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A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers

  • PHASE I STUDIES
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Summary

Purpose ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, a novel cell surface target expressed on most pancreatic and gastric cancers. This first-in-human study of ASG-5ME evaluated safety, pharmacokinetics, and preliminary activity of ASG-5ME in advanced pancreatic and gastric cancer patients. Experimental Design This phase 1, dose-escalation, multicenter study determined the maximum tolerated dose (MTD) and assessed safety and antitumor activity. The dose-escalation portion enrolled metastatic pancreatic adenocarcinoma patients; gastric adenocarcinoma patients were included in the dose-expansion portion. Patients received ASG-5ME intravenously on Days 1, 8, and 15 of 28-day cycles. Results Thirty-five pancreatic cancer patients (median age 63 years; performance status 0 [40 %] or 1 [60 %]) were treated at doses of 0.3 to 1.5 mg/kg (median duration 8.1 weeks). The MTD was exceeded at 1.5 mg/kg (n = 7) with 1 dose-limiting toxicity (DLT) of Grade 4 gastrointestinal hemorrhage. Four patients experienced non-DLT Grade 3 or 4 neutropenia. Fifteen gastric cancer patients (median age 59 years; performance status 0 [33 %] or 1 [67 %]) were treated at the identified MTD of 1.2 mg/kg (median duration 8.7 weeks). Common drug-related adverse events included fatigue (29 %), nausea (23 %), and vomiting (23 %) for pancreatic cancer patients and fatigue (33 %) and decreased appetite (33 %) for gastric cancer patients. Best clinical response was 1 partial response in each cohort. Disease-control rates of 33 % (pancreatic) and 47 % (gastric) were observed at the MTD. All patient biopsies (23 pancreatic, 15 gastric) expressed the SLC44A4 antigen. Conclusions ASG-5ME treatment was generally well tolerated with limited evidence of antitumor activity.

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Acknowledgments

Research funding for the study was provided by Seattle Genetics, Inc. The authors wish to acknowledge Scott Truesdell for medical writing assistance, under the sponsorship of Seattle Genetics, Inc.

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Authors and Affiliations

  1. Seattle Cancer Care Alliance, University of Washington, 825 Eastlake Ave E, Seattle, WA, 98109, USA

    Andrew L. Coveler

  2. Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA

    Andrew H. Ko

  3. University of Chicago, Chicago, IL, USA

    Daniel V. T. Catenacci

  4. TGen Clinical Research Service at Scottsdale Healthcare, Scottsdale, AZ, USA

    Daniel Von Hoff

  5. Texas Oncology, Baylor Sammons Cancer Center, Dallas, TX, USA

    Carlos Becerra

  6. Seattle Genetics, Inc., Bothell, WA, USA

    Nancy C. Whiting & Jing Yang

  7. Dana-Farber Cancer Institute, Boston, MA, USA

    Brian Wolpin

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  1. Andrew L. Coveler
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  2. Andrew H. Ko
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  3. Daniel V. T. Catenacci
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  4. Daniel Von Hoff
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  5. Carlos Becerra
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  7. Jing Yang
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Corresponding author

Correspondence to Andrew L. Coveler.

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Funding source

This work was supported by Seattle Genetics, Inc., Bothell, WA, USA.

Author disclosures

A.L. Coveler, A.H. Ko, D.V.T.Catenacci, D.Von Hoff, C.Becerra, and B. Wolpin were investigators funded by Seattle Genetics, Inc. do to this study. N.C. Whiting and J.Yang are Seattle Genetics, Inc. employees.

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Translational relevance

Antibody-drug conjugates (ADCs) are a novel treatment strategy combining rationally developed monoclonal antibodies conjugated to a payload of a highly potent cytotoxic agent with the goal of improving potency of therapy while limiting systemic toxicity. This approach has shown activity in the setting of Hodgkin’s lymphoma and HER-2 positive breast cancer. ASG-5ME is an ADC that delivers the microtubule-disrupting drug monomethyl auristatin E (MMAE) to cells expressing the SLC44A4 antigen. SLC44A4 is differentially overexpressed on the majority of pancreatic and gastric cancer cells, making it an ideal target for delivering a potent chemotherapeutic agent. Here we report the results of a phase I study of ASG-5ME in pancreatic and gastric cancer patients.

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Coveler, A.L., Ko, A.H., Catenacci, D.V.T. et al. A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers. Invest New Drugs 34, 319–328 (2016). https://doi.org/10.1007/s10637-016-0343-x

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  • DOI: https://doi.org/10.1007/s10637-016-0343-x

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