A phase I study of ridaforolimus in adult Chinese patients with advanced solid tumors

Journal of Hematology & Oncology

Jin Li¹  Li Yan²  Li Xin Zhang²  Sylvia Waajen²  Anthe S Zandvliet²  Wen Liu²  Sheng Zhang¹  Zuguang Xia¹  Fangfang Lv¹  Wenhua Li¹  Wen Zhang¹  Lian Liu¹ 

[1] Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China;Merck Research Laboratory, Merck and Co., Inc., Pennsylvania, USA

关键词: Adverse event;    Pharmacokinetic analysis;    Phase I study;    MTOR inhibitor;   

Others  :  804614
DOI  :  10.1186/1756-8722-6-48

 received in 2013-06-21, accepted in 2013-07-04,  发布年份 2013

【 摘 要 】

Purpose

Ridaforolimus (AP23573, MK-8669 or deforolimus) is an inhibitor of mammalian target of rapamycin (mTOR), an important regulator in the cell survival pathway. This open-label, single center phase I study aimed to investigate the pharmacokinetic (PK) and safety profiles of ridaforolimus in Chinese patients with treatment-refractory advanced or relapsed solid tumors. The PK data generated from these Chinese patients were further compared with those previously reported in Caucasian and Japanese patient populations.

Experimental design

The patients were given an oral dose of 40 mg of ridaforolimus on Day 1 of the study. On Day 8, patients were initiated on a treatment regimen that comprised a once daily dose of 40 mg of ridaforolimus for five consecutive days, followed by a 2-day off-drug interval. Patients repeated this regimen until disease progression or intolerance. Blood samples were collected at specific times pre- and post-treatment to establish the PK profile of ridaforolimus in all patients.

Results

Fifteen patients were given at least one dose of 40 mg of ridaforolimus. The median absorption lag-time was 2 hours, the median T_max was 4 hours and the mean elimination half-life was 53 hours. The accumulation ratio for AUC_0-24hr was 1.3 on day 19 (steady state)/day 1 (after a single dose). The most common drug-related adverse events (AEs) that occurred in ≥40% of patients were stomatitis, proteinuria, leukopenia, hyperglycemia, and pyrexia. Grade 3/4 drug-related AEs were anemia, stomatitis, fatigue, thrombocytopenia, constipation, gamma glutamyltransferase increase, and proteinuria. All 11 evaluable patients achieved stable disease.

Conclusions

Oral ridaforolimus at a daily dose of 40 mg were generally well tolerated in Chinese patients with advanced or refractory solid tumors. Adverse events and PK profiles of ridaforolimus in this study were similar to those from Caucasian and Japanese patients reported previously.

【 授权许可】

   
2013 Liu et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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