A simple single-gene test can guide chemotherapy dosing and help prevent toxicity common to a particular three-drug regimen, according to preliminary results presented last week at the American Society of Clinical Oncology in Orlando, Fla., by researchers from the Mayo Clinic.
The three drugs irinotecan, oxaliplatin, and capecitabine are considered the best chemotherapeutics for gastrointestinal cancer, Matthew Goetz, an assistant professor of oncology at the Mayo Clinic in Rochester and head researcher of the study, told Pharmacogenomics Reporter.
Generally, two of the drugs are given in combination oxaliplatin or irinotecan is usually given with capecitabine or its metabolite, 5-fluorouracil, said Goetz. "But when people have tried to give all three drugs together and there is a rationale to do that there has been very, very significant toxicity, which has precluded the development [of treatments using] all three drugs," he said.
A major cause of toxicity neutropenia, specifically in some patients is irinotecan, which is metabolized through the action of the gene UGT1A1. So Goetz and colleagues hypothesized that stratifying patients by UGT1A1 genotype would allow them to determine appropriate dosing for each group, homozygous variant, heterozygous, and homozygous wild type.
Approximately 15 percent of African-Americans and Caucasians are homozygous-variant carriers, said Goetz.
Once patients were genotyped using an Applied Biosystems Genotyper, "we did essentially the same Phase I study in each of these groups," said Goetz. "We started at dose level 1 [for homozygous variant, or high-risk] patients to determine what their tolerability would be, and we saw significant toxicity," he said. "The heterozygous patients were able to tolerate dose level one, so we opened up the study for all patients, [and] patients who were wild type began therapy at dose level two."
In their findings, presented at the American Society of Clinical Oncology meeting, but not yet published the Mayo oncologists demonstrated three different dose tolerances based on genotype, said Goetz. "We are currently enrolling patients at dose-level five for the wild-type group; for patients who are heterozygous, we have reached dose-limiting toxicity and the maximally tolerated dose at dose-level one," he said. "Patients who are homozygous variant had significant toxicity nearly lethal in two patients at dose level one, so we are currently enrolling at dose-level minus two."
At this point, the researchers are still conducting dose-escalation to find the maximally tolerated dose for homozygous wild-type patients, Goetz said. "For the high-risk (homozygous variant) patients, who are at dose-level minus 2, two patients there had excellent tolerability, so we're believing that that may be a tolerable dose for those patients," he said.
Interestingly, the drugs still exhibited good efficacy in homozygous-variant patients taking reduced doses, despite clinical intuition that this would not be the case, Goetz said. "Although this is a heavily pre-treated group of patients, we have seen responses at all dose levels. In fact, our first patient enrolled at dose minus two has a near-complete response," he said. "What this signifies is that it's not the dose that's important, it's the exposure to the drug."
The next step is to test the same drug regimen in a genotype-stratified Phase II study of patients with adenocarcinoma of the small bowel, Goetz said. Based on genotype, "we'll examine in that setting whether this regimen is well tolerated, and also whether it's effective," he said.
"I know there are a number of companies that are looking at" the group's results, Goetz said. "I know Pfizer actually took the UGT1A1 genetic marker to the FDA I believe it was last fall to inquire about whether it should be made commercially available," he said. No action has been taken by the agency yet, to Goetz' knowledge. "Our findings would suggest that this represents a new paradigm about how you should potentially do irinotecan drug development," said Goetz.
A Pfizer representative could not be reached before presstime.
The investigators are "still in the process of escalating and de-escalating" to determine the maximally tolerated dose for two cohort groups, Goetz said. He and colleagues will be studying the pharmacokinetics of a group of patients at each maximally tolerated dose to determine how genotype affects exposure to irinotecan and a toxic metabolite. Goetz suspects their results will be published in about six to nine months.
In total, the study will have involved "about 80" patients, said Goetz.
Chris Womack ([email protected])