Abstract
SELISARC: A Spanish Sarcoma Group (GEIS) phase I/II trial of selinexor plus gemcitabine in selected sarcoma subtypes—Results of the phase I part.
Author
Javier Martin Broto
Fundacion Jimenez Diaz University Hospital and Health Research Institute-Fundación Jiménez Díaz University Hospital, Autonomous University of Madrid (IIS-FJD, UAM), Madrid, Spain
info_outline
Javier Martin Broto, Antonio Casado, David Moura, Luis Ortega, Andres Redondo, Daniel Bernabeu, Javier Martinez-Trufero, Claudia Valverde, Antonio Gutierrez, Jose Lucinio Mondaza-Hernandez, Aránzazu Manzano, Gloria Marquina, Nadia Hindi
Full text
Authors
Javier Martin Broto
Fundacion Jimenez Diaz University Hospital and Health Research Institute-Fundación Jiménez Díaz University Hospital, Autonomous University of Madrid (IIS-FJD, UAM), Madrid, Spain
info_outline
Javier Martin Broto, Antonio Casado, David Moura, Luis Ortega, Andres Redondo, Daniel Bernabeu, Javier Martinez-Trufero, Claudia Valverde, Antonio Gutierrez, Jose Lucinio Mondaza-Hernandez, Aránzazu Manzano, Gloria Marquina, Nadia Hindi
Organizations
Fundacion Jimenez Diaz University Hospital and Health Research Institute-Fundación Jiménez Díaz University Hospital, Autonomous University of Madrid (IIS-FJD, UAM), Madrid, Spain, Hospital Clinico San Carlos, Madrid, Spain, Health Research Institute-Fundación Jiménez Díaz University Hospital, Autonomous University of Madrid (IIS-FJD, UAM), Madrid, Spain, Hospital Clínico San Carlos, Madrid, Spain, Hospital Universitario La Paz, Madrid, Spain, Hospital U. Miguel Servet, Zaragoza, Spain, Vall d'Hebron University Hospital, Barcelona, Spain, Son Espases University Hospital, Palma De Mallorca, Spain, Hospital Clínico San Carlos and IdISSC, Madrid, Spain, Hospital Universitario Fundación Jiménez Díaz and Health Research Institute-Fundación Jiménez Díaz University Hospital, Autonomous University of Madrid (IIS-FJD, UAM), Madrid, Spain
Abstract Disclosures
Research Funding
Other
Spanish Group for Research in Sarcoma, Karyopharm
Background:
Selinexor (KPT-330) (S), a small-molecule inhibitor of the nuclear export mediator exportin-1 (XPO-1), is able to reduce mRNA and protein expression of DNA damage repair (DDR) gene products, being synergistic with DNA damage agents as gemcitabine (G) in preclinical experiments. We hypothesized that selinexor would have a synergistic effect with gemcitabine in selected sarcoma patients (pts).
Methods:
Adult progressing pts, ECOG 0-1, with up to 2 previous systemic therapies for advanced disease (localized unresectable/metastatic) with centrally confirmed diagnosis of undifferentiated pleomorphic sarcoma (UPS), leiomyosarcoma (LMS), alveolar soft part sarcoma (ASPS), or osteosarcoma (OS) were eligible. S (days 1, 8, 15) and G (days 1, 8) were given in four dose levels, L1: S 60 mg + G 1,000 mg/m2 30 min, L2: S 60 mg + G 1,000 mg/m2 (10 mg/m2/min), L3: S 60 mg + G 1,200 mg/m2 (10 mg/m2/min), and L4: S 80 mg + G 1,200 mg/m2 (10 mg/m2/min). A -1 level was defined with S 60 mg + G 800 mg/m2 (30 min). A classic 3+3 design was used to determine the RP2D based on DLTs observed during the first 21-day cycle.
In vitro
research was performed in LMS and OS cell lines to test the synergy of the combination (MTS and flow cytometry assays).
Results:
Between November 2020 and June 2022, 17 pts (M/F 9/8), ECOG 0/1 (14/3), median age 50 years (22-71) were recruited. The median of previous lines was 1 (1-2). Diagnosis was: 9 LMS (52.9%), 6 OS (35.3%), 1 ASPS and 1 synovial sarcoma (SS) (5.9%). Three pts were treated in each of the first 3 levels and 8 pts in L4 (2 pts were not evaluable for DLT due to improper dosing). Only one DLT was observed in L4 (G4 thrombocytopenia) and this level was selected as RP2D. G3/4 toxicity: Neutropenia (52.9%), thrombocytopenia (41.2%), febrile neutropenia (11.8%), anemia, nausea, asthenia, vomiting, alopecia, and lipase increased (5.9% each). There were 3 RECIST PR, 7 SD, and 7 PD. Median PFS for LMS was 7 months (95% CI: 3-11). No relevant clinical activity was observed in OS.
In vitro
cell viability studies shown that S+G was synergistic in the majority of LMS cell lines tested (combination index of 0.789 for CP0024, 0.791 for SK-UT-1, 0.604 for AA and 1.186 for IEC005). However, our results indicated antagonism of S+G in OS cell lines, with values for the combination index of 1.67 for MG63, 1.54 for SAOS2 and 1.23 for U2OS. Apoptosis assays by flow cytometry confirmed these observations in LMS and OS cells.
Conclusions:
At the RP2D, S 80 mg + G 1,200 mg/m2 (10 mg/m2/min) is a feasible scheme with manageable toxicity. S+G has shown promising clinical activity for LMS, which warrants further investigation in a phase II. Preclinical studies shown the synergy and the antagonism of S+G in LMS and OS, respectively. Clinical trial information: NCT04595994.
Clinical status
Clinical
1 clinical trial
8 organizations
2 drugs
2 targets
Clinical trial
Phase I/II Randomized Clinical Trial of Selinexor Plus Gemcitabine in Selected Advanced Soft-tissue Sarcoma and OsteosarcomaStatus: Recruiting, Estimated PCD: 2025-11-30
Organization
Fundacion Jimenez Diaz University HospitalOrganization
Hospital Clinico San CarlosOrganization
Hospital Universitario La Paz - CIBERONCOrganization
Hospital U. Miguel ServetOrganization
Son Espases University HospitalOrganization
Hospital Universitario Fundación Jiménez DíazDrug
SelinexorDrug
FF-10832Target
exportin-1 (XPO-1)Target
DNA