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

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.

This is a preview of subscription content, log in to check access.

Fig. 1

References

  1. 1.

    Tannock IF et al (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351(15):1502–1512

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    de Bono JS et al (2010) Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376(9747):1147–1154

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    O'Regan S et al (2000) An electric lobe suppressor for a yeast choline transport mutation belongs to a new family of transporter-like proteins. Proc Natl Acad Sci U S A 97(4):1835–1840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Hediger MA et al (2004) The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteinsIntroduction. Pflugers Arch 447(5):465–468

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Mattie M et al (2016) The discovery and preclinical development of ASG-5ME, an antibody-drug conjugate targeting SLC44A4-positive epithelial tumors including pancreatic and prostate Cancer. Mol Cancer Ther 15(11):2679–2687

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Pettit GR (1997) The dolastatins. Fortschr Chem Org Naturst 70:1–79

    CAS  PubMed  Google Scholar 

  7. 7.

    NCI and NIH (2010) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03

  8. 8.

    Scher HI et al (2008) Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate Cancer clinical trials working group. J Clin Oncol 26(7):1148–1159

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Danila, D.C., et al., Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res, 2007. 13(23): p. 7053-8

  10. 10.

    de Bono JS et al (2008) Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 14(19):6302–6309

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Verma S et al (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367(19):1783–1791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Younes A et al (2010) Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363(19):1812–1821

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Fanale MA et al (2012) A phase I weekly dosing study of brentuximab vedotin in patients with relapsed/refractory CD30-positive hematologic malignancies. Clin Cancer Res 18(1):248–255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Wright, G.L., Jr., et al., Expression of prostate-specific membrane antigen in normal, benign, and malignant prostate tissues. Urol Oncol, 1995. 1(1): p. 18–28

  15. 15.

    Endocyte (2014) Phase 1 of EC1169 In Patients With Recurrent MCRPC

  16. 16.

    Gumbiner B (1987) Structure, biochemistry, and assembly of epithelial tight junctions. Am J Phys Cell Phys 253(6):C749–C758

    Article  CAS  Google Scholar 

  17. 17.

    Yoshida M et al (2004) Human neonatal fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells. Immunity 20(6):769–783

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Ghetie V et al (1996) Abnormally short serum half-lives of IgG in β2-microglobulin-deficient mice. Eur J Immunol 26(3):690–696

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Dickinson BL et al (1999) Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line. J Clin Investig 104(7):903

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Spiekermann GM et al (2002) Receptor-mediated immunoglobulin G transport across mucosal barriers in adult life. J Exp Med 196(3):303–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Israel E et al (1997) Expression of the neonatal fc receptor, FcRn, on human intestinal epithelial cells. Immunology 92(1):69–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Coveler AL et al (2016) A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers. Investig New Drugs 34(3):319–328

    Article  CAS  Google Scholar 

  23. 23.

    Petrylak DP et al (2014) A phase II trial of prostate-specific membrane antigen antibody drug conjugate (PSMA ADC) in taxane-refractory metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 32(4):5s

    Google Scholar 

Download references

Funding

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

Author information

Affiliations

Authors

Corresponding author

Correspondence to Michael J. Morris.

Ethics declarations

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

McHugh, D., Eisenberger, M., Heath, E.I. et al. A phase I study of the antibody drug conjugate ASG-5ME, an SLC44A4-targeting antibody carrying auristatin E, in metastatic castration-resistant prostate cancer. Invest New Drugs 37, 1052–1060 (2019). https://doi.org/10.1007/s10637-019-00731-5

Download citation

Keywords

  • Prostate Cancer
  • Castration-resistant
  • Antibody drug conjugate