Pharmacokinetics of sepantronium bromide (YM155), a small-molecule suppressor of survivin, in Japanese patients with advanced solid tumors: dose proportionality and influence of renal impairment

14099 Background: E7080 selectively inhibits receptor phosphorylation of vascular endothelial growth factor (VEGF), platelet- derived growth factor (PDGF), fibroblast growth factor (FGF) and suppresses tumor angiogenesis and growth in preclinical studies. Methods: E7080 was orally administered to Japanese patients with advanced solid tumors twice daily by a 2 week-on 1 week-off schedule. The primary objectives were to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and the recommended dose for further study. The secondary objectives were to evaluate pharmacokinetics (PK), pharmacogenomics, and efficacy. Results: Twelve patients have been enrolled into cohorts of 1, 2, 4 or 8 mg/day. Major toxicities were hypertension and hyperlipidemia. Thus far, no DLTs or severe toxicities were reported. PK analysis in cohorts of 1, 2 and 4 mg/day showed the dose-proportional increase of Cmax and AUC. Three patients in cohorts of 1 and 2 mg/day experienced long stable disease (SD) for 18 weeks or longer. One patient with colorectal cancer in 4 mg/day cohort showed significant tumor shrinkage of multiple pulmonary metastasis. Biomarkers such as plasma angiogenic proteins and cytokines, circulating endothelial cells and circulating endothelial progenitor cells are exploratively evaluated. Conclusions: E7080 is well tolerated at doses up to 8 mg/day by a 2 week-on 1 week-off schedule. Some patients experienced clinical benefit without severe toxicity. MTD has not been reached and enrollment is ongoing. No significant financial relationships to disclose.

Download Full-text

Tolerability and safety of oral neratinib (HKI-272) in Japanese patients with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e14505 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e14505-e14505

Author(s):

Y. Ito ◽

K. Hatake ◽

S. Takahashi ◽

M. Yokoyama ◽

M. Suenaga ◽

...

Keyword(s):

Solid Tumors ◽

Kinase Inhibitor ◽

Phase 1 ◽

Japanese Patients ◽

Maximum Tolerated Dose ◽

Primary Diagnosis ◽

Continuous Treatment ◽

Clinical Activity ◽

Advanced Solid Tumors ◽

Continuous Administration

e14505 Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor. In non-Japanese pts, neratinib was found to have clinical activity against solid tumors and dose-limiting toxicity (DLT) of diarrhea. The maximum tolerated dose (MTD) was 320 mg daily and the recommended dose (RD) was 240 mg because of the diarrhea. In this phase 1 study, the MTD was determined and safety and preliminary efficacy were assessed in Japanese pts with advanced solid tumors. Methods: Pts (3- 6/cohort) received 80, 160, 240, or 320 mg oral neratinib. Each pt participated in only 1 dose group and received single doses of neratinib followed by 1 wk of observation; pts then received daily continuous administration at the same dose. DLTs were assessed from the first single dose to the end of 14 days of continuous treatment. Pharmacokinetics (PK) will be analysed via a noncompartmental method. Tumor measurements were made at screening and at the end of every 8 weeks (2 cycles) by RECIST. Results: Preliminary data for 21 pts as of 30 Oct 2008 are presented. Pts had a median age [range] of 61 yrs [39–78], were 62% male, and had all received ≥2 prior chemotherapy regimens. Tumor types at primary diagnosis were advanced colorectal (81%), breast (14%), and gastric (5%) cancer. Median duration of neratinib treatment [range] was 10 wks [3–29].Two patients at the 320-mg dose had DLTs of diarrhea plus anorexia. Therefore the MTD was determined to be 240 mg. Neratinib-related AEs, any grade in ≥25% of pts included diarrhea (95%), fatigue (67%), anorexia (43%), nausea (43%), abdominal pain (38%), decreased hemoglobin (38%), increased AST (33%), and rash (29%). Neratinib-related AEs, grade ≥3 in ≥1 pts were anorexia (3 pts) and diarrhea (2 pts). Two pts had partial response (PR), 8 pts had stable disease (SD) ≥8 wks, 2 had SD≥16 wks, 9 had progressive disease. The 2 pts with PR had ErbB-2+ advanced breast cancer. PK analysis is still ongoing. Conclusions: In Japanese pts, the MTD for neratinb was determined to be 240 mg and the RD will be confirmed as 240 mg. Neratinib is tolerable and demonstrates preliminary antitumor activity in pts with solid tumors. [Table: see text]

Download Full-text