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- Title
A phase I, first-in-human study of TAK-164, an antibody–drug conjugate, in patients with advanced gastrointestinal cancers expressing guanylyl cyclase C.
- Authors
Kim, Richard; Leal, Alexis D.; Parikh, Aparna; Ryan, David P.; Wang, Shining; Bahamon, Brittany; Gupta, Neeraj; Moss, Aaron; Pye, Joanna; Miao, Harry; Inguilizian, Haig; Cleary, James M.
- 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.
- Subjects
GUANYLATE cyclase; CANCER patients; ANTIBODY-drug conjugates; MONOCLONAL antibodies; PLATELET count; LIVER failure; IMMUNOGLOBULINS
- Publication
Cancer Chemotherapy & Pharmacology, 2023, Vol 91, Issue 4, p291
- ISSN
0344-5704
- Publication type
Article
- DOI
10.1007/s00280-023-04507-w