Sistema de Salut de Catalunya
Institut Català de la Salut
[Romesser PB] Memorial Sloan Kettering Cancer Center, New York, New York. [Capdevila J] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. IOB QuironTeknon, Barcelona, Spain. [Garcia-Carbonero R] Hospital Universitario 12 de Octubre, Imas12, UCM, Madrid, Spain. [Philip T] Northwell Health Cancer Institute, Lake Success, New York. [Fernandez Martos C] Initia Oncología, Quirónsalud Hospital Group, Valencia, Spain. [Tuli R] USF Health Morsani College of Medicine, Tampa, Florida
Vall d'Hebron Barcelona Hospital Campus
2024-02-21T12:44:49Z
2024-02-21T12:44:49Z
2024-02-15
DNA-PK inhibitor peposertib; Neoadjuvant chemoradiation; Rectal cancer
Inhibidor de l'ADN-PK peposertib; Quimioradiació neoadjuvant; Càncer de recte
Inhibidor de ADN-PK peposertib; Quimiorradiación neoadyuvante; Cáncer de recto
Purpose: Peposertib—an orally administered DNA-dependent protein kinase inhibitor—has shown potent radiosensitization in preclinical models. This dose-escalation study (NCT03770689) aimed to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of peposertib plus capecitabine-based chemoradiotherapy (CRT) and assessed its safety and efficacy in locally advanced rectal cancer. Patients and Methods: Patients were treated for 5 to 5.5 weeks with 50- to 250-mg peposertib once daily, capecitabine 825 mg/m2 twice daily, and radiotherapy (RT), 5 days per week. Following clinical restaging (8 weeks after CRT completion), patients with clinical complete response (cCR) could opt for surveillance. Total mesorectal excision was recommended upon incomplete response (IR). Results: Nineteen patients were treated with peposertib at doses of 50 mg (n = 1), 100 mg, 150 mg, and 250 mg (n = 6 each). Dose-limiting toxicities occurred in one out of five (100 mg), one out of six (150 mg), and three out of six (250 mg) evaluable patients. Peposertib ≤150 mg once daily was tolerable in combination with CRT. After 8 weeks of treatment with peposertib and CRT, the cCR was 15.8% (n = 3). Among the three patients with cCR, two underwent surgery and had residual tumors. Among the 16 patients with IR, seven underwent surgery and had residual tumors; five of the remaining nine patients opted for consolidative chemotherapy. The combined cCR/pathologic complete response (pCR) rate was 5.3% (n = 1, 100 mg cohort). Conclusions: Peposertib did not improve complete response rates at tolerable dose levels. The study was closed without declaring the MTD/RP2D.
Article
Published version
English
Proteïnes quinases - Inhibidors - Ús terapèutic; Quimioteràpia combinada; Recte - Càncer - Tractament; ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols; DISEASES::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms::Rectal Neoplasms; ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Combined Modality Therapy::Chemoradiotherapy; CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors; TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada; ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales::neoplasias del recto; TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::tratamiento combinado::quimiorradioterapia; COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas
American Association for Cancer Research
Clinical Cancer Research;30(4)
https://doi.org/10.1158/1078-0432.CCR-23-1129
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
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