Resumen

Este es un estudio en dos partes (fase 2/fase 3) de intismeran autogene, una terapia individualizada de neoantígenos (INT), más pembrolizumab en participantes con carcinoma espinocelular cutáneo localmente avanzado (CECc LA) resecable. La fase 2 tiene tres brazos: intismeran autogene más pembrolizumab administrado como tratamiento neoadyuvante y adyuvante con tratamiento estándar (TE), tratamiento estándar (resección quirúrgica con/sin radioterapia (RT) adyuvante solo a criterio del investigador) y monoterapia con pembrolizumab administrada como tratamiento neoadyuvante y adyuvante con TE. Esta fase evaluará la seguridad y eficacia de intismeran autogene en combinación con pembrolizumab como terapia neoadyuvante y adyuvante en participantes con CECc LA resecable en comparación con TE solo. La hipótesis primaria es que intismeran autogene más pembrolizumab con TE es superior al TE solo con respecto a la supervivencia libre de eventos (SLE) evaluada por el investigador. La expansión de fase 3 se determinará mediante una decisión preestablecida de continuar/no continuar en la que se aleatorizarán 412 participantes adicionales a intismeran autogene más pembrolizumab con TE y TE solo, sin cambiar los criterios de inclusión/exclusión para la inscripción adicional ni los criterios de valoración del estudio. A partir de la enmienda 04, se detuvo la inscripción y no habrá expansión de fase 3.

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

Has a histologically confirmed diagnosis of resectable cSCC as the primary site of malignancy (metastatic skin involvement from another primary cancer or from an unknown primary cancer is not permitted).
Has LA Stage II-IV (M0) cSCC without distant metastases.
cSCC must be amenable to surgery (resectable) with curative intent.
Has a formalin-fixed, paraffin-embedded (FFPE) tumor sample available or is able to provide one that is suitable for the Next-generation Sequencing (NGS) required for this study.
For males, agrees to be abstinent from penile-vaginal intercourse OR agrees to use a highly effective contraceptive method while receiving adjuvant radiation therapy (RT), and for ≥3 months after the last dose of study intervention
Is female and not pregnant/breastfeeding and at least one of the following applies during the study : is not a woman of childbearing potential (WOCBP), is a WOCBP and uses highly effective contraception (low user dependency method OR a user dependent hormonal method in combination with a barrier method) at least during use of intismeran autogene: 15 days, Pembrolizumab: 120 days, Adjuvant RT, if performed: 90 days after last exposure or is a WOCBP who is abstinent from heterosexual intercourse.
Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology.
Has a life expectancy of \>3 months per investigator assessment.
Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 assessed within 14 days before randomization.
Has adequate organ function.
If hepatitis B surface antigen (HBsAg) positive, must have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization
If there is a history of hepatitis C virus (HCV) infection, HCV viral load must be undetectable at screening
If human immunodeficiency virus (HIV)-infected, must have well controlled HIV on antiretroviral therapy (ART)

Criterios de exclusión

Has any other histologic type of skin cancer other than invasive cSCC as well as mixed histology, eg, basal cell carcinoma that has not been definitively treated with surgery or radiation, Bowen's disease, Merkel cell carcinoma (MCC), or melanoma
Has distant metastatic disease (M1), visceral and/or distant nodal
Has received prior therapy with an anti-programmed cell death receptor 1 (anti-PD-1), anti-programmed cell death receptor ligand 1 (anti-PD-L1), or anti-programmed cell death receptor ligand 2 (anti-PD-L2) agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte associated protein 4 (CTLA-4), OX-40, CD137)
Has received prior systemic anticancer therapy including investigational agents for cSCC before randomization
Has received prior radiotherapy within 2 weeks of start of study intervention, or has radiation-related toxicities, requiring corticosteroids
Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
Has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) within 2 weeks of the screening blood sample (including the NGS blood sample)
Has received prior treatment with another cancer vaccine
Has received prior radiotherapy to the index lesion (in-field lesion). Must have recovered from all radiation-related toxicities prior to randomization and not have had radiation pneumonitis
Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication
Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
History of chronic lymphocytic leukemia (CLL)
History of central nervous system (CNS) metastases and/or carcinomatous meningitis
Has severe hypersensitivity (≥Grade 3) to either intismeran autogene or pembrolizumab and/or any of its excipients
Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed
History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
Has an active infection requiring systemic therapy
Has HIV with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
Has concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection
Has had a myocardial infarction within 6 months of randomization
History of allogeneic tissue/solid organ transplant
Has not adequately recovered from major surgery or have ongoing surgical complications

Ubicaciones

Instituto de Investigaciones Clínicas Mar del Plata ( Site 1213)

Mar del Plata, Buenos Aires, Argentina

Fundacion Estudios Clinicos-Oncology ( Site 1205)

Rosario, Santa Fe Province, Argentina

Sanatorio Finochietto ( Site 1202)

Buenos Aires, Argentina

Investigaciones Clinicas Moleculares (ICM) ( Site 1212)

CABA, Argentina

Hospital Italiano de Córdoba ( Site 1204)

Córdoba, Argentina

Resumen

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

Pembrolizumab

Intismeran autogene

Surgery