A phase I, first-in-human study of TAK-164, an antibody–drug conjugate, in patients with advanced gastrointestinal cancers expressing guanylyl cyclase C
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..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:91 |
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| Enthalten in: |
Cancer chemotherapy and pharmacology - 91(2023), 4 vom: 04. Feb., Seite 291-300 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kim, Richard [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
Biological agents and therapies |
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| Anmerkungen: |
© The Authors 2023. corrected publication 2023 |
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| doi: |
10.1007/s00280-023-04507-w |
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| funding: |
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| Förderinstitution / Projekttitel: |
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SPR049926934 |
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| 100 | 1 | |a Kim, Richard |e verfasserin |0 (orcid)0000-0002-8448-844X |4 aut | |
| 245 | 1 | 2 | |a A phase I, first-in-human study of TAK-164, an antibody–drug conjugate, in patients with advanced gastrointestinal cancers expressing guanylyl cyclase C |
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| 520 | |a 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. | ||
| 650 | 4 | |a Gastrointestinal cancers |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Biological agents and therapies |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Drug targets |7 (dpeaa)DE-He213 | |
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| 650 | 4 | |a Clinical trial results |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Leal, Alexis D. |4 aut | |
| 700 | 1 | |a Parikh, Aparna |4 aut | |
| 700 | 1 | |a Ryan, David P. |4 aut | |
| 700 | 1 | |a Wang, Shining |4 aut | |
| 700 | 1 | |a Bahamon, Brittany |4 aut | |
| 700 | 1 | |a Gupta, Neeraj |4 aut | |
| 700 | 1 | |a Moss, Aaron |4 aut | |
| 700 | 1 | |a Pye, Joanna |4 aut | |
| 700 | 1 | |a Miao, Harry |4 aut | |
| 700 | 1 | |a Inguilizian, Haig |4 aut | |
| 700 | 1 | |a Cleary, James M. |4 aut | |
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