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Background Despite several drugs approved in advanced renal cell carcinoma (RCC), new targets are needed as patients frequently experience progression on current approved therapies. TIM-1 is highly upregulated in RCC. CDX-014 combines a tumour targeting antibody against the mucin stalk of TIM-1 with potent cytotoxic microtubule inhibitor monomethyl E (MMAE) using a valine-citrulline peptide linker. Methods In this first-in-human phase I trial, patients with advanced clear cell or papillary RCC with at least 2 prior therapies including one vascular endothelial growth factor targeted therapy received CDX-014 every 3 weeks with tumor assessment every 6 weeks. Starting dose was 0.15 mg/kg to be escalated to 1.2 mg/kg in single patient cohorts. Further dose escalations up to 2.4 mg/kg was to follow traditional 3 + 3 design. Protocol was amended after escalation through 2 mg/kg to allow for 1.2 mg/kg dose given every 2 weeks in attempt to improve efficacy without increase in toxicity. Results Sixteen patients were enrolled (Table); median number of prior therapies was 4 (range 2-9.) Median number of doses received was 4; 9 patients were on treatment 1 year. Overall response rate was 6.25% with a partial response (PR) seen at 0.30 mg/kg dose lasting 21 months. Tumor shrinkage and progressive disease (PD) as best response occurred in 5 and 6 patients respectively. Clinical benefit rate (PR or Stable disease (SD) ≥6 months) was 25%. TIM-1 expression was noted in > 10% of tumour cells in 13 patients; none of the remaining 3 patients had any tumour shrinkage. 5 dose limiting toxicities were observed in 2 patients, both at 2 mg/kg. Single grade 5 serious adverse event was associated with high free levels of MMAE. Most common Grade ≥ 3 treatment related adverse event was hyperglycemia occurring in 3 patients. Table . 953P Dose (mg/kg) every 3 weeks unless specified # patients enrolled Best overall response 0.15 1 PD 0.3 1 PR 0.6 1 PD 1.2 1 SD 1.8 6 5 SD 1 PD 2 4 2 SD 1 PD 1 NE 1.2 q2wks 2 2 PD NE=not evaluable. Conclusions TIM-1 is a novel target in the treatment of RCC. Optimal dosing strategy of CX-104 has not yet been defined. Clinical trial identification NCT02837991. Legal entity responsible for the study Celldex Pharmaceuticals. Funding Celldex Pharmaceuticals. Disclosure B.A. McGregor: Honoraria (self), Advisory / Consultancy: EMD Serrano; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech; Honoraria (self), Advisory / Consultancy: Janssen; Research grant / Funding (institution): BMS. N. Agarwal: Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Argos; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Exelixis; Honoraria (self), Advisory / Consultancy: EMD Serono; Honoraria (self), Advisory / Consultancy: Ely Lilly; Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Medivation; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Nektar; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Pharmacyclics. S. George: Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self), Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Novartis; Honoraria (self): Exelixis; Honoraria (self): Janssen; Honoraria (self), Research grant / Funding (institution): Corvus; Honoraria (self): Genentech; Honoraria (self): Sanofi/Genzyme; Honoraria (self), Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Acceleron; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Eisai; Honoraria (self): EMD Serono. D.I. Quinn: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self): BMS; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Dendreon; Honoraria (self), Advisory / Consultancy: Exelixis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Honoraria (self): Janssen; Honoraria (self): Novartis; Honoraria (self): Mundipharma; Honoraria (self): Pharmacyclics; Honoraria (self), Advisory / Consultancy: Clovis; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Amgen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Novartis; Research grant / Funding (institution), in addition to Millennium: GlaxoSmithKline. M. Rogalski: Full / Part-time employment: Celldex Pharmaceuticals. T. Keler: Full / Part-time employment: Celldex Pharmaceuticals. T. Hawthorne: Full / Part-time employment: Celldex Pharmaceuticals. T.K. Choueiri: Honoraria (self): AstraZeneca; Honoraria (self): Alexion; Honoraria (self): Bayer; Honoraria (self): Bristol Myers-Squibb; Honoraria (self): Cerulean; Honoraria (self): Eisai; Honoraria (self): foundation medication; Honoraria (self): Exelixis; Honoraria (self): Ipsen; Honoraria (self): Tracon; Honoraria (self): Genentech; Honoraria (self): Roche; Honoraria (self): GlaxoSmithKline; Honoraria (self): Lilly; Honoraria (self): Merck; Honoraria (self): Novartis; Honoraria (self): Peloton; Honoraria (self): Pfizer; Honoraria (self): Prometheus labs; Honoraria (self): Corvus. All other authors have declared no conflicts of interest. |
