en supervivencia global (OS) como en supervivencia libre de progresión (PFS) según los Criterios de Evaluación de Respuesta en Tumores Sólidos versión 1.1 (RECIST 1.1) evaluados por revisión central independiente enmascarada (BICR), en participantes con Puntuación positiva combinada (CPS) de muerte celular programada-ligando 1 (PD-L1) ≥1 y en todos los participantes.

Descripción detallada

El estudio tendrá 2 partes: una Fase de seguridad inicial (Parte 1) y el Estudio principal (Parte 2). En la Parte 1 (Fase de seguridad inicial), aproximadamente 12 participantes serán tratados con lenvatinib en combinación con pembrolizumab y quimioterapia con capecitabina y oxaliplatino (CAPOX), o 5-fluorouracilo (5-FU), leucovorina y oxaliplatino (mFOLFOX6). Los participantes serán estrechamente monitoreados para detectar toxicidades limitantes de dosis durante los 21 días posteriores a la primera dosis de la intervención del estudio. En la Parte 2, hasta 878 participantes elegibles (sin incluir a los de la Parte 1) serán asignados aleatoriamente en una proporción 1:1 a recibir lenvatinib más pembrolizumab más quimioterapia (CAPOX o mFOLFOX6) o quimioterapia sola (CAPOX o mFOLFOX6). Los participantes pueden recibir hasta 18 infusiones (hasta 2 años) de pembrolizumab durante el primer ciclo. Los participantes podrán ser elegibles para recibir un segundo ciclo de pembrolizumab (aproximadamente 1 año) a discreción del investigador. A partir de la Enmienda 8 (con vigencia a partir del 10/06/2025), el segundo ciclo ya no se ofrecerá. Los participantes que actualmente estén recibiendo retratamiento en el segundo ciclo podrán continuar el tratamiento según lo planificado. Las imágenes se realizarán según el estándar de atención local.

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

Has histologically and/or cytologically confirmed diagnosis of previously untreated, locally advanced unresectable or metastatic gastroesophageal adenocarcinoma
Is not expected to require tumor resection during the treatment course
Has gastroesophageal adenocarcinoma that is not human epidermal growth factor receptor 2 (HER-2)/neu positive
Has measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by scan with IV contrast as determined by the local site investigator
Male participants agree to refrain from donating sperm and agree to either remain abstinent from heterosexual intercourse as their preferred and usual lifestyle OR agree to use contraception, during the intervention period and for ≥7 days after last dose of lenvatinib or 90 days after last dose of chemotherapy-whichever comes last
Female participants not pregnant or breastfeeding are eligible to participate if not a women of childbearing potential (WOCBP), or if a WOCBP they either use a contraceptive method that is highly effective OR remain abstinent from heterosexual intercourse as their preferred and usual lifestyle, and do not donate eggs (ova, oocytes) to others or freeze/store for their own use, and abstain from breastfeeding during the intervention period through 120 days after last dose of pembrolizumab, 30 days after last dose of lenvatinib, or 180 days after last dose of chemotherapy-whichever occurs last
Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 3 days prior to the first dose of study treatment
Has adequately controlled blood pressure with or without antihypertensive medications
Has adequate organ function

Criterios de exclusión

Has had previous therapy for locally advanced unresectable or metastatic gastric/gastroesophageal junction (GEJ) esophageal adenocarcinoma
Has had major surgery within 28 days prior to first dose of study interventions
Has had radiotherapy within 14 days of randomization
Has a known additional malignancy that is progressing or has required active treatment within the past 5 years
Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
Has severe hypersensitivity (≥Grade 3) to treatment with an monoclonal antibody (mAb) or known sensitivity or intolerance to any component of lenvatinib, pembrolizumab, study chemotherapy agents and/or to any excipients, murine proteins, or platinum containing products
Has had an allogeneic tissue/solid organ transplant
Has perforation risks or significant gastrointestinal (GI) bleeding
Has GI obstruction, poor oral intake (CAPOX participants), or difficulty in taking oral medication (CAPOX participants)
Has received prior therapy with an anti-programmed cell death 1 (PD-1), anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor
Has received prior therapy with anti- vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor or anti-VEGF mAb
Has received a live or live-attenuated vaccine within 30 days before the first dose of study drug
Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation
Has inadequate cardiac function
Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
Has poorly controlled diarrhea
Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment
Has peripheral neuropathy ≥Grade 2
Has a known history of human immunodeficiency virus (HIV) or HIV 1/2 antibodies
Has a known history of hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid (RNA) \[qualitative\] is detected) infection
Has weight loss of \>20% within the last 3 months

Intervenciones

biological

Pembrolizumab

400 mg Q6W by IV infusion

biological

Lenvatinib

Administered PO QD, 8 mg induction/20 mg consolidation.

drug

Oxaliplatin

130 mg/m\^2 administered by IV infusion on Day 1 of Weeks 1 and 4 of each Q6W cycle as part of CAPOX chemotherapy, or 85 mg/m\^2 administered by IV infusion on Day 1 and Week 1, 3 and 5 of each Q6W cycle as part of mFOLFOX6 chemotherapy.

drug

Capecitabine

1000 mg/m\^2 administered PO twice daily (BID) on Days 1-14, 22-35 of each Q6W cycle as part of CAPOX chemotherapy.

drug

Leucovorin (or Levoleucovorin)

Administered by IV infusion at 400 mg/m\^2 (leucovorin) or 200 mg/m\^2 (levoleucovorin) on Day 1, and Week 1, 3 and 5 of each Q6W cycle as part of mFOLFOX6 chemotherapy.

drug

5-FU

400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous IV infusion administered on Day 1, and Week 1, 3, 5, of each Q2W cycle as part of mFOLFOX6 chemotherapy.

Ubicaciones

IDIM Instituto de Diagnostico e Investigaciones Metabolicas ( Site 0202)

Caba, Buenos Aires, Argentina

Instituto Medico Alexander Fleming ( Site 0208)

Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina

Fundacion Favaloro ( Site 0201)

Buenos Aires, Argentina

Hospital Aleman ( Site 0210)

Buenos Aires, Argentina

Hospital Municipal de Gastroenterologia Dr. Bonorino Udaondo ( Site 0207)

Buenos Aires, Argentina

CEMIC ( Site 0209)

Buenos Aires, Argentina

Hospital Privado de Cordoba ( Site 0204)

Córdoba, Argentina

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

Pembrolizumab

Lenvatinib

Oxaliplatin

Capecitabine

Leucovorin (or Levoleucovorin)

5-FU

Ubicaciones

IDIM Instituto de Diagnostico e Investigaciones Metabolicas ( Site 0202)

Instituto Medico Alexander Fleming ( Site 0208)

Fundacion Favaloro ( Site 0201)

Hospital Aleman ( Site 0210)

Hospital Municipal de Gastroenterologia Dr. Bonorino Udaondo ( Site 0207)

CEMIC ( Site 0209)

Hospital Privado de Cordoba ( Site 0204)

Patrocinadores