CLINICAL TRIALS AND RESEARCH

Research into GIST is moving very fast, and we now know very much more than we did ten years ago. However there are still many questions unanswered:

  • We DO know that most GIST tumours have mutations in the KIT or PDGFRA genes, and we know how to identify which exon these mutations are in.

  • We DON’T know why some GISTs don’t have mutations at these sites, the wild type GISTs. (Presumably they have mutations in other locations.)

  • We DON’T know why pediatric GIST behaves differently from adult GIST.

  • We DON’T know why GISTs with mutations in different exons react differently to Glivec and Sutent.

  • We DON’T know why some GISTs behave more aggressively than others, even if they have the same mutations.

  • We DON’T know whether all patients need the same dose of Glivec or Sutent in order to get the same concentration in the blood.

  • Etc.etc.!

Current research is trying to find answers to some of these questions, as well as continuing to search for new drugs or combinations of drugs which will offer patients total long-term remission or a cure.

CLINICAL TRIALS

There is a very good booklet called Understanding Clinical Trials produced by UK Cancer Research Collaboration UKCRC www.ukcrc.org. This explains the terms you may hear, like placebo, control arm etc. If you are invited to enroll in a trial, this is recommended background reading.

Trials about GIST

Visit our News page to read about the latest trial to compare imatinib and nilotinib for first line treatment.

There are several trials trying to find out whether taking Glivec after complete removal of a GIST helps to prevent recurrence and long-term survival. This is called adjuvant treatment. (ie taking a drug when there is no obvious disease.)

One trial in the US has shown that taking Glivec for a year seems to dramatically increase the time before recurrence after surgery for Kit-positive high risk GIST. (Click here to download the full text of the NOVARTIS press release.) However it seems to make no difference to patients who had low risk GIST.

There are two other trials looking at adjuvant treatment. The pan-European adjuvant trial EORTC 62024 closed after recruiting 750 patients.   Patients with a complete resection (no marginal disease or mets) were randomised to either 400mg imatinib for two years, or to no treatment (which is the standard care).  The aim is to answer the question about whether imatinib has value in preventing recurrence and giving long-term survival. Unlike the US trial, the patients will be followed up for years, so we will have no results for a long time.

Another similar trial being conducted in Scandinavia is comparing the results of taking 400mgs per day of Glivec after surgery, for one year or three years. Again, it will be years before we have the results.

A new trial is the inevitable comparison trial between imatinib and sunitinib on diagnosis with unresectable/metastatic disease.  Both Novartis and Pfizer will be funding this trial which is international, but not in the UK.

In the UK, The Royal Marsden has a Phase II trial of Astra Zeneca's AZD2171 specifically for GIST which has proved resistant to imatinib and/or sunitinib.  Professor Ian Judson thinks this is a "very interesting VEGF inhibitor".  He says it is probably the most effective of a whole crop of VEGF inhibitors which have been appearing. VEGF provides the signaling in a tumour which helps it create a blood supply (angiogenesis). By turning it off the tumour becomes starved of blood and stops growing, or dies - at least that is the theory. Ian Judson hopes that because GIST is such a vascular tumour it may prove very effective. The biggest side effect is raised blood pressure and this means that it is not suitable for people with other problems such as heart disease.

Newcastle is starting a trial of plitidepsin (trade name Aplidin from Pharmamar) for solid tumours including GIST. This is more like a traditional chemotherapy.  It is derived from a marine organism and has shown effect in thyroid cancer. Pharmamar has another product - trabectedin (Yondelis) - which is currently seeking licensing for use in soft tissue sarcoma where it offers stability for a much higher percentage of patients with metastastic disease than anything else before it.

There is also a trial which compares giving 800mgs per day of Glivec with starting Sutent in patients whose GISTs have started growing on 400mgs of Glivec. Prof Judson highlighted the importance of NOT increasing the dose of Glivec before enrolling on this trial and being randomised between the two arms. This trial started in late 2008.

A trial which should start in Dec 2008 or Jan 2009, is of a completely new kind of drug, a HSP90 inhibitor. This will be a difficult trial, because the drug is given into a vein twice a week, so the patient would need to be near the hospital running the trial. There is also a group of patients, one third of the total, who will have to have the infusion, but it will be of salt solution, a placebo! All patients will be very closely and frequently monitored with PET scans. If GISTs in the patients who are not getting the drug start to grow, the patient will be “crossed over” to take the drug. This drug is made by a small American company called Infinity.

We are awaiting publication of results for the first trials of Novartis’ new drug nilotinib. This is the 'son of imatinib' drug.  There should be some Phase II data coming soon.

Compilation of the data from the two big trials which compared 400mg and 800mg of imatinib is now underway and publication is anticipated in 2008.  It will follow an update of the S0033 trial (the US version of the 400/800 comparison) which according to Dr George Demetri includes valuable data about cross-over to 800mg.

There is a European trial of surgery for patients whose GISTs have become stable as a result of taking imatinib. The entry criteria are not yet defined, but the aim is to see whether getting people back to “no disease” by using imatinib and then surgery is valuable for quality of life and for longevity.

Posted 3/12/08

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