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A phase I study of oral LY293111 given daily in combination with irinotecan in patients with solid tumours
Tara Baetz1, Elizabeth Eisenhauer, Lillian Siu
1Cancer Centre of Southeastern Ontario, 25 King St West, Kingston, ON, K7L 5P9, Canada. tara.baetz@krcc.on.ca
Background:
LY293111 is an oral agent known to be a leukotriene B4 (LTB4) receptor antagonist and a 5-lipoxygenase inhibitor resulting in selective inhibition of the lipoxygenase pathway. Lipoxygenases metabolize arachidonic acid and have been involved in cancer cell proliferation and survival. In addition, LY293111 has been found to be a peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonist. Antineoplastic activity of LY293111 has been identified in preclinical models both alone and in combination with chemotherapy agents including irinotecan. The NCIC Clinical Trials Group studied LY293111 in combination with irinotecan to determine the recommended dose of the combination and to describe its tolerability and pharmacokinetic interaction. In addition the anti-tumour activity of LY293111 in combination with irinotecan was documented.
Patients And Methods:
Twenty-eight patients with advanced solid tumours were treated on seven dose levels with the combination of irinotecan and LY293111. Irinotecan was administered intravenously every 21-days as a single dose. LY293111 was administered twice daily continuously by mouth.
Results:
Dose limiting toxicity (DLT) of grade 3 diarrhea was seen in two patients with doses of irinotecan 300 mg/m(2) IV every 21-days in combination with LY293111 300 mg BID. Subsequently the dose of irinotecan was decreased to 250 mg/m(2) IV every 21-days with escalating doses of LY293111. A DLT of grade 3 abdominal pain was seen at dose 600 mg BID of LY293111 with irinotecan 250 mg/m(2). The pharmacokinetics (PK) indicated that the administration of LY293111 did not have an effect on the PK of irinotecan or its metabolite SN-38. No responses were seen; seven patients had stable disease of a median duration of 4.4 months (range 2.8-13 months).
Conclusion:
The recommended phase II dose of LY293111 is 600 mg orally BID in combination with irinotecan 250 mg/m(2) IV every 21-days. Gastrointestinal adverse effects were common but could be well managed.
Insights
The recommended Phase II dose for LY293111 combined with irinotecan is 600 mg BID and 250 mg/m2 IV, respectively. Gastrointestinal side effects were manageable.
Area of Science:
- Oncology
- Pharmacology
Background:
- LY293111 is a leukotriene B4 receptor antagonist and 5-lipoxygenase inhibitor with preclinical antineoplastic activity.
- LY293111 also acts as a peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonist.
- Preclinical studies indicated antineoplastic activity of LY293111 alone and with chemotherapy agents like irinotecan.
Purpose of the Study:
- Determine the recommended dose of LY293111 in combination with irinotecan.
- Evaluate the tolerability and pharmacokinetic interaction of the combination therapy.
- Document the anti-tumour activity of LY293111 and irinotecan combination.
Main Methods:
- Twenty-eight patients with advanced solid tumours were enrolled in a dose-escalation study.
- Irinotecan was administered intravenously every 21 days; LY293111 was given orally twice daily.
- Dose-limiting toxicities (DLTs) were monitored to establish safety and recommended dosages.
Main Results:
- Dose-limiting toxicities included grade 3 diarrhea and abdominal pain at specific irinotecan and LY293111 doses.
- Pharmacokinetics showed no significant impact of LY293111 on irinotecan or SN-38 levels.
- Seven patients achieved stable disease for a median of 4.4 months; no objective responses were observed.
Conclusions:
- The recommended Phase II dose is LY293111 600 mg orally twice daily with irinotecan 250 mg/m2 intravenously every 21 days.
- The combination therapy was generally well-tolerated, with manageable gastrointestinal adverse effects.
- This study established a safe and tolerable dose for further investigation of LY293111 and irinotecan in cancer treatment.
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