Cancer experts on GIST

Gleevec dosage level is still unresolved at the 40th annual ASCO meet

By Jim Hughes and Norman Scherzer

Conflicting interim study results on GIST progression and dosage levels cropped up again at the 40th annual meeting of the American Society of Clinical Oncology held June 5-8. The meeting drew more than 27,000 cancer professionals to New Orleans, La. Updated results for the U.S. phase III Gleevec (Glivec/imatinib) dosage study S0033 were presented by Dr. Cathryn Rankin (abstract 9005). The European phase III Gleevec dosage study 62005 update was given by Dr. John R. Zalcberg (abstract 9004). Abstracts relating to GIST oral presentations and posters can be found online at the ASCO Web site, www.asco.org, and will soon be on the Life Raft Web site, www. liferaftgroup.org.

Both oral presentations were summarized by Dr. Allan Van Oosterom. The U.S. and European trials continue to report differences with regard to dosage level and time to disease progression. The Americans report no difference in time to progression between 400 mg. and 800 mg., while the Europeans report that higher doses were correlated with longer time to progression. Van Oosterom offered that the differences might be due to the size of the study cohorts — that the smaller American study group (746 patients) would have the same results as the European group (946 patients) if the two studies were the same size.

PHASING IN HIGHER DOSES POSSIBLE

Van Oosterom reviewed Zalcberg’s data that showed patients who started at 800 mg. were more likely (55 percent) to reduce their dosage than patients who increased their dose to 800 mg. (25 percent) due to disease progression. He also said that 90 percent of those who started at 800 mg. and reduced their dosage did so within the first six months. The presumption is that side effects decrease over time and patients can tolerate the higher doses after being on Gleevec for some time (see Gleevec Clearance). He indicated that Novartis has now agreed to study this issue. This is important because a precise sub-group of patients that may need the higher dose has not yet been identified. He expected that by next year we might know how the dose could be modified based on mutations.

GLEEVEC CLEARANCE DATA COMING

Van Oosterom gave an oral presentation on Gleevec clearance rates. He had previously shared this data with the Life Raft Group at the Life Fest 2004 in May – namely, that Gleevec clearance rates have been observed to increase over time. Van Oosterom indicated that Dr. Ian Judson will publish this finding shortly in the journal Cancer Chemotherapy and Pharmacology. Van Oosterom said pharmacokinetic data “showing Gleevec levels in patients in which we increased dosage (upon progression) was substantially lower (than at the beginning of treatment).”

INCREASE TO 800 mg. SHOWS BENEFIT

Overall benefit from crossover to 800 mg. on progression ranged from 33 percent to 39 percent in two phase III study updates involving more than 200 patients who had disease progression on 400 mg.

Zalcberg reported European study results for patients crossing over to a higher dosage after progression. A total of 133 went from 400 mg. to 800 mg. in accordance with the study protocol. Of these, 2.5 percent achieved some tumor shrinkage and 30.3 percent had stable disease. The higher dose did cause more fatigue and anemia. Curiously, neutropenia was more likely to get better. In a growth modulation index analysis, the time to progression improved by more than 30 percent in a quarter of the patients who crossed over in the European study. In his conclusions, Zalcberg said the study suggests that 800 mg. of Gleevec has specific activity in a proportion (25 percent) of patients who have disease progression on 400 mg.

In the U.S. study, Rankin reported that of the 77 patients who crossed over, five (7 percent) achieved some tumor shrinkage and 25 (32 percent) achieved stability.

INTERMITTENT GLEEVEC NOT ADVISED

Dr. Jean-Yves Blay (abstract 9006) reported on a French study that compared continuous to intermittent Gleevec treatment. Not unexpectedly they found that there was a high risk of progression after stopping Gleevec. Referring to this study in his summary list of “GIST Treatment Certainties,” Van Oosterom included the advice “Do not stop (Gleevec) even if CR (complete response)” and that Gleevec dose interruption should occur “only in carefully designed clinical trials.”

