A phase I, first-in-human study of TAK-164, an antibody-drug conjugate, in patients with advanced gastrointestinal cancers expressing guanylyl cyclase C.

Abstract

PURPOSE:

Guanylyl cyclase C (GCC) is highly expressed in several gastrointestinal malignancies and preclinical studies suggest that it is a promising target for antibody-based therapeutics. This phase I trial assessed the safety and tolerability of TAK-164, an investigational, anti-GCC antibody-drug conjugate (NCT03449030).

METHODS:

Thirty-one patients with GCC-positive, advanced gastrointestinal cancers received intravenous TAK-164 on day 1 of 21-day cycles. Dose escalation proceeded based on cycle 1 safety data via a Bayesian model.

RESULTS:

Median age was 58 years (range 32-72), 25 patients (80.6%) had colorectal carcinoma, and median number of prior therapies was four. No dose-limiting toxicities (DLTs) were reported during cycle 1 DLT evaluation period. After cycle 2 dosing, 3 patients reported dose-limiting treatment-emergent adverse events (TEAEs): grade 3 pyrexia and grade 5 hepatic failure (0.19 mg/kg), grade 4 hepatic failure and platelet count decreased (0.25 mg/kg), grade 3 nausea, grade 4 platelet and neutrophil count decreased (0.25 mg/kg). The recommended phase II dose (RP2D) was 0.064 mg/kg. Common TAK-164-related TEAEs included platelet count decreased (58.1%), fatigue (38.7%), and anemia (32.3%). There was a dose-dependent increase in TAK-164 exposure over the range, 0.032-0.25 mg/kg. TAK-164 half-life ranged from 63.5 to 159 h. One patient (0.008 mg/kg) with high baseline GCC expression had an unconfirmed partial response.

CONCLUSIONS:

TAK-164 appeared to have a manageable safety profile at 0.064 mg/kg. Hepatic toxicity was identified as a potential risk. The RP2D of 0.064 mg/kg was considered insufficient to derive clinical benefit; there are no plans for further clinical development.

CLINICAL TRIAL REGISTRATION:

NCT03449030.

• Authors: Richard Kim, Alexis D Leal, Aparna Parikh, David P Ryan, Shining Wang, Brittany Bahamon, Neeraj Gupta, Aaron Moss, Joanna Pye, Harry Miao, Haig Inguilizian, James M Cleary
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 91 Issue 4 Pg. 291-300 (04 2023) ISSN: 1432-0843 [Electronic] Germany
• PMID: 36738333 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Authors.

Chemical References

• Antibodies
• Antineoplastic Agents
• Immunoconjugates
• Receptors, Enterotoxin

Topics

• Adult
• Aged
• Humans
• Middle Aged
• Antibodies
• Antineoplastic Agents (adverse effects, therapeutic use)
• Bayes Theorem
• Dose-Response Relationship, Drug
• Gastrointestinal Neoplasms (drug therapy, pathology)
• Immunoconjugates (adverse effects, therapeutic use)
• Maximum Tolerated Dose
• Receptors, Enterotoxin (metabolism)