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GROUP. Fundraising charges on LIFE RAFTAFT. Life Raft study presented at CTOS annual meeting Starting vs. actual dose significant

Life Raft study presented at CTOS annual meeting Starting vs. actual dose significant A groundbreaking study of cancer patients done by the cancer patients and caregivers themselves was presented at the
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Life Raft study presented at CTOS annual meeting Starting vs. actual dose significant A groundbreaking study of cancer patients done by the cancer patients and caregivers themselves was presented at the Nov meeting of the Connective Tissue Oncology Society s in Montreal, Canada. The study undertaken by the Life Raft Group was presented Friday afternoon, Nov. 12, to over 300 sarcoma and GIST specialists from around the world. It affirmed preliminary results of a large European study on dose levels of Gleevec (imatinib) for GIST (gastrointestinal stromal tumor), and also tackled the thorny issue of clinical trial patients who begin a clinical trial at a certain dose, but then change that dose. The results of clinical trials are usually based upon the starting, or intent to treat dosages even though patients sometimes have their dosage reduced due to side effects or changed by the patients themselves without notifying the trial clinician. Researchers generally do not take into account these dosage changes when reporting their findings. The Life Raft study, however, suggests that cancer patients, particularly See STUDY, Page 2 Fundraising charges on G IST patients and supporters walked through the park, ran the New York City Marathon and played Texas Hold em to help research and support the vital work of the Life Raft Group. GIST Walk tops $90,000 for GIST research More than 300 cancer patients, friends, family and supporters helped raise more than $90,000 to fight GIST at the 4th Annual Walk For A Cure held Oct. 10 in Congers, New York. According to organizers Tania and Robert Stutman, the fund-raiser was the biggest walk to date and drew people from across the country. Participants came from California, Texas, Florida, S. Carolina, Oklahoma, Virginia, W. Virginia, Connecticut, Massachusetts, and New York, among others. The walk was again held at Rockland Lake State Park in Congers. Greeting participants was Walk Frazier, one of the greatest players in the history of the National Basketball Association. Now an announcer and analyst for the New York Knickerbockers basketball team, Frazier is a member of the Basketball See FUNDRAISING, Page 3 Battling gastrointestinal stromal tumor LIFE RAFTAFT GROUP November-December 2004 Vol. 5, No. 11 In memory of Myrtle Brickman, Ray Carbott, Thomas Fredgren and Martin Scharf Life Raft Pediatric GIST Meeting Pictured at the first international pediatric GIST meeting clockwise from lower right are part of the group: Jaap Verweij (back to camera), Tricia McAleer, Cristina Antonescu, David Josephy, Karen Albritton George Demetri, Alberto Papo, Dick Singleton and Daniel Stepan See story/page 6 those on long term oral therapy, might be better served if dosage changes were considered as well. In the LRG study of 169 patients with metastatic GIST receiving Gleevec, there was a Ensuring That No One Has To Face GIST Alone Newsletter of the Life Raft Group November-December 2004 PAGE 2 STUDY From Page 1 % Relapsed significant difference in the observation of resistance when the actual dose being taken was considered versus the intent to treat, or starting dose. The patients studied all had metastatic GIST, had been on Gleevec one year or longer, and had experienced initial tumor shrinkage. The objective of the study was twofold: to see if there s a correlation in this group between dose and the cancer becoming resistant to Gleevec; and to evaluate the difference in methodology between using starting dosage ( intent to treat ) vs. actual dosage. Of the 169 patients, 91 reported continued stable disease following shrinkage. The other 78 had experienced tumor growth after their initial response. Forty percent of the 169 patients were initially prescribed 600 mg. or more of Gleevec daily, while 60 percent were prescribed less than 600 mg. When considering starting dosage alone, the LRG study did find a correlation between dosage and relapse, but it was not statistically significant (p = 0.265). The relapse rate for patients taking 600 mg. or more was 41.2 percent, while it was 49.5 percent for those taking less than 600 mg. It is interesting that this 8.3 percent higher relapse rate is not far off the 6 percent higher relapse rate reported in the European/Italian/Australian (EORTC, ISG, AGITG) Phase III study of 946 GIST patients of patients taking 400 mg. or 800 mg. of Gleevec daily. The companion American/Canadian study of a somewhat smaller group of patients has failed to report 49.5% any relationship between 41.2% dosage and resistance thus far. In looking at the starting dose vs. actual 600 dose issue, the 600 Life Raft study Start found that 38 percent of patients had a