Preclinical and first-in-human phase I studies of KW-2450, an oral tyrosine kinase inhibitor with insulin-like growth factor receptor-1/insulin receptor selectivity.

Numerous solid tumors overexpress or have excessively activated insulin-like growth factor receptor-1 (IGF-1R). We summarize preclinical studies and the first-in-human study of KW-2450, an oral tyrosine kinase inhibitor with IGF-1R and insulin receptor (IR) inhibitory activity. Preclinical activity of KW-2450 was evaluated in various in vitro and in vivo models. It was then evaluated in a phase I clinical trial in 13 patients with advanced solid tumors (NCT00921336). In vitro, KW-2450 inhibited human IGF-1R and IR kinases (IC50 7.39 and 5.64 nmol/L, respectively) and the growth of various human malignant cell lines. KW-2450 40 mg/kg showed modest growth inhibitory activity and inhibited IGF-1-induced signal transduction in the murine HT-29/GFP colon carcinoma xenograft model. The maximum tolerated dose of KW-2450 was 37.5 mg once daily continuously; dose-limiting toxicity occurred in two of six patients at 50 mg/day (both grade 3 hyperglycemia) and in one of seven patients at 37.5 mg/day (grade 3 rash). Four of 10 evaluable patients showed stable disease. Single-agent KW-2450 was associated with modest antitumor activity in heavily pretreated patients with solid tumors and is being further investigated in combination therapy with lapatinib/letrozole in patients with human epidermal growth factor receptor 2-postive metastatic breast cancer.

Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole.

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.

Predicting 5-FU sensitivity using human colorectal cancer specimens: comparison of tumor dihydropyrimidine dehydrogenase and orotate phosphoribosyl transferase activities with in vitro chemosensitivity to 5-FU.

BACKGROUND: In tumor cells, the enzyme orotate phosphoribosyl transferase (OPRT) contributes to 5-fluorouracil (5-FU) phosphorylation and another enzyme, dihydropyrimidine dehydrogenase (DPD), is associated with 5-FU catabolic action. We measured OPRT and DPD activities and, to determine whether their levels might serve as indicators of 5-FU sensitivity, simultaneously assayed in vitro chemosensitivity to 5-FU. METHODS: Tissue specimens were obtained from colorectal cancer patients and in vitro chemosensitivity was tested using fluorescein diacetate assay (FDA) or histoculture drug response assay (HDRA). DPD and OPRT activities were measured by radioassay. RESULTS: The chemosensitivity assay was performed on 62 colorectal cancer specimens. Results were evaluable in 29 of 30 cases (96.7%) for FDA and 30 of 32 cases (98.3%) for HDRA. The positive sensitivity rate was 37.9% by FDA assay and 30% by HDRA assay. In positive specimens, the mean DPD activity was 44.9 +/- 32.6 pmol/min per mg protein, and in negative specimens, it was 53.8 +/- 33.7 pmol/min per mg protein ( P= 0.875). In contrast, the mean OPRT value was significantly higher in positive specimens (0.418 +/- 0.180 nmol/min per mg protein) than in negative specimens (0.325 +/- 0.153 nmol/min per mg protein; P < 0.05). The chemosensitivity test proved positive in 60% of the specimens with ORPT activity of 0.413 or above and 50% of those with DPD activity of 30 or below. Of the patient specimens showing OPRT activity of 0.413 or above and DPD activity of 30 or below, 88.9% were positive for 5-FU sensitivity, suggesting the possibility that the combination of these two levels may be predictive of 5-FU positive sensitivity. CONCLUSION: DPD and OPRT activities within cancer cells may predict positive sensitivity to 5-FU.