First-in-Human Phase I, Dose-Escalation and -Expansion Study of Telisotuzumab Vedotin, an Antibody–Drug Conjugate Targeting c-Met, in Patients With Advanced Solid Tumors
| Autor: | Apurvasena Parikh, Colin D. Weekes, Monica Motwani, Daniel Morgensztern, Huibin Yue, Edward B. Reilly, John Nemunaitis, Todd M. Bauer, Ramesh K. Ramanathan, Daniel E. H. Afar, Rebecca S. Heist, Karen Kelly, Eric Angevin, John H. Strickler, Louie Naumovski |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Oncology Cancer Research Antibody-drug conjugate medicine.medical_specialty C-Met Maximum Tolerated Dose Oncology and Carcinogenesis Clinical Sciences Antineoplastic Agents and over Antibodies Dose-Response Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Neoplasms Internal medicine Monoclonal 80 and over medicine Humans Oncology & Carcinogenesis Lung cancer Aged biology business.industry Middle Aged Proto-Oncogene Proteins c-met medicine.disease Clinical trial 030104 developmental biology Tolerability chemistry 030220 oncology & carcinogenesis biology.protein Immunohistochemistry Female Drug Antibody business |
| Zdroj: | Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol 36, iss 33 Strickler, JH; Weekes, CD; Nemunaitis, J; Ramanathan, RK; Heist, RS; Morgensztern, D; et al.(2018). First-in-Human Phase I, Dose-Escalation and-Expansion Study of Telisotuzumab Vedotin, an Antibody-Drug Conjugate Targeting c-Met, in Patients With Advanced Solid Tumors.. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, JCO2018787697. doi: 10.1200/jco.2018.78.7697. UC Davis: Retrieved from: http://www.escholarship.org/uc/item/8bt41691 |
| ISSN: | 1527-7755 0732-183X |
| Popis: | Purpose This first-in-human study evaluated telisotuzumab vedotin (Teliso-V), formerly called ABBV-399, an antibody–drug conjugate of the anti–c-Met monoclonal antibody ABT-700 and monomethyl auristatin E. Materials and Methods For dose escalation, three to six patients with advanced solid tumors were enrolled in eight cohorts (0.15 to 3.3 mg/kg). The dose-expansion phase enrolled patients with non–small-cell lung cancer (NSCLC) with c-Met–overexpressing tumors (c-Met positive; immunohistochemistry membrane H-score ≥ 150). Patients received Teliso-V monotherapy intravenously on day 1 once every 3 weeks. Safety, tolerability, pharmacokinetics, and maximum tolerated dose were determined. Results Forty-eight patients were enrolled (median age, 65 years; 35.4% NSCLC; median four prior therapies). One patient each in the 3.0-mg/kg (n = 9) and 3.3-mg/kg (n = 3) cohorts experienced dose-limiting toxicities. Although the maximum tolerated dose was not formally identified, the recommended phase II dose was defined as 2.7 mg/kg on the basis of overall safety and tolerability. The most frequent treatment-emergent adverse events (any grade) were fatigue (42%), nausea (27%), constipation (27%), decreased appetite (23%), vomiting (21%), dyspnea (21%), diarrhea (19%), peripheral edema (19%), and neuropathy (17%). The most frequent Teliso-V–related grade ≥ 3 adverse events were fatigue, anemia, neutropenia, and hypoalbuminemia (4% each). Teliso-V and total antibody pharmacokinetics were approximately dose proportional, with a mean harmonic half-life of 2 to 4 days each. Prospective screening identified 35 (60%) of 58 patients with c-Met–positive NSCLC. Of 16 patients with c-Met–positive NSCLC who were treated with Teliso-V 2.4 to 3.0 mg/kg, three (18.8%; 95% CI, 4.1% to 45.7%) achieved a partial response (median response duration, 4.8 months; median progression-free survival, 5.7 months; 95% CI, 1.2 months to 15.4 months). No other patients experienced a response. Conclusion Teliso-V monotherapy demonstrated favorable safety and tolerability profiles, with encouraging evidence of antitumor activity in patients with c-Met–positive NSCLC. |
| Databáze: | OpenAIRE |
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