GIST Support Wiki

 


This page is for information related to IPI-504, one of the Clinical Trial Drugs. Feel free to add your own experiences with the drug in the comments section or any other links to useful resources.

Contents

Basic Information

Manufacturer Information: Infinity Pharmaceuticals

Molecular Targets: Heat shock protein 90 (HSP90)

Trial: Phase I trial started January 2006 at Dana Farber Cancer Center and completed - see here

RING Trial: Phase III trial initiated and then suspended as of April 2009

GIST Support International website page: Link here

Additional Information

Added 3/25/07

According to the protocol at clinicaltrials.gov, the IPI 504 trial has a trial site in Michigan in addition to the site at Dana Farber. I notice we are nearing the March 2007 "expected completion date" however, perhaps more is coming....

""United States, Michigan University of Michigan Hosptials, Ann Arbor, Michigan, 48109, United States; Recruiting Rashmi Chugh, MD 734-936-0453 rashmim@umich.edu Rashmi Chugh, MD, Principal Investigator""

http://clinicaltrials.gov/ct/show/NCT00276302?order=12


Safety Study of IPI-504 for Gastrointestinal Stromal Tumors (GIST)

This study is currently recruiting patients. Verified by Infinity Pharmaceuticals February 2007 Sponsored by: Infinity Pharmaceuticals Information provided by: Infinity Pharmaceuticals ClinicalTrials.gov Identifier: NCT00276302

Purpose

The primary objectives of the study are:

  • Determine the safety and maximum tolerated dose (MTD) of IPI-504 in

GIST patients who have failed prior therapies

  • Recommend a dose for subsequent studies of IPI-504

Condition Intervention Phase Gastrointestinal Stromal Tumors Drug: IPI-504 Phase I

MedlinePlus related topics: Intestinal Cancer

Study Type: Interventional Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled, Parallel Assignment, Safety Study

Official Title: A Phase 1, Safety Assessment and Pharmacokinetic Study of IPI-504 in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (GIST) Further study details as provided by Infinity Pharmaceuticals: Primary Outcomes: To determine the safety and maximum tolerated dose (MTD) of IPI-504 in GIST patients who have failed prior therapies; To recommend a dose for subsequent studies of IPI-504 Secondary Outcomes: To examine the pharmacokinetic (PK) parameters of IPI-504 in GIST patients; To assess in a preliminary way the potential anti-tumor activity of IPI-504 in GISTTo explore potential pharmacodynamic (PD) markers of biologic activity of IPI-504 in GIST Expected Total Enrollment: 40

Study start: December 2005; Expected completion: March 2007 Last follow-up: December 2006; Data entry closure: January 2007 IPI-504 is a novel, water-soluble analog of 17-AAG and a potent inhibitor of Hsp90. Hsp90’s role in the cell is to control the proper folding, function, and viability of various “client” proteins. Many of these client proteins (such as AKT, Her-2, Bcr-Abl, PDGFR-α, and c-Kit) are oncoproteins or important cell signaling proteins. In patients with GIST, mutations in the tyrosine kinase receptor Kit play a critical role in the pathogenesis of this disease. Inhibition of Kit signaling with the tyrosine kinase inhibitor Imatinib (IM) is a very effective treatment for GIST patients. However, new mutations arise in Kit conferring resistance to IM treatment which results in disease progression. Kit is a client protein of Hsp90 and is sensitive to IPI-504. This provides a scientific rationale for Phase 1 clinical testing of IPI-504 in patients with metastatic and/or unresectable GIST who have failed prior therapies.

