RESUMEN
BACKGROUND: KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. METHODS: A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. RESULTS: Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level. CONCLUSIONS: The proposed phase II study of the RP2D for the triple-drug combination did not progress because of anticipated difficulty in patient enrollment and further clinical development of KW-2450 was terminated.
RESUMEN
BACKGROUND: KHK2866 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed at heparin-binding epidermal growth factor-like growth factor (HB-EGF). OBJECTIVE: To determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, potential immunogenicity, and preliminary clinical efficacy of KHK2866 monotherapy in patients with advanced and refractory cancer in a first-in-human, phase 1 study. MATERIALS AND METHODS: Using a standard 3 + 3 dose-escalation design, 20 patients received KHK2866 (0.3, 1, and 3 mg/kg) intravenously once weekly. Two additional patients received 0.1 mg/kg in a cohort which was subsequently added following protocol amendment. RESULTS: The first three patients enrolled experienced grade 2 hypersensitivity (acute infusion reactions) after the first dose of KHK2866. After prophylactic treatment with an H1-blocker and corticosteroids in subsequently recruited patients, two grade 2 hypersensitivity reactions were observed in the remaining 19 patients. Grade 2/3 neurotoxicity appeared to be dose-limiting at 3 mg/kg in the original dose-escalation cohorts (n = 2), at 1 mg/kg in the MTD dose expansion cohort (n = 1), and at 0.1 mg/kg (n = 1). Neurotoxicity was manifested as complex partial seizure activity, aphasia, and confusion after first-dose administration. Pharmacokinetic exposure to KHK2866 increased proportionally to dose. Mean elimination half-life was 71.9-118 h over the dose range from 0.3 to 3 mg/kg. All KHK2866 doses decreased serum free HB-EGF levels, generally below the lower limit of quantification. CONCLUSIONS: The study was terminated because of neuropsychiatric toxicity. The only predictive factor for neuropsychiatric toxicity was administration of KHK2866. These effects were reversible, but were not predictable. Their etiology is not presently understood. [Study registered at ClinicalTrials.gov #NCT0179291].