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

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

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.

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

Cancer Chemotherapy & Pharmacology, 2017, Vol 79, Issue 4, p673

0344-5704

Academic Journal

10.1007/s00280-017-3245-5