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Phase 1, randomized, double-blind trial of 7-allyl-8-oxoguanosine (loxoribine) in advanced cancer
S S Agarwala1, J M Kirkwood, J Bryant
1University of Pittsburgh Cancer Institute, PA, USA. Agarwala@msx.upmc.edu
Abstract:
Guanine ribonucleosides substituted at the 8 position of the guanine ring are a unique class of immunomodulators, the lead compound of which is 7-allyl-8-oxoguanosine (loxoribine). We conducted a double-blind randomized phase I study to evaluate the safety, pharmacokinetics, and immunologic effects of single ascending doses of loxoribine in patients with advanced cancer. Twenty-four patients were treated in three dose tiers of 8 patients each, utilizing a unique statistical design, so that within each group, patients were randomized in blocks of 4 to receive loxoribine initially and then placebo 4 weeks later--a sequence that was reversed in the remaining 4 patients. In 23 courses of loxoribine and 20 courses of placebo, toxicity was mild and infrequent at all dose tiers (1 mg/kg, 5 mg/kg and 10 mg/kg. Both antibody-dependent cellular cytotoxicity and lymphokine-activated killer cytotoxicity were transiently depressed following loxoribine administration at all doses. Loxoribine is safe at doses up to 10 mg/kg in patients with advanced cancer, and produces modest immunologic effects. Further testing, particularly in conjunction with other immunologic agents, is warranted.
Insights
7-allyl-8-oxoguanosine (loxoribine) is a safe immunomodulator for advanced cancer patients. This phase I study found loxoribine well-tolerated up to 10 mg/kg, with mild side effects and transient immune cell activity changes.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- 8-substituted guanine ribonucleosides are novel immunomodulators.
- 7-allyl-8-oxoguanosine (loxoribine) is the lead compound in this class.
- Assessing novel immunomodulators requires rigorous safety and efficacy studies.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, and immunologic effects of single ascending doses of loxoribine.
- To determine the maximum tolerated dose of loxoribine in patients with advanced cancer.
- To explore the impact of loxoribine on cellular cytotoxicity.
Main Methods:
- Double-blind, randomized, placebo-controlled phase I clinical trial.
- Single ascending dose escalation of loxoribine (1 mg/kg, 5 mg/kg, 10 mg/kg) in 24 advanced cancer patients.
- Patients received either loxoribine then placebo, or placebo then loxoribine, separated by 4 weeks.
Main Results:
- Loxoribine was safe and well-tolerated at doses up to 10 mg/kg, with mild and infrequent toxicity.
- Pharmacokinetic data indicated transient depression of antibody-dependent cellular cytotoxicity and lymphokine-activated killer cytotoxicity.
- No serious adverse events were reported, and toxicity was manageable across all dose tiers.
Conclusions:
- Loxoribine demonstrates a favorable safety profile in patients with advanced cancer.
- The immunomodulator produced modest immunologic effects, warranting further investigation.
- Future studies should explore loxoribine in combination with other immunologic agents for enhanced therapeutic potential.
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