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

Abstract

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 doseescalation, 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.

Systemic Administration of Pegylated Arginase-1 Attenuates the Progression of Diabetic Retinopathy

“…For decades, Arg1 has been used as a marker of M2-like reparative MΦ/microglia, and its promotion of an anti-inflammatory phenotype has long been recognized [ 60 ]. While it has been well established that the effect of systemic PEG-Arg1 is primarily due to its depletion of circulating levels of L-arginine in cancers [ 61 , 62 ], the downstream mechanisms that underlie the anti-inflammatory and neuroprotective effects have yet to be fully elucidated. One possible mechanism is that due to the decreased intracellular L-arginine from the PEG-Arg1 treatment, the mechanistic target of rapamycin (mTORC) pathway is inhibited.…”

Dietary Manipulation of Amino Acids for Cancer Therapy

“…In patients with hepatocellular carcinomas, this drug was well tolerated and showed anticancer activity alone [251][252][253] and in combination with chemotherapy (capecitabine plus oxaliplatin) [254]. PEG-BCT-100 also showed anticancer activity in melanoma and prostate cancer patients [255], and induced complete remission in an immunotherapy-resistant melanoma patient with an absent expression of the enzymes involved in the synthesis of Arg [256]. ADI-PEG20 has received more clinical attention, with 30 completed or ongoing clinical trials, three of them in phase III [257].…”

Arginine Deprivation in SCLC: Mechanisms and Perspectives for Therapy

“…35 rhArg-PEG (BCT-100) has been studied in several phase I and II clinical trials in patients with HCC, melanoma, prostate adenocarcinoma or leukaemia; however, no data are available specifically in SCLC. [36][37][38][39] Another rhArgPEG that is cobalt-substituted (Co-Arg1-PEG or pegzilarginase) also displayed robust activity in 8/12 patientderived xenograft (PDx) models of SCLC and the related Merkel cell cancer, an aggressive skin neuroendocrine cancer.…”