Safety, PK/PD and preliminary anti-tumor activities of pegylated recombinant human arginase 1 (BCT-100) in patients with advanced arginine auxotrophic tumors

• Published in: Investigational new drugs 2021-12, Vol.39 (6), p.1633-1640
• Main Authors: Cheng, Paul N. M., Liu, Angela M., Bessudo, Alberto, Mussai, Francis
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Anticancer properties; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Antitumor agents; Area Under Curve; Arginase; Arginase - administration & dosage; Arginase - adverse effects; Arginase - pharmacokinetics; Arginase - therapeutic use; Arginine; Arginine - blood; Cancer therapies; Castration; Depletion; Disease; Disease control; Dose-Response Relationship, Drug; Drug dosages; Enrollments; Female; Half-Life; Humans; Intravenous administration; Liver cancer; Male; Medicine; Medicine & Public Health; Melanoma; Melanoma - drug therapy; Middle Aged; Oncology; Patients; Pharmacodynamics; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Phase I Studies; Population; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Recombinant Proteins - administration & dosage; Recombinant Proteins - adverse effects; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - therapeutic use; Safety; Skin cancer; Skin Neoplasms - drug therapy; Statistical analysis; Toxicity; Tumors
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-021-01149-8

Summary Background  The study determined the safety, pharmacokinetics/pharmacodynamics (PK/PD), and recommended Phase II dose of BCT-100 for arginine auxotrophic tumours in a non-Chinese population. Methods This is a Phase I, 3 + 3 dose-escalation, open-label, multi-centre study in two arginine auxotrophic cancers—Malignant Melanoma (MM) and Castration Resistant Prostate Cancer (CRPC). Patients were enrolled to receive weekly intravenous BCT-100. The dose cohorts were respectively 0.5 mg/kg, 1.0 mg/kg, 1.7 mg/kg and 2.7 mg/kg. Results There were 14 MM and 9 CRPC patients, 16 males and 7 females with a median age of 71. No dose-limiting toxicities were reported. Among all the AEs, 18 were drug-related (mostly were Grade 1). Although there were individual variations in PKs amongst the patients in each cohort, the median arginine level was maintained at 2.5 µM (lower limit of quantification) in all 4 cohorts of patients after the second BCT-100 injection. Therapeutic Arginine Depletion was found in the 1.7 and 2.7 mg/kg/week cohorts when anti-tumor activities were observed. The two cohorts had a similar AUC (20,947 and 19,614 h*µg/ml respectively). Since the 2.7 mg/kg/week cohort had a more sustained arginine depletion for 2 weeks, the 2.7 mg/kg/week dose is chosen as the future phase II dose. There were two complete remissions (1 MM & 1 CRPC), 1PR (MM) and 2 stable diseases with a disease control rate (CR + PR + SD) of 5/23 (22%). Conclusions BCT-100 is safe in a non-Chinese population and has anti-tumor activities in both MM and CRPC. Weekly BCT-100 at 2.7 mg/kg is defined as the optimal biological dose for future clinical phase II studies.