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Phase IB study of sorafenib in combination with gemcitabine and cisplatin in patients with refractory solid tumors
B Schultheis1, G Kummer, M Zeth
1Department of Haematology and Medical Oncology, University of Bochum (Marienhospital Herne), Hoelkeskampring 40, 44625 Herne, Germany. beate.schultheis@marienhospital-herne.de
Purpose:
Sorafenib (BAY 43-9006), a multikinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. This study investigated the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with gemcitabine and cisplatin.
Methods:
Patients with advanced solid tumors were treated with 75 mg/m(2) cisplatin on day 1 and 1,250 mg/m(2) gemcitabine on days 1 and 8 of each 21-day cycle. On day 5 of cycle 1, sorafenib 400 mg twice daily was started and continued throughout the complete treatment cycles without interruption.
Results:
Nineteen patients were valid for safety analysis. The most frequent toxicities related to the cytotoxic agents were hematological disorders. Sorafenib-related toxicities were skin-related, gastrointestinal, and constitutional symptoms. No clinically relevant pharmacokinetic drug-drug interaction between sorafenib, cisplatin, and gemcitabine was detected. AUC(0-72) and C (max) of total and unbound platinum were only marginally changed by concomitant sorafenib. Concomitant sorafenib increased mean AUC and C (max) of gemcitabine by 12 and 21%.
Conclusions:
Sorafenib as continuous oral treatment in combination with gemcitabine and cisplatin demonstrated an acceptable safety profile. No clinically relevant pharmacokinetic interaction was detected. Preliminary antitumor activity, pharmacokinetic, and safety data support the recommendation of 400 mg sorafenib twice daily in combination with cisplatin and gemcitabine to be further evaluated in clinical studies.
Insights
This study found that sorafenib combined with gemcitabine and cisplatin has an acceptable safety profile for advanced solid tumors. Preliminary data suggest this combination warrants further clinical evaluation.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Sorafenib is a multikinase inhibitor targeting tumor growth and angiogenesis.
- It inhibits Raf kinase, VEGFR, and PDGFR.
Purpose of the Study:
- To investigate the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with gemcitabine and cisplatin.
- To evaluate sorafenib (400 mg twice daily) with cisplatin (75 mg/m²) and gemcitabine (1250 mg/m²).
Main Methods:
- Patients with advanced solid tumors received cisplatin and gemcitabine in 21-day cycles.
- Sorafenib was initiated on day 5 of cycle 1 and continued throughout treatment.
Main Results:
- Nineteen patients were included in the safety analysis.
- Most frequent toxicities included hematological disorders (cytotoxics) and skin/GI/constitutional symptoms (sorafenib).
- No clinically relevant pharmacokinetic interactions were detected; gemcitabine AUC and Cmax increased by 12% and 21% respectively.
Conclusions:
- Sorafenib, gemcitabine, and cisplatin demonstrated an acceptable safety profile.
- The combination showed preliminary antitumor activity and no significant pharmacokinetic interactions.
- Further clinical studies are recommended for this combination therapy.
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