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; cancer; first-in-human dose study; monoclonal antibody; reactive cutaneous capillary endothelial proliferation.

Conflict of interest statement

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.

© 2020 Lickliter et al.

Figures

Figure 1

Development of RCCEP in a breast cancer patient treated with 1 mg/kg of camrelizumab. (A, B) The initial RCCEP lesion was observed at approximately 2 weeks after the first dose of study drug on the lateral chest followed by lesions on the anterior chest. (C–E) Since this patient showed stable disease (SD) at Day 56 and subsequently a partial response (PR) at Day 112, she continued to receive camrelizumab and additional RCCEP appeared on her upper trunk and neck. (F–H) After interrupting camrelizumab treatment for 28 days in response to cellulitis requiring hospitalization, there was substantial regression of the RCCEP. (I) Upon re-starting camrelizumab, one of the previous RCCEP lesions re-grew without progression of RCCEP lesions elsewhere. Blue solid arrow represents treatment time, while hatched blue color represents the treatment pause. Black arrows connect the timing of RCCEP photographs and the treatment timeline. Abbreviations: SD, stable disease; PR, partial response.

Figure 2

Serum camrelizumab concentration–time curve and receptor occupancy (RO). (A, B) Serum camrelizumab concentration–time curve after single IV infusion in linear (A) and semi-logarithmic (B) scale during the first 28 days after the initial infusion. (C, D) Camrelizumab RO on CD4+ (C) and CD8+ (D) T Cells at the 10 mg/kg dose level and 200 mg flat dose level for the entire treatment period. Blood samples were obtained at the time points shown out to 28 days after the first dose and then prior to the second and subsequent dose (every 28 days). Each line represents an individual patient, with red lines indicating 10 mg/kg treated patients and blue lines indicating 200 mg flat dosing.

Figure 3

Clinical response. (A) Waterfall plot of the maximal percentage reduction from baseline of the sum of longest diameters of target lesions for both dose-escalation and expansion phases. (B) Spider plot of the percentage change from baseline in the sum of longest diameters of target lesions over time. (C) Duration of treatment (n=46). Each individual patient treatment time is plotted from time of first dose (x-axis) based on the dose level and dose regimen. Patients with partial responses (green square), stable disease (blue star), progressive disease (yellow star), complete response (red triangle) and death (black circle) are shown along with the start of RCCEP. Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; RCCEP, reactive cutaneous capillary endothelial proliferation.