Eligibility Ages Eligible for Study: 18 Years and above, Genders Eligible for Study: Both Criteria

Inclusion Criteria:

  • Pathologically confirmed diagnosis of GIST
  • Failed prior therapies
  • ECOG performance status of 0-2
  • Ability to adhere to the study visit schedule and all protocol

requirements

Exclusion Criteria:

  • Previous treatment with 17-AAG, DMAG, or other known Hsp90 inhibitor
  • Participation in any investigational drug study or treatment with any

other kinase inhibitor therapy within 2 weeks preceding start of treatment

  • Concurrent radiation therapy is not permitted
  • Concurrent treatment with any agent that alters CYP3A activity
  • Concurrent treatment with any agent that may prolong the QTc interval
  • Myocardial infarction or active ischemic heart disease within 6 months
  • History of arrhythmia
  • Baseline QTc >450
  • Grade 3 or greater peripheral neuropathy
  • Renal insufficiency, serum creatinine >1.5 x ULN
  • Platelets < 100,000 mm3
  • AST and / or ALT > 2.5 x ULN
  • ANC <1,500 cells/mm3
  • Alkaline phosphatase > 2.5 x ULN
  • Amylase and lipase > 1.5 x ULN
  • Hemoglobin < 9.0 g/dL

Location and Contact Information Please refer to this study by ClinicalTrials.gov identifier NCT00276302

Michael T Quigley, RN 617-632-5117 Michael_Quigley@dfci.harvard.edu

United States, Massachusetts Dana-Farber Cancer Institute, Boston, Massachusetts, 02115, United States; Recruiting George Demetri, MD, Principal Investigator

United States, Michigan University of Michigan Hosptials, Ann Arbor, Michigan, 48109, United States; Recruiting Rashmi Chugh, MD 734-936-0453 rashmim@umich.edu Rashmi Chugh, MD, Principal Investigator

Study chairs or principal investigators

George D Demetri, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute Rashmi Chugh, MD, Principal Investigator, University of Michigan Hospitals

Jun 5, 2007

CAMBRIDGE, Mass. and GAITHERSBURG, Md., Jun 5, 2007 (PrimeNewswire via COMTEX) -- Infinity Pharmaceuticals, Inc today announced updated interim results from a Phase I clinical trial of the companies' heat shock protein 90 (Hsp90)inhibitor, IPI-504, in patients with relapsed, refractory gastrointestinal stromal tumors (GIST) and other advanced soft tissue sarcomas. The data, presented at the 2007 Annual Meeting of the American Society for Clinical Oncology (ASCO), indicate that IPI-504 continues to be well tolerated and to show evidence of biological activity. To date, 28 patients have received IPI-504 on two schedules of administration at dose levels ranging from 90 to 400 mg/m2. Assessment of biological activity in response to IPI-504 administration utilized positron emission tomography (PET) imaging to measure the decrease in tumor uptake of 18-fluorodeoxyglucose, an imaging agent used to measure metabolic activity. Scans were taken at baseline and during the first cycle of treatment after at least two doses.

PET results for "Schedule A" (21-day cycle with patients treated on days 1, 4, 8, and 11, followed by 10 days off treatment) were assessed using the European Organization for Research and Treatment of Cancer's (EORTC) PET response criteria which entails a quantitative measurement using SUVmax (maximum standardized uptake value). PET results for "Schedule B" (uninterrupted twice-weekly dosing without a drug holiday) were assessed qualitatively. (See below for additional information about PET imaging and SUVmax.)

EORTC criteria for PET responses define Stable Disease as a change in SUVmax between 25 percent above and 25 percent below baseline, and a Partial Response as a decrease in SUVmax of 25 percent or more compared to baseline. Fifteen of 18 (83 percent) evaluated patients treated on Schedule A achieved Stable Disease or better by the EORTC criteria, and 4 of 18 patients (22 percent)achieved Partial Responses by PET. Emerging patient data for Schedule B shows continuing evidence of biological activity for IPI-504, with 3 of 4 evaluable GIST patients showing a decrease in PET avidity as determined by a qualitative assessment of PET images. In addition to the reported PET responses, histologic and CT changes in GIST patients consistent with biological activity were also observed during treatment with IPI-504. IPI-504 has been well-tolerated at all dose levels tested, and a maximum tolerated dose has not been reached on either schedule of administration. The trial is currently enrolling at three sites: Dana-Farber Cancer Institute in Boston, Mass.; University of Michigan in Ann Arbor, Mich.; and Premiere Oncology in Santa Monica, Calif. "These data add significantly to the growing body of evidence supporting the hypothesis that IPI-504 has important antineoplastic activity in cancers such as GIST that are driven by mutated signaling mechanisms," said George D. Demetri, M.D., Director of the Ludwig Center at Dana-Farber/Harvard, Director of Dana-Farber's Center for Sarcoma and Bone Oncology, and Principal Investigator on this Phase I trial of IPI-504. "We are very enthusiastic to optimize the use of this agent and pursue further clinical development as efficiently as possible."

