Fletcher tells Life Rafters of new type of trial

By Jerry Call
Science Coordinator Life Raft Group

D r. Jonathan Fletcher met with Life Raft Group representatives after the CTOS meeting. Fletcher is one of the top researchers in the field of molecular biology of GIST. He is a wonderful speaker and his opinions are always highly sought in meetings like CTOS. In addition to being a top GIST researcher, Fletcher is a medical oncologist who spent the first part of his career working in pediatric oncology.

One of the items discussed was a GIST tumor bank. Fletcher told us of a few of the problems with setting up a tumor tissue bank and made a few suggestions.

On another topic, Gleevec-resistant patients and tissues are the focus of the majority of GIST research work, and they should be. We wanted to talk to Fletcher about efforts being made to obtain and analyze tissue from patients other than those resistant to Gleevec. Specifically, we asked about tissue from patients who were stable but have not had significant shrinkage to Gleevec, and about residual viable tumor cells from patients that were responding well to Gleevec. While stability is generally considered to be a major victory by both patients and doctors, there are a small number of GIST patients that have very large tumor burdens for whom stability is not enough. Fletcher told us that a significant amount of work had been or was being done in this area.

Gleevec often kills most GIST tumor cells, but seldom kills them all. This is why GIST patients must continue to take Gleevec as long as it continues to work for them. Over time, most GIST patients become resistant to Gleevec. It therefore makes sense to try to find out what is stopping those Gleevecresistant cells from dying. Fletcher said that some work was ongoing to analyze these residual viable cells.

We also asked Fletcher about the concept of earlier “combination treatment” clinical trials, the theory being that the addition of a second agent to Gleevec might be more effective while cells were still sensitive to Gleevec. Fletcher seemed generally supportive of this concept. While we generally did not discuss details of this concept, we did discuss one very interesting specific. Fletcher told us of a different kind of clinical trial concept called an “investigational window.” In theory, this innovative clinical trial concept could be used to investigate whether a particular drug had at least some signs of activity in GIST during the initial stages of drug treatment, before Gleevec, and before a patient became resistant to Gleevec.

Gleevec-resistant GIST is much harder to treat than Gleevec-sensitive GIST. The question that arises is whether a second drug, given at an earlier time when tumors are still sensitive to the effects of Gleevec, might be more effective than at a later time when cells are becoming resistant to Gleevec.

The concept of an investigational window, as we understood it, is that a newly diagnosed patient with metastatic GIST might be able to receive a candidate drug for a short time while he or she is not in danger. The theory being that some patients probably had a “window” of time, perhaps two weeks or so, that they could afford to take a chance to see if a new drug/ treatment showed immediate initial benefit (perhaps an early indicator might be PET scans).

The benefit of an investigational window-type trial would seem to be the possibility of identifying a drug that might have benefit in combination with Gleevec in the early phases of treatment when this same drug might have little or no benefit in Gleevecresistant GIST. The possibility of reduced time to identify these drug combinations would seem to be another potential benefit.

The potential drawback to an investigation window-type trial would seem to be in getting patients to agree to take a chance on an unapproved drug when a “wonder drug” like Gleevec is approved and waiting on the shelf. It would take special patients to appreciate the potential long-term benefit. Newly diagnosed patients are typically in shock from being diagnosed with cancer. Patients who had a primary tumor removed, then had a recurrence perhaps a year or two later might be better equipped to appreciate the potential for long-term benefit. These patients are typically over their initial shock and have often become quite educated thanks in part to support groups like the Life Raft Group.

The possibility of extending the investigational window concept to stable patients should also be considered. These patients might just need a little something added to Gleevec to nudge Gleevec-sensitive cells into apoptosis (cell death).

Another question that we had for Fletcher was whether he still considered GIST to be a role model for other cancers. He replied that GIST was the model for every other molecularlytargeted cancer therapy in solid tumors. He said that chronic myelogenous leukemia was also a role model for targeted therapies.