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Investigational New Drugs

, Volume 37, Issue 5, pp 1052–1060 | Cite as

A phase I study of the antibody drug conjugate ASG-5ME, an SLC44A4-targeting antibody carrying auristatin E, in metastatic castration-resistant prostate cancer

  • Deaglan McHugh
  • Mario Eisenberger
  • Elisabeth I. Heath
  • Justine Bruce
  • Daniel C. Danila
  • Dana E. Rathkopf
  • Jarett Feldman
  • Susan F. Slovin
  • Banmeet Anand
  • Rong Chu
  • Jacqueline Lackey
  • Leonard Reyno
  • Emmanuel S. Antonarakis
  • Michael J. MorrisEmail author
PHASE I STUDIES

Summary

Background Antibody drug conjugates (ADC) offer the potential of maximizing efficacy while minimizing systemic toxicity. ASG-5ME, an SLC44A4-targeting antibody carrying monomethyl auristatin E (MMAE), a microtubule-disrupting agent, was investigated in men with metastatic castration resistant prostate cancer. Methods The primary objective of this phase I study was to determine maximum tolerated dose (MTD) and recommended phase II dose. Secondary objectives were safety, antitumor activity, pharmacokinetic properties, immunogenicity, and the detection of SLC44A4 on circulating tumor cells. Patients (pts) were treated among 7 dose levels every 21 days. A dose expansion phase enrolled 20 additional pts. at the MTD. Results Twenty-six and 20 pts. were treated in dose escalation and dose expansion cohorts respectively. The MTD was 2.7 mg/kg. Dose-limiting toxicities occurred in 4 pts.: grade 3 fatigue (n = 1); grade 3 abdominal pain, diarrhea and fatigue (n = 1); grade 4 neutropenia and hyponatremia and grade 3 maculopapular rash, constipation and hypoxia (n = 1); grade 3 troponin elevation without cardiac sequelae (n = 1). Fatigue and diarrhea were the most prevalent adverse events (AEs) across all cycles. Two grade 5 AEs occurred in the dose expansion cohort, each after 1 dose: 1 pt. developed grade 3 hyperglycemia, renal insufficiency and leukopenia; 1 pt. developed grade 3 hyperglycemia complicated by bacteremia. Free MMAE levels did not accumulate with repeat dosing. Of evaluable pts., 52% had either stable disease or a partial response. Conclusions Further development of ASG-5ME is not being pursued due to its narrow therapeutic index. Some toxicities were potentially related to on-target effects on normal tissue expressing the SLC44A4 protein. However, other toxicities were consistent with studies of previous MMAE-containing ADCs. Unconjugated MMAE is a less likely etiology based on prior data.

Keywords

Prostate Cancer Castration-resistant Antibody drug conjugate 

Notes

Funding

This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.

Compliance with ethical standards

Conflict of interest

Deaglan McHugh: Consulting or Advisory Role - Progenics (Inst).

Emmanuel S. Antonarakis: Honoraria - Astellas Pharma; Dendreon; ESSA; Janssen Biotech; Medivation; Sanofi. Consulting or Advisory Role - Astellas Pharma; Dendreon; ESSA; Janssen Biotech; Medivation; Sanofi. Research Funding - Aragon Pharmaceuticals (Inst); Astellas Pharma (Inst); Dendreon (Inst); Exelixis (Inst); Genentech (Inst); Janssen Biotech (Inst); Johnson & Johnson (Inst); Millennium (Inst); Novartis (Inst); Sanofi (Inst); Tokai Pharmaceuticals (Inst). Travel, Accommodations, Expenses - Dendreon; Medivation; Sanof.

Mario A. Eisenberger: Director in the board of directors of VERU, inc. and ownsstocks; Honoraria - pfizer; Sanofi. Consulting or Advisory Role - Astellas Pharma; Bayer; Ipsen; pfizer; Sanofi; Sanofi. Research Funding - Genentech; Sanofi; Tokai Pharmaceuticals. Travel, Accommodations, Expenses - Astellas Pharma; Bayer; Pfizer; Sanofi.

Elisabeth Heath: Honoraria - Bayer, Sanofi, Dendreon. Consulting or Advisory Role – Agensys. Speaker’s Bureau – Sanofi.

Justine Bruce: No disclosures.

Daniel C. Danila: Honoraria - Angle; Astellas Scientific and Medical Affairs Inc.; Bayer; Xian-Janssen Pharmaceutical. Consulting or Advisory Role - Angle; Bayer. Research Funding - Genentech; Janssen Research & Development (Inst); Prostate Cancer Foundation. Patents, Royalties, Other Intellectual Property - GENE EXPRESSION PROFILE ASSOCIATED WITH PROSTATE CANCER. Travel, Accommodations, Expenses - American Austrian Open Medical Institute; Angle; Bayer; Cambridge Healthtech Institute; Global Technology Community; Oncology Education; Prostate Cancer Foundation; Xian-Janssen Pharmaceutical.

Dana Rathkopf: Consulting or Advisory Role - Janssen Oncology. Research Funding - AstraZeneca (Inst); Celgene (Inst); Ferring (Inst); Genentech/Roche (Inst); Janssen Oncology (Inst); Medivation (Inst); Millennium (Inst); Novartis (Inst); Taiho Pharmaceutical (Inst); Takeda (Inst); TRACON Pharma (Inst).

Jarett Feldman: No disclosures.

Susan Slovin: Consulting or Advisory Role – Bayer.

Banmeet Anand: No diclosures.

Rong Chu: No discosures.

Jacqueline Lackey: No disclosures.

Leonard Reyno: No disclosures.

Emmanuel S. Antonarakis: Honoraria - Astellas Pharma; Dendreon; ESSA; Janssen Biotech; Medivation; Sanofi. Consulting or Advisory Role - Astellas Pharma; Dendreon; ESSA; Janssen Biotech; Medivation; Sanofi. Research Funding - Aragon Pharmaceuticals (Inst); Astellas Pharma (Inst); Dendreon (Inst); Exelixis (Inst); Genentech (Inst); Janssen Biotech (Inst); Johnson & Johnson (Inst); Millennium (Inst); Novartis (Inst); Sanofi (Inst); Tokai Pharmaceuticals (Inst). Travel, Accommodations, Expenses - Dendreon; Medivation; Sanof.

Michael Morris: Consulting or Advisory Role - Astellas Pharma; Bayer; Endocyte. Research Funding - Bayer (Inst); Endocyte (Inst); Progenics (Inst); Sanofi (Inst). Travel, Accommodations, Expenses - Bayer; Endocyte.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Deaglan McHugh
    • 1
  • Mario Eisenberger
    • 2
  • Elisabeth I. Heath
    • 3
  • Justine Bruce
    • 4
  • Daniel C. Danila
    • 1
    • 5
  • Dana E. Rathkopf
    • 1
    • 5
  • Jarett Feldman
    • 5
  • Susan F. Slovin
    • 1
    • 5
  • Banmeet Anand
    • 6
  • Rong Chu
    • 6
  • Jacqueline Lackey
    • 6
  • Leonard Reyno
    • 6
  • Emmanuel S. Antonarakis
    • 2
  • Michael J. Morris
    • 1
    • 5
    Email author
  1. 1.Genitourinary Oncology Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Johns Hopkins UniversityBaltimoreUSA
  3. 3.Karmanos Cancer InstituteWayne State UniversityDetroitUSA
  4. 4.Carbone Cancer CenterUniversity of WisconsinMadisonUSA
  5. 5.Department of MedicineWeill Cornell Medical CollegeNew YorkUSA
  6. 6.Agensys, Inc.Santa MonicaUSA

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