Irinotecan and Other Agents in New Combinations and Other Tumor Types

The 4th Investigators’ Workshop sponsored by TheUniversity of Texas M. D. Anderson Cancer Center was held on July 25-29, 2001,in Colorado Springs, Colorado. The purpose of these annual workshops has been toreview the latest data on new agents, with a particular focus on the broadlyused agent irinotecan (CPT-11, Camptosar).

Investigators from around the world were invited to present current research.The forums were highly interactive and frank, thus allowing stimulation of newideas and directions. The meetings were more like a workshop rather thandidactic sessions. Six separate scientific sessions were held, and therespective sessions covered colorectal carcinoma, uppergastrointestinal/genitourinary carcinoma, lung carcinoma, and new combinationsand other tumor types.

In addition to stimulating research, another purpose of these workshops is todevelop enduring material for wider distribution to those who did not attend.Thus, four publications are intended. This third volume is devoted to newcombinations and other tumor types. The two previous volumes focused oncolorectal cancers and upper gastrointestinal/genitourinary carcinomas. Thefourth and final volume will be devoted to lung malignancies.

New Agents in Antiangiogenesis

In this volume, Jordan Berlin reviews preclinical and clinical data leadingto the current trials of two new agents that inhibit pathways associated withtumor angiogenesis. Standard first-line therapy for patients with metastaticcolorectal cancer consists of IFL (fluorouracil, leucovorin, and irinotecan).Bevacizumab (Avastin), a recombinant humanized monoclonal antibody to vascularendothelial growth factor (VEGF), is being assessed in a randomized trial of IFLwith or without bevacizumab. The tyrosine kinase inhibitor SU5416, targetedagainst the Flk-1 receptor for VEGF, is being tested in a phase I/II trialcombined with IFL.

Irinotecan and Epirubicin in Advanced Cancer

John Marshall and coworkers present a phase I clinical study that representsan investigation of the first combination of irinotecan and epirubicin (Ellence)in patents with advanced cancer. These drugs are significant chemotherapeuticagents that are used in the management of many different cancers. Each agentworks through the inhibition of topoisomerases, and inhibition of topoisomerasesI and II may result in significant clinical synergy. Evidence of clinicalactivity was observed, including activity in two typically resistant tumortypes. There was significant myelosuppression in the original cohort thatrequired a modification in the initial dose-escalation scheme, and accrual tothese lower doses is ongoing.

Irinotecan and Mitomycin

Other agents, such as mitomycin (Mutamycin), also possess significantsingle-agent activity against several tumor types, and mitomycin activatestopoisomerase I, the cellular target of irinotecan. Miguel Villalona-Calero andJill Kolesar discuss data from a phase I dose-escalation study of irinotecan andmitomycin in 37 evaluable patients with solid tumors. The response rate was 49%,including 2 complete responses, 5 partial responses, 10 minor responses, and aCA 19-9 tumor marker response. These encouraging data provided the rationale forongoing phase II clinical trials in breast and esophageal/gastroesophagealjunction adenocarcinomas at the recommended doses and schedule.

Irinotecan in Non-Hodgkin’s Lymphomas

Andreas Sarris et al investigate the activity of irinotecan in relapsed orrefractory non-Hodgkin’s lymphomas (NHLs). The every-21-days irinotecanschedule is attractive for the treatment of lymphoma, because irinotecan may becombined with other myelosuppressive drugs that are active in lymphoma—whichare also usually given every 21 days—and can be supported by hematopoieticgrowth factors to minimize or prevent neutropenia. In 32 evaluable patients,response rates were 43% for 7 indolent, 0% for 3 mantle cell, 44% for 18relapsed aggressive, and 20% for 5 refractory aggressive NHLs. Grade 3/4toxicities included myelosuppression, neutropenic fever, and diarrhea. Accrualis continuing in this ongoing study.

EIAEDs and the Pharmacokinetics of Irinotecan

Enzyme-inducing antiepileptic drugs (EIAEDs) such as phenytoin andcarbamazepine induce several metabolic pathways relevant to irinotecan’selimination. John Kuhn discusses the North American Brain Tumor Consortium phaseI study that is designed to determine the maximum tolerated dose andpharmacokinetics of irinotecan given every 3 weeks to patients who are receivingEIAEDs. The EIAEDs altered both the pharmacokinetics and pharmacodynamics ofirinotecan, and peak concentrations and the area under the plasma-time curvesfor irinotecan and SN-38 were significantly decreased in patients receivingEIAEDs. The recommended phase II dose of irinotecan administered every 3 weeksis 750 mg/m2 for patients who have been receiving stable doses of EIAEDs.

Conclusion

In conclusion, I believe that the data presented at The University of TexasM. D. Anderson Cancer Center Investigators’ Workshop provided currentinsights, trends, and practices in relevant areas of oncology. I hope you willfind the information in this and other volumes useful in designing newinvestigations and educating your colleagues, in addition to contributing to thebetter management of all patients.