Reference Detail

Ref Type

Journal Article

PMID

(30725389)

Authors

McHugh D, Eisenberger M, Heath EI, Bruce J, Danila DC, Rathkopf DE, Feldman J, Slovin SF, Anand B, Chu R, Lackey J, Reyno L, Antonarakis ES, Morris MJ

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Investigational new drugs	37	5	2019 10	1052-1060	Invest New Drugs

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
ASG-5ME	ASG-5ME	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
ASG-5ME		ASG5ME\|ASG 5ME		ASG-5ME is an antibody-drug conjugate (ADC) comprising an anti-SLC44A4 antibody linked to MMAE, which delivers the cytotoxic agent to SLC44A4-expressing tumor cells, potentially resulting in increased tumor cell death and decreased tumor growth (PMID: 27550944, PMID: 30725389).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References