A phase 1 study of anti-TGFβ receptor type-II monoclonal antibody LY3022859 in patients with advanced solid tumors.

Autor:	Tolcher, Anthony, Berlin, Jordan, Cosaert, Jan, Kauh, John, Chan, Emily, Piha-Paul, Sarina, Amaya, Alex, Tang, Shande, Driscoll, Kyla, Kimbung, Richard, Kambhampati, S., Gueorguieva, Ivelina, Hong, David, Tolcher, Anthony W, Berlin, Jordan D, Piha-Paul, Sarina A, Kambhampati, S R Prasad, Hong, David S
Předmět:	TUMOR necrosis factor receptors MONOCLONAL antibodies TUMORS DRUG dosage PHARMACOKINETICS CLINICAL trials DRUG administration PATIENTS THERAPEUTIC use of monoclonal antibodies ANTINEOPLASTIC agents CELL receptors COMPARATIVE studies CYTOKINES DOSE-effect relationship in pharmacology DRUG toxicity INTRAVENOUS therapy LONGITUDINAL method RESEARCH methodology MEDICAL cooperation RESEARCH RESEARCH funding TIME EVALUATION research TREATMENT effectiveness
Zdroj:	Cancer Chemotherapy & Pharmacology; Apr2017, Vol. 79 Issue 4, p673-680, 8p
Abstrakt:	Purpose: LY3022859 is an anti-TGFβRII IgG1 monoclonal antibody that inhibits receptor-mediated signaling activation. The primary objective of this phase I study was to determine a phase II dose in patients with advanced solid tumors. Secondary objectives were to assess safety and pharmacokinetics (PK).Methods: LY3022859 was infused intravenously (IV) at 1.25 mg/kg over 1 h every 2 weeks (Q2W) (cohort 1A) and at flat doses of 12.5 mg (cohort 1B) and 25 mg (cohort 2) over 3 h Q2W.Results: Fourteen patients were enrolled in cohorts 1A (n = 2), 1B (n = 5), and 2 (n = 7). DLTs were experienced by both patients in cohort 1A (infusion-related reaction) and 2 patients in cohort 2 (cytokine release syndrome and infusion-related reaction). No MTD was determined. At the 25 mg dose level (cohort 2), after fifth infusion, LY3022859 had a short t1/2 (4.37-7.80 h) and rapid clearance (CLss, 0.412 L/h). Exposure increased twofold (from 28.5 to 60.2 μg·h/mL) with increase in dose from 12.5 to 25 mg. No accumulation was observed after repeat administration.Conclusions: The MTD for LY3022859 was not determined. Dose escalation beyond 25 mg was considered unsafe due to worsening symptoms (uncontrolled cytokine release) despite prophylaxis (corticosteroids and antihistamines).Trial Registration: clinicaltrials.gov Identifier: NCT01646203. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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