reported change of dosage, most because the clinician had changed the dosage but some because the patient had changed the dosage themselves without notifying the clinician. Most (30.2 percent) reduced Actual v. Starting Dosage Relapse Rates Totals 60.0% 50.0% 40.0% 30.0% 20.0% % 0.0% A ct ual Actual 30.0% 52.9% Actual v. Starting Dosage Relapse Rates Females % Relapsed 60.0% 50.0% 40.0% 30.0% 20.0% % 0.0% Actual % 52.5% Start 39.3% 46.9% their dosage but some (7.7 percent) had a dosage increase. When the actual dose was considered, the difference in relapse rates 600 between the higher and lower dosage groups was dramatic. Based upon actual dosage there was a significantly lower relapse rate for higher versus lower dose (p =.001) Going by intent to treat dosage, the relapse rate was 49.5 percent for those on less than 600 mg., and 41.2 percent for those on 600 mg. or more. But when the actual dose was considered, the relapse rate was 52.9 percent for those on the lower dose, and just 30 percent for those on the greater dose. Put another way, the lower dose group had an 8% higher relapse rate based upon starting dose but a 23% higher relapse rate based upon actual dose. Further, although not statistically significant, likely due to small numbers, the actual dosage data does suggest a gender difference that needs to be watched in future studies. When the study looked at relapse rates based upon actual dosage over time, relapse rates were relatively consistent in five six month time periods starting with month 13 (the first study month). Relapse rates overall 600 and separately by gender were significantly lower for higher dose. What this means is that patients on lower doses who have not relapsed cannot take any comfort in that fact and face the same risk of resistance in each six month time period evaluated thus far. Conclusions: When looking at actual dosage, patients on 600 mg or more of Gleevec are significantly more likely to have lower relapse rates than do patients on less than 600 mg. Actual dosage produces substantially different results than starting dosage. It is important to note that the meth- See STUDY, Page 10 Ensuring That No One Has To Face GIST Alone Newsletter of the Life Raft Group November-December 2004 PAGE 3 FUNDRAISING From Page 1 Hundreds Walk for a Cure Hall of Fame and the NBA s 50th Anniversary All-Time Team. Some noted GIST specialists joined in the walk, including Drs. Ronald De- Matteo from Memorial Sloan- Kettering and Margaret Von Mehren from Fox Chase Cancer Center. Also represented were pharmaceutical companies Novartis and Pfizer, who helped sponsor the walk. You all should be commended for your effort, determination, commitment, kindness and support, said Tania Stutman, a GIST patient since The day was great not only because it was a sunny day, but because everyone s face had the most beautiful glow of happiness, and there was the greatest feeling of belonging to such a special family. This year s walk was held in memory of Dean Gordanier, an attorney and GIST warrior who took part in the clinical trials of both Gleevec and SU Gordanier gained the admiration and respect of fellow patients as he gave generously of his time and shared his experience, knowledge, wit and wisdom with GIST patients worldwide as he participated in GIST cancer support groups. His outlook was always positive and uplifting. With the latest walk, the GIST Cancer Research Fund has raised more than $215,000. The money goes exclusively to GIST researchers, and has provided grants to Fox Chase Cancer Center in Philadelphia, Dana-Farber Cancer Institute in Boston, Oregon Health & Sciences University in Portland, and Memorial Nan Mustard, center, and husband, Tim, traveled all the way from the San Francisco Bay Area to participate in the 4th Annual Walk for a Cure held Oct. 10 at Rockland State Park in New York. More than 300 people turned out for the event. Sloan-Kettering Cancer Center in New York City. Dr. Ephraim Casper of Memorial Sloan-Kettering serves as medical advisor to the GIST Cancer Research Fund. Team LRG Completes New York City Marathon Team Life Raft: Jennifer Corrao and Michael Byrne at the finish line of the 2004 ING New York City Marathon On November 7, more than 30,000 athletes ran in the New York Marathon, covering five bridges, five boroughs, and 26.2 miles. Amongst the athletes were Team Life Raft Group s own Michael Byrne and family friend Jennifer Corrao. The Byrne and Corrao team raised over $11,000 for the LRG with a campaign that reached out to family and friends to sponsor them for the run. A sea of runners flooded the streets and after they were finished they walked back to their homes and hotel rooms wrapped in a piece of foil and a great sense of accomplishment. Michael and Jennifer made it to the finish line in a little over four hours. The LRG held a special dinner in Manhattan to honor Michael & Jennifer. Michael & Jennifer arrived exhausted, but they were pumped full of adrenaline from their physical and mental accomplishment. Norman Scherzer, LRG Executive Director, presented Michael and