These data were presented at the Annual Meeting of ASCO in two posters. A poster entitled, "Inhibition and flare patterns of metabolic response to the heat shock protein 90 (Hsp90) inhibitor IPI-504 visualized by FDG-PET in patients with advanced gastrointestinal stromal tumors (GIST) resistant to tyrosine kinase inhibitor (TKI) therapy," (Poster Number 1, Abstract No: 3530) was presented on June 2, 2007. A poster entitled, "Inhibition of the Heat Shock Protein 90 (Hsp90) chaperone with the novel agent IPI-504 to overcome resistance to tyrosine kinase inhibitors (TKIs) in metastatic GIST: Updated results of a phase I trial," (Poster Number 8, Abstract No: 10023) was presented on June 4, 2007.

Preliminary data from the trial were initially announced in November 2006 at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Prague, Czech Republic. These data are also posted on Infinity's website at _www.ipi.com_ (http://www.ipi.com/) .

About IPI-504 IPI-504 is a small molecule drug candidate being developed jointly by Infinity and MedImmune. IPI-504 has been well-tolerated in its ongoing Phase I studies and has shown promising biological activity in a Phase I clinical trial in patients with relapsed, refractory Gleevec(r)-resistant GIST. IPI-504 is also being evaluated in a Phase I/II clinical trial in patients with advanced non-small cell lung cancer. In preclinical studies, IPI-504 has been shown to inhibit Hsp90 potently and selectively, thereby killing cancer cells. IPI-504 has also demonstrated, in preclinical studies, broad potential to treat certain cancers as both a single agent as well as in combination with existing anti-cancer drugs. The water-based formulation of IPI-504 is delivered as an intravenous infusion; an oral formulation of IPI-504 is currently in preclinical development.

About Hsp90 Hsp90 is an emerging therapeutic target of interest for the treatment of cancer. Proteins are the mainstay of structural and signaling elements of all cells. Hsp90 is a molecule that maintains the conformation and activity of specific proteins in the cell known as "client proteins" of Hsp90. Many cancers result from specific mutations in, or aberrant expression of, these client proteins. Examples of oncogenic client proteins of Hsp90 include c-Kit in GIST, epidermal growth factor receptor, (EGFR), in NSCLC, and Bcr-Abl in chronic myelogenous leukemia. Hsp90 enables those cancers' survival by maintaining the function of oncogenic client proteins. In preclinical studies, inhibition of Hsp90 has been shown to lead to the degradation of these proteins and cell death, or apoptosis. In addition, oncogenic client proteins that have become resistant to approved targeted therapies have also been shown preclinically to remain sensitive to Hsp90 inhibition. Inhibition of Hsp90 has broad therapeutic potential for the treatment of patients with solid tumors and blood-related cancers, including cancers that are resistant to other drugs.

About Gastrointestinal Stromal Tumors (GIST) and Hsp90 The American Cancer Society (ACS) reports that GIST is the most frequent form of gastrointestinal sarcoma, a life-threatening disease highly resistant to traditional cytotoxic chemotherapy or radiation treatment. The ACS estimates that between 4,500 and 6,000 Americans develop GIST each year. In the majority of GIST cases, specific mutations in cellular signaling enzymes ("kinases") called KIT or PDGFRA cause the growth and survival signal of the cell to become permanently active, leading to cancer. Both KIT and PDGFRA are client proteins of Hsp90, suggesting that inhibition of Hsp90 in GIST is an attractive area for clinical study.

