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Interim analysis of a phase I dose escalation trial of the antibody drug conjugate (ADC) AGS15E (ASG-15ME) in patients (Pts) with metastatic urothelial cancer (mUC)

Date

09 Oct 2016

Session

Genitourinary tumours, non-prostate

Presenters

Daniel Petrylak

Citation

Annals of Oncology (2016) 27 (6): 266-295. 10.1093/annonc/mdw373

Authors

D. Petrylak1, E. Heath2, G. Sonpavde3, S. George4, A.K. Morgans5, B.J. Eigl6, J. Picus7, S. Cheng8, S.J. Hotte9, E. Gartner10, M. Vincent11, R. Chu11, B. Anand11, K. Morrison11, L. Jackson11, A. Melhem-Bertrandt12, E.Y. Yu13

Author affiliations

  • 1 Medical Oncology, Smilow Cancer Hospital at Yale-New Haven, 208032 - New Haven/US
  • 2 Medical Oncology, Karmanos Cancer Institute, 48201 - Detroit/US
  • 3 Medical Oncology, University of Alabama at Birmingham Hospital, 35294-3280 - Birmingham/US
  • 4 Department Of Medicine, Roswell Park Cancer Institute, 14263 - Buffalo/US
  • 5 Hematology/oncology, Vanderbilt Ingram Cancer Center, Nashville/US
  • 6 Oncology, British Columbia Cancer Agency, V5Z 4E6 - Vancouver/CA
  • 7 Oncology, Washington University School of Medicine, 63110 - St Louis/US
  • 8 Medical Oncology, Sunnybrook Odette Cancer Center, Sunnybrook HSC, Toronto/CA
  • 9 Oncology, Juravinski Cancer Centre, L8V 5C2 - Hamilton/CA
  • 10 Development, Seattle Genetics, Inc., Seattle/US
  • 11 Development, Agensys Inc., 90404 - Santa Monica/US
  • 12 Clinical Research, Astellas Pharma, Northbrook/US
  • 13 Medical Oncology, Univ. Washington/VAPSHCS, Seattle/US
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Background

SLITRK6 is a protein highly expressed on bladder cancer cells. ASG-15ME is an ADC that delivers a small molecule microtubule-disrupting agent, monomethyl auristatin E (MMAE), to tumors expressing SLITRK6.

Methods

mUC pts previously treated with ≥ 1 prior chemo were enrolled using a modified continual reassessment method design. Slitrk6 expression was determined by immunohistochemistry (IHC). Disease assessments were performed every 8 weeks (wks) using RECIST v 1.1. ASG-15ME was administered IV wkly for 3 out of every 4 wks until no further benefit. Six dose levels were studied: 0.1, 0.25, 0.5, 0.75, 1, and 1.25 mg/kg.

Results

As of 5/2/16, 51 pts were enrolled. 93% were SLITRK6 positive. Median age was 64 yrs; 100% were ECOG PS ≤ 1; 26 pts (52%) had ≥ 2 prior therapies (tx). Of 42 evaluable pts at doses considered active (doses ≥0.5 mg/kg), 1 has a complete response (CR) currently at 39 wks and 13 had a partial response (PR) (ORR =33%), including 4/11 pts (36%) with liver metastases and 5/12 pts (42%) who failed checkpoint inhibitor (CPI) tx. Median duration on ASG-15ME is currently 13 wks. Median progression free survival and duration of response are 16 and 15 wks, respectively. 42 pts (91%) had adverse events (AEs). The most common tx-related AE was fatigue (44%). 23 pts (50%) had Grade (G) 3/4 AEs, 9 (20%) of which were considered related. Ten pts had reversible ocular AEs (1 G3). 4 pts had protocol defined dose limiting toxicities. There were 2 deaths, none related to tx. Serum concentrations of ASG-15ME decreased multi-exponentially and half-life is 3.1 days. Exposure was dose-proportional. Enrollment continues at the 1 and 1.25 mg/kg dose levels to define a dose for future studies. Updated results will be presented.

Antitumor Activity

Dose (mg/kg) 0.5 0.75 1 1.25
Evaluable pts* (n = 42) 8 14 15 5
ORR (CR + PR) n (%) 1 (13) 4 (29) 7 (47) 2 (40)

* ≥ 1 dose of drug and ≥ 1 post-baseline DA

Conclusions

ASG-15ME, a novel ADC, is well tolerated with encouraging antitumor activity in heavily pretreated mUC pts. These results warrant further studies in mUC.

Clinical trial identification

Protocol AGS15E-13-1

Legal entity responsible for the study

Agensys Inc.

Funding

Agensys Inc.

Disclosure

D. Petrylak: Bayer, Bellicum Pharmaceuticals, Dendreon, Sanofi, Johnson & Johnson, Exelixis, Ferring, Millenium, Medivation, Pfizer, Progenics, Genentech, Astellas, Oncogenix, Merck, GTX, and Novartis. E. Heath: I do business with or have received research funding from the following conpanies: Agensys, Bayer, Dendreon, Sanofi, Tokai Pharmaceuticals, Seattle Genetics, Genentech/Roche, Millennium, Celdex, Inovio Pharmaceutical and Celgene. G. Sonpavde: Bayer, Genentech Inc, Sanofi, Merck, Novartis, Pfizer, Argos Therapeutics, Agensys Inc. Onyx, Bayer and Boehringer Ingelheim. S. George: I have done business with or have research funding from the following companies: Amgen, Briston Meyers Squibb, Novartis, Pfizer, Bayer, Acceleron, Agensys, Astellas, Xcenda and Onclive. A.K. Morgans: I have done business with or have received research funding from the following companies: Genentech, Bayer and Dendreon. J. Picus, B. Anand, K. Morrison, L. Jackson: Agensys Inc. S. Cheng: Roche Boehringer Ingelheim. S.J. Hotte: Astellas Scientific and Medical Affairs, Janssen Oncology, Janssen Pharmaceuticals, Oncogenex, Astra Zeneca, Novartis, Bayer, Boehringer Ingelheim, Roche Genentech, and Sanofi E. Gartner: Seattle Genetics Inc. M. Vincent: Amgen Pfizer. R. Chu: Amgen Inc. Vertex Gilead. A. Melhem-Bertrandt: Astellas Pharma. E.Y. Yu: Dendreon, Janssen Pharmaceuticals, Medivation, Sanofi, Bayer, Tolmar, Seattle Genetics Inc, Merck,Genentech/Roche, Tokai Pharmaceutical, Agensys, Ferring, Exelixis, Lilly, Astellas, GTX, Oncogenex and Lilly/ImClone. All other authors have declared no conflicts of interest.

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