Jennifer with the LRG Volunteer Award for an astounding effort on their parts. Several other Life Rafters joined Team Life Raft for their congratulatory celebration. See FUNDRAISING, Page 4 Ensuring That No One Has To Face GIST Alone Newsletter of the Life Raft Group November-December 2004 PAGE 4 FUNDRAISING From Page 3 Michael Byrne and Jennifer Corrao receive the LRG volunteer award In attendance at the dinner were Michael, Mia and Matthew Byrne, Jennifer & her husband, Phil Corrao, Katie Byrne, LRG members, Dan Cunningham, Rita Raj and Marilen Danguilan, and David and Ruth Portnoy. The LRG staff members present were Norman and Anita Scherzer, Tricia McAleer, Pam Barckett and Matt Mattioli. Special thanks to the Byrne and Corrao families and all those who supported them! The line to enter was literally out the door. Jerry Cudzil and his wife, Lorie, made an opening announcement introducing the Life Raft Group, explaining their connection and thanking everyone for their help and support. It was time to play poker! They were playing Texas Hold'em. There would only be one winner so the serious players had their heads in the game immediately. By the end, only one man was left standing. The 1 st place winner was Ken Kiarash, followed by Steve Duncker in 2 nd place and Michael Levine in 3 rd place. Many generous players and invitees made contributions to Fun was had by all players as well as spectators. The participants were extremely generous. Even those who lost left with a good feeling It was a night not to be forgotten. Again, thank you to the Cudzil and Roth families and all those who attended for all your support!! Life Raft Group Second Annual Fundraising Drive Off To Good Start The second annual LRG Thanksgiving campaign is up and running. To date we have raised over $30,000! LRG members have pitched in to ask their family and friends to lend a hand to the Life Raft Group. Poker Tournament Nets over $47,000 for Life Raft On Thursday, November 18, Life Raft Board member Jerry Cudzil hosted a poker tournament in New York City to raise money for the Life Raft Group. Over 100 family, friends and colleagues poured into the Park Avenue Country Club for a night of friendly play and a chance to win a ticket to the E.S.P.N. World Series of Poker in Atlantic City, NJ in January The event raised over $47,000 for the Life Raft Group. Over 100 men and women sat down to play Texas Hold em for the Life Raft Group the LRG in addition to their initial $500 entrance fee. Jerry and Lorie conducted a 50/50 raffle as well during the game. The winner of the 50/50 donated $500 of his winnings back to the LRG. We would like to thank everyone who has contributed as well as those who continue to put in the footwork needed to keep the Life Raft afloat. Last year, Life Rafters raised over $100,000 dollars We are trying to surpass that goal this See year. STUDY, Page 6 Ensuring That No One Has To Face GIST Alone Newsletter of the Life Raft Group November-December 2004 PAGE 5 Putting Gleevec tablets in glycerin capsules raises serious concerns By Jerry Call and Norman Scherzer L ast month we published a short article in our October Newsletter headlined Life Rafter members find solution to Gleevec tablet nausea. We reported that several GIST patients who had switched from the original orange Gleevec capsules to the tablet form had experienced increased side effects, including nausea. The article went on to cite a possible solution-namely, to put the Gleevec tablets inside empty glycerin capsules. The rationale was that this would allow the tablets to travel further down the gut before dissolving, bypassing sensitive regions where nausea arises. The source of this advice was said to be an oncology nurse and an oncologist. By Jerry Call A t 7:00 a.m. on Friday morning, prior to the start of the formal CTOS agenda, the Life Raft Group met with Dr. Jaap Verweij, Erasmus University Medical Center, Rotterdam, the Netherlands and Dr. Martine Van Glabbeke, EORTC Data Center, Brusssels, Belgium. Verweij and Van Blabbeke were two of the investigators in the large phase III European Gleevec trial for GIST patients. The primary purpose of the meeting was to discuss some of the We have since spoken to several people at Novartis who had concerns about our article, most noteworthy Dr. Bin Peng, MD, PhD, the Senior Clinical Pharmacokineticist in the Department of Clinical Pharmacology. Dr. Peng received his medical degree from Sun Yet-sen University of Medical Sciences in China. He completed his postdoc- fellowship in Manchester Dr. Bing Peng, Novartis, Jerry Call, LRG and Barbara Kennedy, Novartis University, UK with Prof. Malcolm Rowland. He has authored and coauthored more than 50 papers and abstracts on clinical pharmacokinetics/ pharmacodynamics in the field of anticancer drugs. As a clinical pharmacokineticist, he has been involved in methodology differences between the European phase III study and the Life Raft Group (LRG) study on relapse. Another great benefit of the meeting was just a chance to meet and strengthen relationships with some of the top European