About PET Imaging and SUVmax Positron emission tomography, also called PET, is an imaging technology that measures functional processes in the body. A radioactive isotope is attached to a metabolically active molecule related to glucose; the combined tracer molecule is then injected into the human body where it is taken up and trapped within the tumor cells. The most common tracer used in oncology for PET imaging is 18-fluorodeoxyglucose, or 18-FDG. Different colors or degrees of brightness on a PET image represent different levels of tissue or organ metabolic activity. PET imaging in oncology takes advantage of the fact that cancer cells exhibit higher-than-normal levels of glucose uptake and, therefore, show up clearly as bright spots on PET images. Oncologists often use PET scans to detect tumors, or to examine the effects of a cancer therapy by measuring the metabolic activity of the cancer cell before and after treatment.

Standardized Uptake Value (SUV) is a quantitative assessment of the metabolic activity of cells attained by PET imaging. SUV quantifies the ratio of uptake of a radioactive isotope, such as 18-FDG, for any given point in the body to the expected level. SUVmax measures SUV for the single point within a tumor lesion that has the highest SUV value. Tracking SUVmax for a single tumor lesion over time provides a standardized approach for assessing the decrease or increase in metabolic activity of the cancer during and after treatment by a cancer therapy. To date, 18-FDG PET imaging results and SUVmax have correlated with positive clinical outcomes in GIST patients treated with molecular targeted therapies.

June 2007

Data presented at ASCO from an early-stage trial of IPI-504 involving 21 GIST patients showed that it was able to decrease tumor activity or cause the disease to stabilize in a majority of patients, with minimal side effects. "We're really pleased with this drug so far," says Demetri, a principle investigator of the drug. "It certainly warrants further study."

22 Sep 2008

Subject: Second site for the phase III IPI504 study is now open

A second site for the IPI504 phase III study=A0has now opened: Dr. Richard Gorman New Bern Cancer Care, 1010 Medical Park Ave, New Bern, NC 28562 252 6365135 rgorman@cchealthcare.com

Another study site is: Park Ridge, Illinois, United States, 60068

Preliminary data from a single arm phase I study indicated that 75% of GIST pts who were resistant to both imatinib and sunitinib received clinical benefit from IPI504 with 12 weeks as the=A0median time to progression (the time when the tumors started to grow again in 50% of pts).

The goal of this phase III study is to generate data that will address the statistical requirements of regulatory agencies who will then decide if the new drug should be approved for the market.

IPI504 brings a new mechanism of action to the treatment of GIST. In theory, HSP90 inhibitors may accelerate the destruction of KIT in GIST cells, and may be a way to circumvent the problem of heterogenous secondary mutations in patients, making them resistant to single agent tyrosine kinase inhibitors, Gleevec, Sutent, Sorafenib, Tasigna..etc...

This trial has a blinded placebo control arm, so that neither pt nor doctor know who is receiving the investigational IPI504 or placebo. One third of pts will be assigned into the placebo arm. If a patient has objective tumor growth as determined by CT measurements, then he will be unblinded. Those who were on placebo will have an opportunity to cross over to the IPI504 arm of the trial, and receive drug. Patients need to discuss carefully with their doctors the potential consequences of a placebo assignment. This trial is not suitable for everyone, particularly those patients who have a very heavy tumor load or others who are receiving some partial disease control from staying on tyrosine kinase inhibitors even in the face of=A0certain growing tumors. There is a risk that a cross over to the investigational drug will not reverse the growth of the disease or the increase in symptoms that occurred during placebo.

Sometimes even Gleevec/Sutent resistant GIST may grow even more rapidly if a tyrosine kinase inhibitor is stopped completely, and patients may sick en more rapidly.=A0=A0You need to discuss your particular situation with your doctor.

You may find the study protocol here: http://clinicaltrials.gov/ct2/show/NCT00688766?term=3Dipi504&recr=3DOpen&ra= nk=3D2

24 Oct 2008

Subject: Phase III IPI504 informational website is now live

http://www.ringtrial.com/

Infinity Pharmaceuticals has launched a website for their phase III IPI504 trial for Gleevec and Sutent resistant GIST.