STOPPING GLEEVEC RISKS FLARE-UP

A major finding at ASCO was that patients who stop Gleevec experience tumor “flare-up” on PET scans in just seven to 10 days. Flare-up indicates increased tumor activity. The precaution that patients should not stop Gleevec treatment even if progressing was common. Van Oosterom reported that CT scans did not show this same progression for two to three months. In Van Oosterom’s words, “in normal cells [and] cancer cells, renewal and growth is a continuing process; administering a tyrosine kinase inhibitor intermittently might therefore not be optimal.” Dr. Charles Blanke of Oregon Health & Sciences University reported that the National Comprehensive Cancer Network’s GIST Task Force has recommended patients with limited progression on Gleevec do continue the drug. (You can see the current NCCN GIST Practice guidelines at: http://www.nccn.org/ professionals/physician_gls/PDF/ sarcoma.pdf ; go to pages 14-18)

PROMISING NEW THERAPIES ON THE HORIZON

SU11248: On Sunday, June 6, Dr. George D. Demetri gave an oral presentation on very promising data from the phase II trial of SU11248 (abstract 3001). Some 65 percent of 98 patients had overall objective benefit, including 8 percent who had a “partial response” based on RECIST criteria.
(tumor shrinkage of 30 percent or more as measured by CT scans). The overall benefit rate (complete response + partial response + stable disease) compares well with the early phase III Gleevec results of 75 percent presented last year at ASCO. However, the RECIST-based response of 8 percent lagged behind the 43 percent for Gleevec phase III trial. This confirms earlier reports that SU11248 does not shrink tumors as much as Gleevec. However, when looking at the durability of the response in those patients with 10 to 20 percent shrinkage, Demetri reported that there is a good indication of longer-term benefit with SU11248. In other words, RECIST is not a good indicator of the benefits of SU11248.

Less shrinkage may have another benefit. For the small number of patients who can’t tolerate the bleeding caused by tumors shrinking on Gleevec, SU11248 may be a less risky option.

Particularly striking in Demetri’s report was the fact that for the 41 trial patients for whom GIST genotype data was available, this drug seemed to work best against genetic mutations for which Gleevec was only moderately effective.

Gleevec seems to do best against exon ll mutations. SU11248, in contrast, seems to work best against exon 9 mutations. For 15 patients who had exon 9 mutations, the response rate was virtually the same as that for all patients in the Gleevec phase III study. Six (40 percent) had objective response and 12 (80 percent) showed overall benefit.

Caution is advised as the numbers are still small. There were nine wildtype GISTs (no detectable KIT or PDGFRA mutations) in the genotype data group; one obtained RECIST response and five obtained benefit. This is a teasingly small sample but it is of particular interest to pediatric GIST patients, almost all of who demonstrate the wild-type KIT/PDGFRA GISTs.

Another facet of Demetri’s presentation was the availability of molecule structure data for the KIT tyrosine kinase. The crystal structure of KIT, done by C. Mol at Cyrix and published in the Journal of Biological Chemistry 2004, will permit 3-D structural analysis of KIT interaction with Gleevec and other tyrosine kinase inhibitors. This will show “how they (TKI’s) interact mechanistically with the threedimensional conformation of the KIT kinase and eventually mutate,” said Demetri. This is a very promising development for the design of future KIT inhibitors.

If this genetic mutation response data holds up, one could speculate that a combination of Gleevec and SU11248 offers some promise, given the complementary targets of the two drugs. Demetri was asked about future trials combining Gleevec and SU11248, and replied,“certainly that’s a study that is planned for the future and not too distant future at that.”

No data was available yet from the relatively new phase III trial of SU11248 trial that started in December at sites around the world. Accrual of approximately 350 patients is in progress. During Q&A after his presentation, Demetri was asked about the controversial inclusion of a placebo in the phase III trial, the crossover design and the washout period. “

We do have a crossover in that study,” Demetri replied. “It is a two-to-one asymmetric randomization. Two patients get, in a blinded way, the SU11248, one patient, in a blinded way, receives placebo. And there is a very close follow-up of those patients. And if they worsen, then they are able to cross over to the active study drug in an unblinded way. But we felt for a drug (SU11248) that does not have a major objective remission rate, that this was the safest and most effective way to prove the worth of this agent and not run the risk of inappropriately calling an active agent inactive …”

“The other important thing that I would say that you brought up is patients, once taken off Gleevec, can progress quickly; we really have to minimize the washout period before patients enter this study. And I think that is an important consideration as kinase inhibitors seem to need to be dosed continuously.”

