Skip to main content

Advertisement

Log in

A phase 1, dose-escalation study of PF-06664178, an anti-Trop-2/Aur0101 antibody-drug conjugate in patients with advanced or metastatic solid tumors

  • PHASE I STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Purpose and Methods Trop-2 is a glycoprotein over-expressed in many solid tumors but at low levels in normal human tissue, providing a potential therapeutic target. We conducted a phase 1 dose-finding study of PF-06664178, an antibody-drug conjugate that targets Trop-2 for the selective delivery of the cytotoxic payload Aur0101. The primary objective was to determine the maximum tolerated dose and recommended phase 2 dose. Secondary objectives included further characterization of the safety profile, pharmacokinetics and antitumor activity. Eligible patients were enrolled and received multiple escalating doses of PF-06664178 in an open-label and unblinded manner based on a modified continual reassessment method. Results Thirty-one patients with advanced or metastatic solid tumors were treated with escalating doses of PF-06664178 given intravenously every 21 days. Doses explored ranged from 0.15 mg/kg to 4.8 mg/kg. Seven patients experienced at least one dose limiting toxicity (DLT), either neutropenia or rash. Doses of 3.60 mg/kg, 4.2 mg/kg and 4.8 mg/kg were considered intolerable due to DLTs in skin rash, mucosa and neutropenia. Best overall response was stable disease in 11 patients (37.9%). None of the patients had a partial or complete response. Systemic exposure of PF-06664178 increased in a dose-related manner. Serum concentrations of free Aur0101 were substantially lower than those of PF-06664178 and total antibody. No correlation of Trop-2 expression and objective response was observed, although Trop-2 overexpression was not required for study entry. The intermediate dose of 2.4 mg/kg appeared to be the highest tolerated dose, but this was not fully explored as the study was terminated early due to excess toxicity. Conclusion PF-06664178 showed toxicity at high dose levels with modest antitumor activity. Neutropenia, skin rash and mucosal inflammation were dose limiting toxicities. Findings from this study may potentially aid in future antibody drug conjugate design and trials.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Lambert JM, Morris CQ (2017) Antibody-drug conjugates (ADCs) for personalized treatment of solid tumors: a review. Adv Ther 34:1–21

    Article  CAS  Google Scholar 

  2. Beck A, Goetsch L, Dumontet C, Corvaïa N (2017) Strategies and challenges for the next generation of antibody–drug conjugates. Nat Rev Drug Discov 16:315–337

    Article  PubMed  CAS  Google Scholar 

  3. Lipinski M, Parks DR, Rouse R V, Herzenberg L a (1981) Human trophoblast cell-surface antigens defined by monoclonal antibodies. Proc Natl Acad Sci U S A 78:5147–5150

  4. Bignotti E, Zanotti L, Calza S et al (2012) Trop-2 protein overexpression is an independent marker for predicting disease recurrence in endometrioid endometrial carcinoma. BMC Clin Pathol 12:22

    Article  PubMed  PubMed Central  Google Scholar 

  5. Trerotola M, Cantanelli P, Guerra E et al (2013) Upregulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene 32:222–233

    Article  PubMed  CAS  Google Scholar 

  6. Fong D, Moser P, Krammel C et al (2008) High expression of TROP2 correlates with poor prognosis in pancreatic cancer. Br J Cancer 99:1290–1295

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Ning S, Guo S, Xie J et al (2013) TROP2 correlates with microvessel density and poor prognosis in hilar cholangiocarcinoma. J Gastrointest Surg 17:360–368

    Article  PubMed  Google Scholar 

  8. Zhao W, Zhu H, Zhang S et al (2016) Trop2 is overexpressed in gastric cancer and predicts poor prognosis. Oncotarget 7:6136–6145

    PubMed  Google Scholar 

  9. Ohmachi T, Tanaka F, Mimori K et al (2006) Clinical significance of TROP2 expression in colorectal cancer. Clin Cancer Res 12:3057–3063