The website gives an overview of the trial, and a list of the currently open trial sites. 50 sites are planned globally, with about 26 or so sites in the US and Canada.

The trial is called the "RING trial" for Retaspimycin IN GIST. Retaspimycin is the generic name for the investigational drug IPI504. The trial is a phase III registration trial with the goal of collecting statistical data to satisfy the proof of efficacy requirements for the licensing for market by health regulatory agencies such as the FDA.

The trial has a placebo control arm, and patients considering this trial should discuss the trial design with their own doctors. Everyone's situation is different including tumor load and rate of tumor growth and whether the patient is fully resistant to TKI's or partially resistant to TKIs. Patients need to consider how a potential placebo placement in the trial might impact their overall chances. The situation for some patients might make the risk of placebo placement unacceptable to them. These are discussions to be held between the patient and his own doctor. Patients assigned to placebo will have an opportunity to cross over to the drug IPI504 arm of the trial after they have experienced RECIST defined tumor growth.

As explained in the IPI504 website, study patients may be eligible for reimbursment of certain travel expenses associated with trial participation. Again, this is a discussion between the patient and his trial site, since the policies may differ according to the country or location of the trial site.

IPI504 has shown clinical benefit in Gleevec/Sutent resistant GIST in a small phase I trial: Results showed that patients with GIST (n=3D36), who were heavily pre- treated, experienced a 70% (n=3D25) overall disease control rate, with 3%(n=3D1) Partial Response and 67% (n=3D24) Stable Disease at six weeks. Estimated median progression-free survival for these patients was 12 weeks. IPI-504 was generally well-tolerated. The most common side effects observed to date in the study were fatigue, headache and nausea.

Marina

17 Apr 2009

Subject: Re: update, sadness about HSP90

I too have been surprised that there hasn't been much discussion about the RING trial development on any of the GIST listservs. The development is a blow to an idea that had come pretty far since we first heard about it in 2005which to be an approach to address some of the tough molecular mechanisms of Gleevec resistance, and which was innovative too.

Blocking HSP90 with IPI504 or another HSP90 inhibitor has/had the theoretical potential to eliminate some of the hard to treat mutations in KIT that cause hard core resistance to all the tyrosine kinase inhibitors. (exon 17 mutations in KIT, certain exon 18 mutations in PDFRA). Blocking HSP90 had the potential to address the problem of MULTIPLE resistance causing mutations in a single patient. Heterogeneous resistance is a toughie, as most TKI drugs (gleevec,sutent, tasigna, etc) are like rigid "keys" that can only unlock certain padlocks and not others (KIT is the padlock). We need a TKI that can block exon 17 mutants.

Also, HSP90 inhibitors had the potential to stop GISTs in a "broad stroke way" since about 40+ proteins that help cancer to grow require HSP90 for their activity. Blocking HSP90 could have reduced signals from many different types of protein kinases that sustain the growth of GIST. Maybe with an effective blockade of HSP90, there wouldn't have been a need to sequence every tumor in every pt to match genotype to a TKI...maybe that would have been pratical for us.

There is a poster at the AACR next week describing the synergy of combining Gleevec with IPI504 to kill more GIST cells in laboratory experiments than Gleevec kills as a single agent. I wish that I could stand in front of that poster next week and ask "now what?"

What we don't know where the problem lies in the safety issue: a) the way this specific trial was set up (dosage, pt profile--very sick pts)?? b) the toxicity profile of this particular drug molecule?? c) the nature/toxicity of blocking the HSP90 target with any drug--or in otherwords is the problem not the drug per se but the target HSP90 itself?? (Remember the Cox-2 inhibitors, it wasn't the various drugs per se, but rather the very act of blocking Cox-2 itself itself that ended up causing the cardiac toxicity)

For now, there are other HSP90 inhibitor trials, noting that some of them don't preclude prior treatment with another HSP90 inhibitor: http://www.gistsupport.org/treatments/clinical-trials/current-trials.php

IPI504 (or IPI493) is available in a couple of phase I trials that are at MSKCC and Colorado. Should a resistant GIST pt consider these trials, or not?


