Anti-GITR agonist TRX518 in combination with gemcitabine in advanced solid cancers: Preliminary safety and efficacy from a multi-center phase Ib trial
Authors: V. Velcheti, T. Bauer, J. Luke, O. Rixe, D. Bajor, G.S. Naik, C. Sirard, D. Davar
Journal: Annals of Oncology (2018)

Background: Anti-GITR (glucocorticoid-induced TNFR-related protein) agonist and gemcitabine (gem) combination improves anti-tumor activity pre-clinically compared to either therapy alone. We investigated the effect of this combination as part of a multi-center phase 1b multi-dose escalation and expansion trial in patients (pts) with advanced solid cancers. Methods: Part C of the phase 1b trial enrolled adult pts with advanced solid cancers for which gemcitabine was clinically appropriate. Pts had failed at-least one prior systemic therapy, had measurable disease and were ECOG PS 0-1 at baseline. All pts received gem (1000mg/m2) IV on D1 and D8 and TRX518 on D2 of a 21-day cycle in two escalation cohorts (2mg/kg or 4mg/kg load[L] in C1 followed by 1mg/kg maintenance[M] from C2). The highest tested safe dose identified in escalation was further evaluated in expansion. Primary endpoint was safety. Secondary and exploratory endpoints included response (RECIST v1.1), PK and PD. Results:Table80PPart C: TRX518 + Gemcitabine (1000mg/m2)NResponse- EvaluableSDPDNECohort/TRX518 doseCohort 1 - 2mg/kg L/1mg/kg M42022*One patient was replaced as patient discontinued before completion of C1 and DLT assessment and the other patient withdrew consent before staging scan but was evaluable for DLT assessment.Cohort 2 - 4mg/kg L/1mg/kg M65411*One patient had clinical progression and did not have a staging scan.Expansion - Cohort 2 dose167439*Patients have not had C3 scans at the time of this report $ Four of 6 pts have not had C3 scans at the time of this report.PBC1610646$Overall26148612* One patient was replaced as patient discontinued before completion of C1 and DLT assessment and the other patient withdrew consent before staging scan but was evaluable for DLT assessment.** One patient had clinical progression and did not have a staging scan.*** Patients have not had C3 scans at the time of this report $ Four of 6 pts have not had C3 scans at the time of this report. Open table in a new tab From January to September 2018, 26 pts were dosed;16/26 had pancreaticobiliary cancers (PBC) of which14/16 had prior gem. There was 1 treatment-related SAE (G3 anemia, G4 lymphopenia, G3 hypoalbuminemia [DLT] and G3 hypokalemia [DLT]). No treatment-related deaths occurred. Of the 14 response-evaluable pts in cohorts 1 (n = 2), 2 (n = 5) and expansion (n = 7), 57.1% (8/14) had SD. At the 4mg/kg L/1mg/kg M TRX518 dose, 66.7% (8/12) of evaluable pts had SD. 60% of PBC had clinical benefit of which 87.5% had prior gem. Conclusions: In pts with heavily pre-treated advanced cancer, for which gem is clinically appropriate, TRX518 plus gem was well tolerated with no new safety signals. Preliminary evidence of clinical benefit was observed including in pts with PBC previously treated with gem. This study is ongoing. Clinical trial identification: NCT02628574. Legal entity responsible for the study: Leap Therapeutics. Funding: Leap Therapeutics. Disclosure: V. Velcheti: Advisory/Consultant Role: Merck, BMS, AstraZeneca, Genentech, Celgene, Takeda, Foundation Medicine, Nektar Therapeutics. T. Bauer: Employment - Sarah Cannon Research Institute; Tennessee Oncology Consulting or advisory role - Guardant Health; Ignyta (Inst); Loxo; Moderna Therapeutics (Inst); Pfizer Research funding - Abbvie (Inst); Aileron Therapeutics (Inst); Amgen (Inst). J. Luke: Scientific advisory board: 7 Hills, Actym, Alphamab Oncology, Array, BeneVir, Mavu Consultancy: Aduro, AstraZeneca, Bristol-Myers Squibb, Castle, CheckMate, Compugen, EMD Serono, Ideaya, Janssen, Merck, NewLink, Novartis, RefleXion. O. Rixe: Research Funding: Bexion, Kyowa Hakko Kirin, Leap Therapeutics, Medimmune, Newlink Genetics, Pfizer, Regeneron, Rgenix, Seattle Genetics; Travel, accommodations, expenses: Bexion. D. Bajor: Research funding: Apexigen, Roche/Genentech, Seattle Genetics, Tesaro. G.S. Naik: Former employee: Biocon, current employee: Leap Therapeutics. C. Sirard: Current employee: Leap Therapeutics. D. Davar: Consulting or advisory role: Incyte, Merck; Research funding: Bristol-Myers Squibb, Checkmate Pharmaceuticals, Incyte, Merck.