Phase I rapid dose-escalation study of AGS-1C4D4, a human anti-PSCA (prostate stem cell antigen) monoclonal antibody, in patients with castration-resistant prostate cancer: a PCCTC trial.
OBJECTIVE
AGS-1C4D4 is a human monoclonal antibody against prostate stem cell antigen (PSCA), a cell-surface protein expressed by most prostate cancers. AGS-1C4D4 is produced in Chinese hamster ovary (CHO) cells and has an identical sequence to AGS-PSCA, an anti-PSCA antibody produced in mouse hybridoma cells that has completed Phase I testing. Preclinical studies demonstrated comparability of AGS-1C4D4 to AGS-PSCA with respect to pharmacokinetics (PK) and tumor inhibition. However, because of differences in antibody-dependent cellular cytotoxicity between AGS-PSCA and AGS-1C4D4, a limited Phase I trial using AGS-1C4D4 was performed evaluating safety and PK.


METHODS
Thirteen patients with metastatic castration-resistant prostate cancer were enrolled. AGS-1C4D4 was administered intravenously every 3 weeks for four planned doses at 6, 12, 24, or 48 mg/kg. Primary endpoints were safety and PK. Secondary endpoints were immunogenicity and clinical activity. Disease assessments were conducted every 12 weeks and included radiographic and PSA evaluations. Patients with stable disease could receive extended treatment beyond four infusions.


RESULTS
Adverse events were primarily grade 1-2, without any grade 3-4 drug-related toxicities or infusion reactions. Anti-AGS-1C4D4 antibodies were not detected. Similar to AGS-PSCA, serum AGS-1C4D4 concentrations declined biphasically and elimination was characterized by slow clearance (CL) and a long terminal half-life (t                            (1/2)). Median CL for the four dose levels ranged from 0.10 to 0.14 ml/h kg, and t                            (1/2) ranged from 2.2 to 2.9 weeks. No PSA reductions ≥50% were observed. Six patients (46%) had radiographically stable disease, lasting a median of 24 weeks.


CONCLUSIONS
AGS-1C4D4 was well-tolerated and demonstrated linear PK. Despite preclinical differences in antibody-dependent cellular cytotoxicity, AGS-1C4D4 and AGS-PSCA have similar safety and PK profiles. The recommended Phase II dose is 48 mg/kg.
Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, CRB1-1M59, 1650 Orleans Street, Baltimore, MD 21231, USA.
Emmanuel S
ES
Antonarakis
Michael A
MA
Carducci
Mario A
MA
Eisenberger
Samuel R
SR
Denmeade
Susan F
SF
Slovin
Kathy
K
Jelaca-Maxwell
Martha E
ME
Vincent
Howard I
HI
Scher
Michael J
MJ
Morris
D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
D000726:Androgen Antagonists; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human; D017430:Prostate-Specific Antigen