Some of these other HSP90 inhibitor drugs are very different than IPI504 at a molecular level. IPI504 and 17 AAG are based on a natural antibiotic (geldanamycin)--in fact there is not much about the antibiotic's structure that would allow an untrained eye to predict at a glance that it blocks HSP90, but it does--or at least one small portion of the antibiotic, bends and twists itself to fit neatly into HSP90 protein's binding pocket....medicinal chemistry is tricky in that way. I imagine that some of the other structural areas of this antibiotic might have actions in a cell that are independent from blocking HSP90. http://geldanamycin.info/17AAG.htm

The Serenex drug, and Biogen drug, just for example, are totally synthetic drugs that are based on the natural ligand called ATP, and the molecular shape of these drugs somewhat resemble ATP. They do not look anything like the antibiotic family of HSP90 inhibitors.

From as much as we know so far, this trial appears to illustrate why regulators want control arms on clinical trials--even if some laypersons off the internet stomp around and make a public fuss--it just might be that these laypersons don't know what they are talking about. We can not always assume that the benefits of a drug outweigh the risks, and comparative arms allow scientists and regulators to get a better idea of the benefits of the drug versus risks.

Marina


Comments from Trial Participants

Chris

15 Jan 2008

Subject: update on Chris-not XL

Chris will NOT be starting XL 820 as I previously posted. Dr. Morgan at DanaFarber called last week to suggest that he try IPI 504 instead. This is a 2 or 3 day a week commitment, but the feeling was that it would enable him to go back on Sutent and get some effect. I have not had alot of faith in the IPI 504 since we lost a few GIST soldiers on this drug but I am told that the dosing has been tweaked. Anyone been down this road?

For now he is off Sutent for 2 weeks prior, it seems like he is still on it though as the side effects have remained the same ("gurgling" and frequent trips to the "reading room"). We start on 1/22/08.

25 Jan 2008

Subject: update on Chris and IPI504

We had testing on the 22nd. There was a major snafu.....we never got the message about fasting before the PET Scan So Chris ate breakfast and couldn't start the scan at 12 ( the PET scan is much longer and more involved than the CAT). We did get the labs done and sign all the paperwork. And we got to see the CRC where the infusions take place it is actually across the street in the Jimmy Fund building. Different check in, free coffee, snacks and they gave us a "Study Mouse" buddy with this poem:

Study Mouse Study Mouse Will this drug be the cure? Will it kill off the cancer and my body restore? Study Mouse Study Mouse In the lab this drug worked for you Here in the CRC, will it work for me too? Study Mouse, Study Mouse Come help me cope Give me strength and infuse me with hope.

I thought they were cute, Chris---not so much ANYWAY...After all the preliminaries EXCEPT the PET we had to go home and come back (actually Chris left me at home and went solo) 3 hours later. Made a looong day excruciatingly longer. The second day, the 24th, was an actual infusion day. We were told it would go like this: labs, EKG (because IPI can affect the electrical impulses in the heart-so they check before and after) Infusion. Go home for 6 hours and come back for labs and EKG's. Well that wasn't totally accurate, Chris had to have labs and EKG's at the 1,2 and 6 hour mark. Meant we had to hang around Longwood. Anyway, the infusion went well. The IPI was a pretty light pink color And he had to have a blood draw and a pee sample (guess what color that was???) every hour! Chris feels GREAT! No headache, nausea or any other side effects (I am not surprised - all the GISTERS I knew on IPI say they have never felt better!)

Chris went into Dana Farber today for a 24 hour blood draw and was heading to work after that. Next week we go Monday, Tuesday and Thursday! Quite the schedule! I'll post at the end of that cycle....unless something really exciting happens!