    Article  PubMed  CAS  Google Scholar 

  10. Guerra E, Trerotola M, Aloisi AL et al (2013) The Trop-2 signalling network in cancer growth. Oncogene 32:1594–1600

    Article  PubMed  CAS  Google Scholar 

  11. Cubas R, Li M, Chen C, Yao Q (2009) Trop2: a possible therapeutic target for late stage epithelial carcinomas. Biochim Biophys Acta - rev. Cancer 1796:309–314

    CAS  Google Scholar 

  12. Strop P, Tran T-T, Dorywalska M et al (2016) RN927C, a site-specific Trop-2 antibody-drug conjugate (ADC) with enhanced stability, is highly efficacious in preclinical solid tumor models. Mol Cancer Ther 15:2698–2708

    Article  PubMed  CAS  Google Scholar 

  13. Strop P, Liu SH, Dorywalska M et al (2013) Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates. Chem Biol 20:161–167

    Article  PubMed  CAS  Google Scholar 

  14. Maderna A, Doroski M, Subramanyam C et al (2014) Discovery of cytotoxic dolastatin 10 analogues with N-terminal modifications. J Med Chem 57:10527–10543. https://doi.org/10.1021/jm501649k

    Article  PubMed  CAS  Google Scholar 

  15. O’quigley J, Pepe M, Fisher L (1990) Continual reassessment method: a practical Design for Phase 1 clinical trials in cancer. Biometrics 46103149:33–48

    Article  Google Scholar 

  16. Iasonos A, O’Quigley J (2014) Adaptive dose-finding studies: a review of model-guided phase I clinical trials. J Clin Oncol 32:2505–2511. https://doi.org/10.1200/JCO.2013.54.6051

    Article  PubMed  PubMed Central  Google Scholar 

  17. Stepan LP, Trueblood ES, Hale K et al (2011) Expression of Trop2 cell surface glycoprotein in normal and tumor tissues: potential implications as a cancer therapeutic target. J Histochem Cytochem 59:701–710. https://doi.org/10.1369/0022155411410430

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Ocean AJ, Starodub AN, Bardia A et al (2017) Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: safety and pharmacokinetics. Cancer. https://doi.org/10.1002/cncr.30789

  19. Heist RS, Guarino MJ, Masters G et al (2017) Therapy of advanced non–small-cell lung cancer with an SN-38-anti-trop-2 drug conjugate, sacituzumab govitecan. J Clin Oncol 35(24):2790–2797. https://doi.org/10.1200/JCO.2016.72.1894

  20. Bardia A, Mayer IA, Diamond JR et al (2017) Efficacy and safety of anti-trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-negative breast cancer. J Clin Oncol 35(19):2141–2148. https://doi.org/10.1200/JCO.2016.70.8297

  21. Ott PA, Hamid O, Pavlick AC et al (2014) Phase I/II study of the antibody-drug conjugate Glembatumumab Vedotin in patients with advanced melanoma. J Clin Oncol 32:3659–3666. https://doi.org/10.1200/JCO.2013.54.8115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Advani RH, Lebovic D, Chen A et al (2017) Phase I study of the anti-CD22 antibody-drug conjugate pinatuzumab vedotin with/without rituximab in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res 23:1167–1176. https://doi.org/10.1158/1078-0432.CCR-16-0772

  23. Devay RM, Delaria K, Zhu G et al (2017) Improved lysosomal trafficking can modulate the potency of antibody drug conjugates. Bioconjug Chem 28:1102–1114

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank all participating patients, their families and caregivers, as well as the network of investigators, research nurses, study coordinators, and operations staff. This study was supported by Pfizer. Specifically, we would like to thank the following Pfizer colleagues for their support: Pamela Garzone, Shu-Hui Liu, Candy Bermingham, Bish Ganguly, Alison Forgie, Pavel Strop and Steve Reich.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gentry T. King.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

King, G.T., Eaton, K.D., Beagle, B.R. et al. A phase 1, dose-escalation study of PF-06664178, an anti-Trop-2/Aur0101 antibody-drug conjugate in patients with advanced or metastatic solid tumors. Invest New Drugs 36, 836–847 (2018). https://doi.org/10.1007/s10637-018-0560-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-018-0560-6

Keywords

Navigation