A phase I study of the antibody drug conjugate ASG-5ME, an SLC44A4-targeting antibody carrying auristatin E, in metastatic castration-resistant prostate cancer Journal Article
| Authors: | McHugh, D.; Eisenberger, M.; Heath, E. I.; Bruce, J.; Danila, D. C.; Rathkopf, D. E.; Feldman, J.; Slovin, S. F.; Anand, B.; Chu, R.; Lackey, J.; Reyno, L.; Antonarakis, E. S.; Morris, M. J. |
| Article Title: | A phase I study of the antibody drug conjugate ASG-5ME, an SLC44A4-targeting antibody carrying auristatin E, in metastatic castration-resistant prostate cancer |
| Abstract: | Background Antibody drug conjugates (ADC) offer the potential of maximizing efficacy while minimizing systemic toxicity. ASG-5ME, an SLC44A4-targeting antibody carrying monomethyl auristatin E (MMAE), a microtubule-disrupting agent, was investigated in men with metastatic castration resistant prostate cancer. Methods The primary objective of this phase I study was to determine maximum tolerated dose (MTD) and recommended phase II dose. Secondary objectives were safety, antitumor activity, pharmacokinetic properties, immunogenicity, and the detection of SLC44A4 on circulating tumor cells. Patients (pts) were treated among 7 dose levels every 21 days. A dose expansion phase enrolled 20 additional pts. at the MTD. Results Twenty-six and 20 pts. were treated in dose escalation and dose expansion cohorts respectively. The MTD was 2.7 mg/kg. Dose-limiting toxicities occurred in 4 pts.: grade 3 fatigue (n = 1); grade 3 abdominal pain, diarrhea and fatigue (n = 1); grade 4 neutropenia and hyponatremia and grade 3 maculopapular rash, constipation and hypoxia (n = 1); grade 3 troponin elevation without cardiac sequelae (n = 1). Fatigue and diarrhea were the most prevalent adverse events (AEs) across all cycles. Two grade 5 AEs occurred in the dose expansion cohort, each after 1 dose: 1 pt. developed grade 3 hyperglycemia, renal insufficiency and leukopenia; 1 pt. developed grade 3 hyperglycemia complicated by bacteremia. Free MMAE levels did not accumulate with repeat dosing. Of evaluable pts., 52% had either stable disease or a partial response. Conclusions Further development of ASG-5ME is not being pursued due to its narrow therapeutic index. Some toxicities were potentially related to on-target effects on normal tissue expressing the SLC44A4 protein. However, other toxicities were consistent with studies of previous MMAE-containing ADCs. Unconjugated MMAE is a less likely etiology based on prior data. © 2019, Springer Science+Business Media, LLC, part of Springer Nature. |
| Keywords: | adult; clinical article; controlled study; aged; unclassified drug; constipation; fatigue; neutropenia; area under the curve; diarrhea; dose response; drug efficacy; drug safety; outcome assessment; antineoplastic agent; leukopenia; kidney failure; antineoplastic activity; abdominal pain; drug dose escalation; hyperglycemia; prostate cancer; hypoxia; hyponatremia; maculopapular rash; adverse outcome; multicenter study; immunogenicity; bacteremia; time to maximum plasma concentration; maximum tolerated dose; phase 1 clinical trial; drug half life; castration resistant prostate cancer; castration-resistant; human; male; priority journal; article; volume of distribution; maximum concentration; antibody drug conjugate; antibody drug conjugate asg 5me |
| Journal Title: | Investigational New Drugs |
| Volume: | 37 |
| Issue: | 5 |
| ISSN: | 0167-6997 |
| Publisher: | Springer |
| Date Published: | 2019-10-01 |
| Start Page: | 1052 |
| End Page: | 1060 |
| Language: | English |
| DOI: | 10.1007/s10637-019-00731-5 |
| PUBMED: | 30725389 |
| PROVIDER: | scopus |
| PMCID: | PMC6684870 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2019 -- Source: Scopus |
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