A First-in-Human Dose Finding Study of Camrelizumab in Patients with Advanced or Metastatic Cancer in Australia

Abstract

Purpose

Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety profiles for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population.

Methods

Camrelizumab was administered to patients with advanced solid tumors who had failed standard therapies. In the dose-escalation phase (n=23), camrelizumab was administered intravenously at 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg every 2 weeks. In dose expansion (n=26), camrelizumab was given at 200 mg or 600 mg every 4 weeks.

Results

Two dose-limiting toxicities were observed during dose escalation: transaminase elevation and diarrhea (both grade 3). Overall, treatment-related adverse events were consistent with the expected toxicity profile of immune checkpoint inhibition, with the striking exception of the dose-related development of angiomatous skin lesions characterized as reactive cutaneous capillary endothelial proliferation. The PK profile showed a dose-progressive increase in half-life from 3 days at 1 mg/kg to 7 days at 10 mg/kg. Moreover, receptor occupancy assays showed a PD-1 occupancy of >50% in most patients out to 28 days post-dose. The objective response rate was 15.2% (95% CI 6.3–28.9).

Conclusion

Camrelizumab has manageable toxicity and encouraging preliminary antitumor activity in advanced solid tumors in Australia.

Clinical Trial Registration

ClinicalTrials.gov Identifier: NCT02492789.

Keywords:

• PD-1
• monoclonal antibody
• first-in-human dose study
• cancer
• reactive cutaneous capillary endothelial proliferation

Acknowledgments

The study team thanks patients and families for their willingness to participate in this study. We thank Atridia for the management of the entire study. Further, we thank all site staff and investigators at the institutions, the trial personnel at Incyte, Tigermed, IQVIA, and Hengrui.

Ethics Approval and Consent to Participate

Each institution’s review board approved the study and all patients signed an informed consent document before study participation (Supplementary Table 5). The study was conducted according to the principles of Good Clinical Practice, applicable laws and regulations, and the Declaration of Helsinki.

Data Sharing Statement

The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request.

Author Contributions

All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

Jason Lickliter and Mark Voskoboynik are employees of Nucleus Network (Australia). Jianjun Zou, Lianshan Zhang and Stacey Luo are employees of Jiangsu Hengrui Medicine Co. Ltd (China). Michael Lahn, Andrea Mannucci and Catello Somma were or are employees of Incyte Biosciences International Sarl (Switzerland). Howard Kallender is employee of Incyte Corporation (USA). Michael Millward and Tarek Meniawy are employees of Linear Clinical Research (Australia). Hui K. Gan reports receiving honoraria from speaker bureau of Bristol-Myers Squibb, Ignyta, Eisai and Merck Serono and is a consultant/advisory board member of AbbVie and Bristol-Myers Squibb. Andrea Mannucci has ownership interests (including stock, patents, etc.) at Incyte Biosciences International Sarl (Switzerland). Michael Millward has been or currently is a member of consultant/advisory board of Merck Sharp & Dohme, Novartis, Bristol-Myers Squib, Roche, AstraZeneca, and Pfizer, and has received travel support from Bristol-Myers Squibb and Roche. Adnan Nagrial is a member of consultant/advisory board of Bristol-Myers Squibb, Merck Sharpe Dohme, Astra Zeneca and Roche, and reports receiving speaking fees from Bristol-Myers Squibb, Merck Sharpe Dohme and Roche. Andreas Behren receives research support from Incyte (Switzerland) for the RO assay. Michael Lahn has ownership interests (including stock, patents, etc.) at Incyte Biosciences International Sarl (Switzerland), AstraZeneca and Eli Lilly. Surein Arulananda reports receiving personal fees from Merck Sharpe Dohme, Astra Zeneca, Roche and Boehringer-Ingelheim. Pablo Fernandez Penas is member of advisory committee (AC) or lecture (L, only educational, non-promotional lectures) of Janssen (AC, L), Lilly (AC, L), Abbvie (AC, L), Novartis (AC, L), UCB (L), MSD (AC), La Roche Posay (L), Merck (AC, L), Roche (AC, L), Amgen (L), Sun Pharma (AC, L), Sanofi (AC), Leo (AC, L), Avene (L), Celgene (AC), Galderma (L) and Schering Plough (L), and reports receiving clinical trial supports from Boehringer Ingelheim, Pfizer, CSL, OncoSec, Lilly, CBP, Abbvie, miRagen, Galderma, Regeneron, BMS, Eisai, Jiangsu Hengrui, Sun Pharma, Novartis, UCB, Leo, Janssen, Arena, Akaal Pharma, Roche, Xoma, Kyowa Hakko Kirin, GSK, Amgen and Merck Sharpe Dohme. No potential conflicts of interest were disclosed by other authors.