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A first-in-human, phase 1, dose-escalation study of ABBV-176, an antibody-drug conjugate targeting the prolactin receptor, in patients with advanced solid tumors

Abstract

ABBV-176 is an antibody-drug conjugate composed of the humanized antibody h16f (PR-1594804) conjugated to a highly potent, cytotoxic cross-linking pyrrolobenzodiazepine dimer (PBD; SGD-1882) targeting the prolactin receptor (PRLR), which is overexpressed in several solid tumor types. This phase 1, dose-escalation study (NCT03145909) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-176 in patients with advanced solid tumors likely to exhibit elevated levels of PRLR. Patients received ABBV-176 once every 3 weeks. Dose escalation was by an exposure-adjusted, continual reassessment method. Dose-limiting toxicities (DLTs) were assessed from the first day of dosing until the next dose of ABBV-176 to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Nineteen patients received ABBV-176 at doses from 2.7–109.35 μg/kg. Patients enrolled had colorectal cancer (n = 11), breast cancer (n = 6), or adrenocortical carcinoma (n = 2). DLTs occurred in 4 patients and included thrombocytopenia (n = 2; both at 99.9-μg/kg dose level), neutropenia (n = 2; 78.3-μg/kg and 99.9-μg/kg dose levels), and pancytopenia (n = 1; 109.35-μg/kg dose level). The most common treatment-emergent adverse events related to ABBV-176 were thrombocytopenia, neutropenia, increased aspartate aminotransferase, nausea, fatigue, and pleural effusions. Effusions and edema were common, and timing of onset suggested possible cumulative ABBV-176 toxicity. Tumor expression of PRLR varied among patients enrolled and analyzed. No patient had an objective response. MTD was not formally determined, as identification of a tolerable dose was confounded by late-onset toxicities. ABBV-176 was associated with significant toxicity in this phase 1, dose-escalation study. Although cytopenias were often dose limiting, effusions and edema were also common and had late onset that suggested cumulative toxicity. No responses were observed, although data were available from a small number of patients with variable tumor PRLR expression. This study was terminated after the dosing of 19 patients.

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Acknowledgments

AbbVie and the authors thank the patients who participated in this clinical trial, the study coordinators, and support staff. This study was funded by AbbVie Inc., North Chicago, IL, USA. Medical writing support was provided by Mary L. Smith, PhD, CMPP, Aptitude Health, Atlanta, GA, USA, funded by AbbVie.

Financial support

AbbVie Inc. provided financial support for the study and participated in the design, study conduct, analysis and interpretation of data, as well as the writing, review, and approval of the manuscript.

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Authors

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The manuscript was written by the authors, with medical writing assistance funded by the sponsor. All authors approved the final manuscript for submission for publication.

Corresponding author

Correspondence to Jasgit Sachdev.

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Conflict of interest disclosure statements

Charlotte Lemech.

No relationships to disclose.

Natasha Woodward

Research funding (institutional) from Medivation; advisory board for Roche, Pfizer; travel, accommodations, and expenses from Roche; stock ownership in CSL; editorial writing support from Pfizer.

Nancy Chan

No relationships to disclose.

Joanne Mortimer

Consulting or advisory role for Novartis, Pfizer, Puma Biotechnology; honoraria from Novartis.

Louie Naumovski, Silpa Nuthalapati, Bo Tong, Fang Jiang, Peter Ansell, and Christine K. Ratajczak

AbbVie employees and may own stock.

Jasgit Sachdev

Research funding from Pfizer, Celgene, Genentech; consulting or advisory role for Celgene, Puma Biotechnology, TTC Oncology, Pfizer, Novartis, TapImmune, Ipsen, Tempus; travel accommodations, and expenses from Celgene; honoraria from Celgene, Ipsen, Puma Biotechnology, Novartis, Pfizer, Tempus.

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All patients provided their informed consent. All study procedures were conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki and Good Clinical Practice guidelines. The protocol received institutional review board approval.

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Lemech, C., Woodward, N., Chan, N. et al. A first-in-human, phase 1, dose-escalation study of ABBV-176, an antibody-drug conjugate targeting the prolactin receptor, in patients with advanced solid tumors. Invest New Drugs 38, 1815–1825 (2020). https://doi.org/10.1007/s10637-020-00960-z

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  • DOI: https://doi.org/10.1007/s10637-020-00960-z

Keywords

  • Antibody-drug conjugate
  • Solid tumor
  • Prolactin receptor
  • Phase 1
  • Pyrrolobenzodiazepine