A phase 1 study of TAK-164, an anti-guanylyl cyclase C (GCC) antibody-drug conjugate (ADC), in patients (pts) with advanced gastrointestinal (GI) cancers expressing GCC.
Authors: Richard D. Kim, James M. Cleary, Alexis Diane Leal, Aparna Raj Parikh, David P. Ryan, Shining Wang, Brittany Bahamon, Neeraj Gupta, Aaron Moss, Joanna Pye, Harry H. Miao, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2021)

3050 Background: TAK-164 is a second-generation ADC comprising a human IgG1 monoclonal antibody targeting GCC conjugated to a DNA-damaging alkylating agent by a peptide linker. TAK-164 demonstrated cytotoxic and antitumor activity in GCC-expressing cells and xenograft mouse models. This first-in-human study investigated the safety, pharmacokinetics (PK), and preliminary efficacy of TAK-164. Methods: Adult pts with GCC-positive, advanced/metastatic GI cancers received TAK-164 intravenously on day 1 of a 21-day cycle (Q3W). Dose escalation proceeded based on cycle 1 safety data via a Bayesian model of modified toxicity probability interval starting at 0.004 mg/kg. Results: Thirty-one pts were enrolled. Median age was 58 years (range 32–72), 58.1% of pts were female and 64.5% had colon carcinoma. The median number of prior lines of therapy was 4 (range 2–9). TAK-164 was given at 0.004 (n = 1), 0.008 (n = 1), 0.016 (n = 1), 0.032 (n = 5), 0.064 (n = 7), 0.12 (n = 7), 0.16 (n = 2), 0.19 (n = 3), 0.25 (n = 3) and 0.32 mg/kg (n = 1). No pts had dose-limiting toxicities (DLT) in cycle 1 up to 0.32 mg/kg. Three pts had adverse events (AEs) after cycle 1 considered to be DLTs: 1 pt receiving 0.19 mg/kg (grade 3 pyrexia and grade 5 hepatic failure) and 2 pts receiving 0.25 mg/kg (1 pt had grade 3 nausea, and grade 4 platelet count decrease and neutrophil count decrease; 1 pt had grade 4 hepatic failure and grade 4 platelet count decrease). Dosing was capped at 0.19 mg/kg due to hepatic toxicity and the recommended phase 2 dose (RP2D) was determined as 0.064 mg/kg based on safety and tolerability beyond cycle 1. Overall, pts received a median of 2 (range 1–8) treatment cycles. TAK-164-related treatment-emergent AEs (TEAEs) reported in 77.4% of pts included platelet count decrease (58.1%), fatigue (38.7%), and anemia (32.3%). TAK-164-related grade ≥3 TEAEs reported in 32.3% of pts included platelet count decrease (12.9%), alanine aminotransferase increase, aspartate aminotransferase increase, fatigue, and anemia (all 9.7%). Three pts discontinued due to TAK-164-related TEAEs. There was a dose-dependent increase in TAK-164 maximum plasma concentration and exposure over the range 0.016–0.32 mg/kg, with no meaningful accumulation in PK with repeat Q3W dosing. One pt receiving TAK-164 0.19 mg/kg showed γH2AX induction via immunohistochemistry in a post-treatment biopsy, demonstrating target engagement. One pt with low baseline GCC expression who received 5 cycles of TAK-164 0.008 mg/kg had an unconfirmed partial response at cycle 4; 11 of 25 (44.0%) evaluable pts had a best overall response of stable disease. Conclusions: TAK-164 appeared to have a manageable safety profile up to 0.064 mg/kg in pts with advanced GI cancers; hepatic toxicity was identified as a potential risk. The RP2D was determined as 0.064 mg/kg but was considered insufficient to derive significant clinical benefit. Clinical trial information: NCT03449030.