A Phase I Dose Escalation Study of Erlotinib in Combination With Theophylline

Official Title

A Phase I, Single-centre, Non-randomized, Open-label Study to Determine the Lowest Effective Theophylline Dose That Decreased Erlotinib's Diarrhea at the Standard Dose of 150 mg/Day and to Determine the Highest Erlotinib Dose in Combination With Theophylline That Can be Administered to Patients

Summary:

This study is to determine the use of theophylline in patients with NSCLC and advanced solid malignancies and whether treatment with theophylline will help lower or diminish the side effect of diarrhea in patients taking erlotinib. Patients will be enrolled in one of two parts of the study to verify the lowest dose of theophylline that is effective and the highest dose of erlotinib that can be tolerated with theophylline. If this study shows that theophylline is able to inhibit erlotinib induced diarrhea, it will help demonstrate that patients using the tyrosine kinase inhibitor (TKIs), erlotinib, can use it effectively at higher doses without experiencing severe diarrhea.

Trial Description

Primary Outcome:

  • The lowest effective dose of theophylline that will prevent or maximally ameliorate erlotinib's diarrhea at the standard dose of erlotinib at 150 mg/day taken daily for 28 days every 28 days
Secondary Outcome:
  • The highest dose of erlotinib that can be administered with theophylline and can be administered with an acceptable safety profile
Erlotinib is a tyrosine kinase inhibitor (TKI), which is a newer, effective treatment for cancer patients. TKIs are the only class of anticancer drugs that are predominately used as single agents. TKIs were hoped to lack side effects but can cause severe enough diarrhea that patients frequently stop treatment, even if TKIs are controlling their cancer. TKIs inhibit nucleoside transporters (NTs), perturbing regulation of adenosine levels in the intestine. It is possible that the reason for the inability to use TKIs in combination therapies has been their additive effects on NTs causing unacceptable diarrhea. It has been shown that TKIs are potent NT inhibitors, therefore it will theoretically inhibit NTs of intestinal epithelial cells causing an accumulation of extracellular adenosine resulting in chloride secretory diarrhea. If this hypothesis is correct, it has profound implications for oncology, since diarrhea is one of the dose-limiting toxicities of TKIs. It has been shown that co-incubating cells with 8-phenyltheophylline (8PT), which is an A2B adenosine receptor antagonist, block chloride secretion caused by nitrobenzyl-mercaptopurine ribonucleoside (NBMPR). Theophylline is also a methylxanthine and is a commercially available and licensed example of a 8PT. As it is already known that erlotinib is effective, it is used as a control factor in the first arm of the study and will be increased in the second arm to see what the maximally tolerated dose is when in combination with a controlled dose of theophylline.

View this trial on ClinicalTrials.gov

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Resources

Canadian Cancer Society

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