researchers. The LRG study had found a significant difference in relapse rates in GIST patients using Gleevec when comparing actual higher doses (600 mg/day or more) to actual lower doses (less than 600 mg/day). The European the first investigations of the pharmacokinetics/pharmacodynamics of Glivec (STI571) in man. Based upon Dr. Peng s input we would like to withdraw our recommended solution. These are the reasons: First, it is unknown if the solubility of the glycerin capsules would compare to that of the original orange Gleevec capsules. Second, it is not known how placing the tablets into the capsules affects the solubility of the tablets. Our understanding is that the patient would probably take a pill cutter and cut the capsule in half. This may produce quite a different result than the original powdered form of Gleevec that went into the original orange capsules. The bottom line is that we do not know how this suggested procedure would affect the absorption of the drug and hence affect the efficacy of the drug. Given that most patients have reported that the increase in side effects accompanied by the switch from capsules to tablets resolves over time, it does not seem that this suggested procedure is worth the potential risks. Life Raft Research Team meets with European researchers Methodology to assess actual dosage compared Patients Progressing on Gleevec: The effect of starting dosage. Patients Progressing At: 400mg 600mg or more European phase III 56% 50% trials LRG study 49% 41% The median follow-up was 760 days in the European trial, and was not computed for the LRG study. The higher dose was 800mg in the European Study and 600mg or more in the LRG Study. study also found a significant difference (in progression-free survival ) when looking at high vs. low starting doses. A companion phase III trial See RESEARCHERS, Page 10 Ensuring That No One Has To Face GIST Alone Newsletter of the Life Raft Group November-December 2004 PAGE 6 Life Raft Hosts First Pediatric GIST Conference O n November 12, 2004 in Montreal Canada, the Life Raft Group hosted a meeting on pediatric GIST, the first such comprehensive meeting ever held. Chaired by LRG Executive Director Norman Scherzer, the two hour conference brought together key players from around the world (there are no experts per se yet for pediatric GIST, only a small number of clinicians and researchers who share some experience with pediatric GIST patients and an interest in learning more). Attending the meeting were: Dr. Karen Albritton, Dana-Farber; Dr. Cristina Antonescu, Memorial Sloan Kettering; Dr. Camille Bedrosian, ARIAD Pharmaceuticals; Mr. Jerry Call, LRG; Dr. Chris Corless, OHSU; Dr. Sean Daly, ARIAD Pharmaceuticals; Dr. George Demetri, Dana-Farber; Dr. Jonathan Fletcher, Brigham and Women s Hospital; Mr. Jim Hughes, LRG; Ms. Margi Hughes, LRG; Dr. David Josephy, LRG; Dr. Ian Judson, Royal Marsden, London; Mr. Kalvin Kochhar, Novartis Pharmaceuticals; Ms. Tricia McAleer, LRG; Mr. David Murphy, Sarcoma Alliance; Dr. Alberto Pappo, Hospital for Sick Children, Toronto; Mr. Norman Scherzer (Chair), LRG; Dr. Richard Singleton, LRG; Dr. Daniel Stepan, AMGEN Pharmaceuticals; and Dr. Jaap Verweij, Erasmus Univ. Medical Center, Netherlands. The objectives of the meeting were to: 1. Bring visibility to the problem of pediatric GIST by convening such a conference 2. Create a working definition for what constitutes pediatric GIST 3. Briefing and discussion of the protocol for the planned pediatric GIST- Gleevec clinical trial 4. Discuss plans for a pediatric GIST data base 5. Discuss plans for a pediatric GIST tissue bank 6. Discuss a best practices protocol for managing current pediatric GIST patients Consider how best to coordinate and support further efforts, including research Visibility: Clearly the first objective of the meeting was achieved by the simple presence and participation of the twenty persons listed. A working definition of pediatric GIST: The consensus was to use a broad definition now until we learn more. The likely upper age limit for the pediatric GIST-Gleevec trial will be 30. Dr. Judson and others observed that biology might serve as a more appropriate indicator with pediatric GIST patients than an artificial age cutoff. Although there is not a great deal of data available it seems that pediatric GIST patients are likely to be c- kit positive but less likely to have a known genetic mutation-in other words they are likely to be wild type c- kit. Chris Corless shared genetic data from OHSU on 14 GIST patients age 17 or less: 1 had exon 9; 1 had exon 11, 1 had a PDGFA mutation and the rest were all wild type c-kit. New clinical trial protocol: Drs. Demetri and Pappo, the primary study coordinators, reviewed the still evolving plans for a clinical trial for Pediatric GIST patients. Demetri will likely take lead for patients over 18 and Pappo for patients under 18. Expected to begin early in 2005, the phase ll trial and data registry will attempt to enroll three groups of patients: those with completel
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