29 Feb 2008

Subject: FW: Chris' IPI 504 update

Chris has had 5 infusions and the latest CAT scan showed that the tumors were still growing....the question (which went unanswered) were they growing slower than they were on Sutent. The sugar uptake of the tumors seems to indicate success of the drug according to the Doctors at Dana Farber (we see Morgan but also saw the new doctor, Buryinski (?sp). Chris has little side effects, save for some muscle aches. His magnesium was off last infusion so he had to get some mag before the infusion. So we are keeping our fingers crossed for the next scan. The "line in the sand" is if the tumors grow 20% the IPI is considered to be ineffective and it will be discontinues (that's what we were told).

29 Feb 2008

From: Marina

Subject: Re: FW: Chris' IPI 504 update

I once heard Dr. Demetri mention that these names seem like car license tag numbers...

IPI504 by Infinity is a Heat Shock 90 Inhibitor. It does NOT bind to the KIT receptor, as does Gleevec, Sutent, and XL820.

Heat Shock 90 "helps" KIT protein to remain in an active three dimensional shape. If HSP90 is blocked with a drug, then KIT becomes "disorganized" in its three dimensional shape. The "tanged up" KIT is destroyed by a cell apparatus called a proteasome. So blocking HSP90 with IPI504 in theory accelerates the destruction of KIT protein. The process is not adversely affected if KIT protein is more mutated, in fact it might even be more favorable if KIT contains secondary mutations.

XL820 is a drug similar to Sutent in some ways, but it is a different molecule. It blocks VEGFR and KIT. XL820 in laboratory conditions can block some secondary mutations in KIT that are resistant to both Sutent and Gleevec. In particular, certain sites in exon 17 of KIT.

These secondary mutations are in addition to the primary mutation of exon 11 KIT. The combination of two mutations in a KIT often causes resistance.

It is believed that Gleevec itself does not cause these secondary mutations, but rather that they were pre-exisiting at low levels in the tumor load before Gleevec therapy began. After the better behaved GIST cells die from Gleevec...the rogue GIST cells with secondary mutations become the predominant population of cells in the tumor load.

28 Mar 2008

Subject: Chris update no more IPI-now OSI

Chris' CAT scan results were in today and we were due for our infusion after a 10 day break. Dr. Morgan told us that 2 of the tumors were stable but the other 3 were growing (2 are in the abdominal wall and one is on his bladder--nothing new here---the bump near his groin turned out not to be a inflamed lymph node but another GIST. So we are coming off the Heat Shock Inhibitor IPI 504 and were given a menu of kinase inhibitors. We chose OSI 930 in trial that closed today. We made it in but have to go through a 30 day wash out of the IPI so we will be on the Sutent until then (if we can get Tufts to cough up 7,000 dollars for thirty pills....).

22 Apr 2008

Subject: Chris update

SUTENT RELOADED

So LOOONG day, long story. The IPI 504 looks to have reactivated the efficacy of the Sutent. Chris has been on Sutent for 17 days and ALL THE TUMORS SHRANK!. It was the 50mg however. Doctor Morgan thought that this might happen, sometimes the IPI shocks reactivates the Sutent somehow .However, we will still be on the OSI 930 trial starting tomorrow. It is a another long day with 10 hours of blood draws at 1 hour intervals.

Today was long because we had a CAT and a PET scan as well as blood draws and EKG's, the the meeting with Dr. Morgan (and Amy the NP) as well as the study nurse. All new releases had to be signed and no we didn't run any of the marathon while we were there!

One year ago Chris was in the Brigham 3 days post op! Where does the time go?

8 Sep 2008

Update on Chris

Chris had 46 GIST's removed on Thursday, September 4th. Only 5 were seen on CAT Scan. The surgeon left one in so that he can qualify for the GDC trail at DFCI. Recovery is slow as he lost his spleen, and there was some bladder involvement ( the outside of the bladder wall had to be cut)Lastly they removed his omentum. We will be at Brigham at least 7 days total, hopefully home on Wenesday. This is his 4th GIST surgery. He has been on Gleevac, Sutent, IPI 504, and Sutent plus Rapamune. Karen

Chris started OSI-930, see OSI-930 page.

Chris then started Nilotinib (Tasigna), see Nilotinib page