Safety and efficacy of CDX-014, an antibody-drug conjugate directed against T cell immunoglobulin mucin-1 in advanced renal cell carcinoma

Abstract

CDX-014 is an antibody-drug conjugate directed against TIM-1, a surface marker highly expressed in renal cell carcinoma (RCC) and ovarian carcinoma. This phase I, first-in-human trial was conducted to evaluate the safety and preliminary activity of CDX-014 in patients with advanced refractory RCC, following a dose-escalation and dose expansion design. CDX-014 was administered intravenously at doses ranging from 0.15 to 2.0 mg/kg every 2 or 3 weeks until progression or unacceptable toxicity. Sixteen patients received at least one dose of CDX-014. The maximum tolerated dose was not identified. Most frequent adverse grade 1 or 2 adverse events included nausea (38%), fatigue, alopecia, elevation of AST and decreased appetite (25% each). Adverse events of grade 3 or more included hyperglycemia (19%), urosepsis (6%), and one multi-organ failure (6%) responsible for one treatment-related death. Two patients discontinued therapy for adverse events including fatigue grade 2 and urosepsis grade 4. CDX-014 showed antitumor activity with one prolonged partial response and a clinical benefit rate (objective response or stable disease >6 months) of 31%. The two patients that exhibited the most marked tumor shrinkage had high TIM-1 expression on tumor tissue. Overall, CDX-014 exhibited a manageable toxicity profile and early signs of activity, supporting further evaluation of antibody-drug conjugates in patients with advanced RCC and potentially other TIM-1 expressing cancers. Trial registration https://ichgcp.net/clinical-trials-registry/NCT02837991 NCT02837991; July 20, 2016.

Keywords: Antibody-drug conjugate; First-in-human; Metastatic renal cell carcinoma; Phase 1 trial; Renal cell carcinoma; Salvage therapy.

Conflict of interest statement

Conflict of interest BAM: discloses payment for consulting with Bayer, Astellas, Astra Zeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech and EMD Serono. He received research support to Dana Farber Cancer Institute (DFCI) from Bristol Myers Squibb, Calithera, Exelixis, Seattle Genetics.

RF: no competing interests.

MG reports other from Medimmune, other from Merck, other from BMS, other from Amgen, other from Tesaro, other from Beigene, other from ABBVIE, other from Aeglea, personal fees and other from Agenus, other from Arcus, other from Astex, other from BluePrint, other from Calithera, other from CellDex, other from Corcept, other from Clovis, other from Eli Lilly, other from Endocyte, other from Five Prime, other from Genocea, other from Neon, other from Plexxicon, personal fees and other from Imaging Endpoints, other from Revolution Medicine, other from Seattle Genetics, other from Serono, other from SynDevRx, other from Toleron, personal fees and other from Tracon, personal fees and other from Deciphera, personal fees and other from Salarius, outside the submitted work.

NA discloses payment for consultancy to Astellas, Astra Zeneca, BMS, Bayer, Clovis, Eisai, Exelixis, EMD Serono, Ely Lilly, Foundation Medicine, Genentech, Janssen, Merck, Novartis, Nektar, Pfizer, Pharmacyclics.

SG reports grants and personal fees from Bayer, grants and personal fees from BMS, grants from Novartis, personal fees from Exelixis, personal fees from Janssen, grants and personal fees from Corvus, personal fees from Genentech, personal fees from Sanofi/ Genzyme, grants and personal fees from Pfizer, grants from Acceleron, grants from Merck, grants from Agensys, grants from Eisai, personal fees from EMD Serono, outside the submitted work.

DIQ discloses payment for consulting with Bayer, BMS, Exelixis, Merck, Novartis and Pfizer.

MR, TH and TK own stock and are employees of Celldex Therapeutics, Inc.

TKC discloses payment for consulting to Analysis Group, AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol-Myers Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Heron Therapeutics, Lilly, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to- Date, NCCN, Analysis Group, Michael J. Hennessy (MJH) Associates, Inc. (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology. He received research support to DFCI from Analysis Group, AstraZeneca, Alexion, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Sanofi/Aventis, Takeda.

Figures

Fig. 1

CONSORT diagram and Enrollment summary

Fig. 2

Best overall RECIST response to CDX-014. CDX-014 dose [mg/kg] and TIM-1 expression [% tumor cells positive] are displayed in parenthesis for each patient. All patients are Q3W schedule unless noted as Q2W

Fig. 3

Response by “spider plots”