Details

Autor(en) / Beteiligte

• Lawrence, Yaacov R
• Shacham-Shmueli, Einat
• Yarom, Nirit
• Khaikin, Marat
• Venturero, Moris
• Apter, Sara
• Inbar, Yael
• Symon, Zvi
• Aderka, Dan
• Halpern, Naama
• Berger, Raanan
• Boursi, Ben
• Jacobson, Galia
• Raskin, Stephen
• Ackerstein, Aliza
• Margalit, Ofer
• Appel, Sarit
• Schvimer, Michael
• Crochiere, Marsha
• Yang, Fan
• Landesman, Yosef
• Rashal, Tami
• Shacham, Sharon
• Golan, Talia

Titel

Nuclear Export Inhibition for Radiosensitization; a Proof-of-Concept Phase I Clinical Trial of Selinexor (KPT-330) Combined with Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer

Ist Teil von

• International journal of radiation oncology, biology, physics, 2022-06

Ort / Verlag

United States

Erscheinungsjahr

2022

Beschreibungen/Notizen

• Selinexor (KPT-330, XPOVIO®) is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound that blocks XPO1, forcing nuclear retention of tumor suppressor proteins. Selinexor potentiates radiation-induced cell death in preclinical models, but has yet to be combined with radiation in the clinic. We hypothesized that selinexor would increase the activity of neoadjuvant fluoropyrimidine-based chemoradiation (ChRT) for locally advanced rectal cancer (LARC). A phase I clinical trial of selinexor plus ChRT for LARC was performed, 3+3 design. Eligibility criteria included stage II-III LARC requiring neoadjuvant chemoradiation, and ECOG 0-1 performance status. Patients received 50.4 Gy over 5.5 weeks plus capecitabine 825 mg/m twice daily on radiation days. Three selinexor dose-levels were tested: 1) 20 mg/m twice weekly concurrent with ChRT, 2) 35 mg/m twice weekly concurrent with ChRT, and 3) 35 mg/m twice weekly concurrent with ChRT, and for an additional two weeks. Subsequently, patients underwent definitive curative resection. DNA variant analysis and RNAseq were performed to characterize responders. Eleven patients were enrolled, median age 60.5 years, six were stage III. Nine completed selinexor plus ChRT; two patients withdrew consent. Side effects attributed to selinexor included fatigue, hyponatremia and mild thrombocytopenia. Dose level 3 was poorly tolerated, (dehydration, anorexia). Of the 9 patients who completed treatment, median volumetric tumor shrinkage was 93% (IQR 59-98). Comparing baseline clinical stage to final pathological stage, 82% of patients were down-staged. Two patients experienced a complete / near-complete pathological response. Expression of PTGS2 and CD177 were identified as potential biomarkers of response. Selinexor combined with neoadjuvant ChRT in LARC is well tolerated. Potential biomarkers were identified based upon a preliminary analysis.