RAD001 + Gleevec: Van Oosterom presented the first data from the phase I trial for RAD001 (Everolimus) plus Gleevec. So far, no objective response has been observed. However, there will be a new phase I trial soon with a very different dose regimen. The reason for this is the knowledge gained about the drug interaction between RAD001 and Gleevec.

GIST – WHAT’S NEW

Blanke, in his summary analysis of the Sugen and RAD001 presentations, commented on the controversial design of the phase III SU11248 trial.

“Historically new compounds are used in refractory populations. Usually the first line therapy to which the tumor is resistant, in this case being Gleevec, is stopped. There may even be a significant washout period required when the patient receives no therapy.

“Besides setting the bar rather high by selecting such resistant clones, I believe a major problem with this strategy is the discontinuation of Gleevec … If a new drug must be tested second line, I believe it should be added to Gleevec. The Pfizer phase III concept testing SU11248 against placebo is somewhat bothersome to potential patients and possibly rightly so. As we just talked about in differing from the front line situation, patients discontinuing Gleevec after showing progression tend to get sick very quickly. They may never have the opportunity for benefiting from the new drug.

“If agents must be tested alone in refractory patients, the study participants should be watched extremely closely. And the period off Gleevec and/or the potentially active new agent must be as short as possible.”

Regarding SU11248, Blanke added the drug “shows activity across a wide range of patients.” In a press release issued shortly after ASCO, Blanke announced that OHSU would go ahead with the phase III trial of SU11248.

“A lot is new under the sun,” Blanke concluded. “Today’s presentations were good. But it is certainly too early to say we have a second magic bullet against GIST.”

NO DISCUSSION OF PKC412

This long-delayed trial of PKC412 plus Gleevec did not come up either in formal or behind-the-scenes discussions. This phase I trial should be under way at OHSU.

INTERFERON

There was an interesting poster (abstract 9027) by Dr. Ernest Borden of Cleveland Clinic on an in-vitro study of interferon (IFN-B) and GIST cell lines. Borden is interested in working with the Life Raft Group to explore starting a clinical trial. This poster showed that Interferon alpha 2, and especially Interferon beta, were able to inhibit KIT and AKT, and cause cell death in the GIST cell line tested. In these laboratory studies on GIST cell lines, interferon beta appeared to be as effective as Gleevec.

BMS354825

This phase l trial for solid tumors, including GIST, should begin shortly at Dana-Farber in Boston and in Glasgow, Scotland. This promising drug targets SRC in addition to C-Kit and PDGRF. SRC is a downstream target of KIT. This trial builds upon the phase l experience with 30 chronic myelogenous leukemia patients. It will be a dose escalation trial starting at 70 mg. per day, which is higher than the beginning dose in the phase I CML trial. Although there is no clinical data yet, this drug occupies a high profile spot on both Bristol Meyer Squibb and Life Raft Group radar screens.

AMG706

This Amgen drug was not on the ASCO agenda but it is due to undergo clinical trials starting this summer in a number of locations. The Life Raft Group now has anecdotal reports of two GIST patients responding to this drug, one with tumor shrinkage and one with stability.

ARIAD (AP23573)

This interesting drug was presented in a poster session (abstract 3076) presented by Dr. Monica M. Mita. This is a new rapamycin analog that is heading toward a phase II trial. Mita showed data regarding one GIST patient who is projected to have partial response on AP23573. Dr A. A. Desai of the University of Chicago also presented a poster (abstract 3150) showing phase I PK/PD data for this drug.

GLEEVEC + BEVACIZUMAB

According to Dr. Blanke “A trial design combining Bevacizumab (Avastin) with Gleevec is going before the NCI shortly.”

Disclaimer: This report was prepared by Life Raft Group member Jim Hughes and Executive Director Norman Scherzer and edited by Life Raft Group Science Coordinator Jerry Call and Newsletter Editor Richard Palmer. Corrections and comments are welcome.