Gleevec has revolutionized the treatment of GIST, however some GIST patients do not respond to it, or they eventually stop responding to it. On January 26, 2006, Sutent was approved in the United States by the Food and Drug Administration (FDA) for the treatment of patients with GIST whose disease has progressed or who are unable to tolerate treatment with Gleevec. Sutent is also approved in Canada and the United Kingdom.

Patients in these countries that fail treatment with Gleevec now have a choice between Sutent or participating in a clinical trial. Some trials, especially those of drugs that inhibit the VEGF receptors, might not allow participation by patients that have had previous VEGF inhibitors such as Sutent.

We recommend that whenever possible, patients that fail Gleevec and Sutent participate in the clinical trials process. There are many advantages to this such as:

• Access to the latest drugs
  
• A medical team that is familiar with GIST
  
• Clinical trials move GIST research forward
  
• Medical treatment and monitoring are usually better
  

Visit the Learning about clinical trials section of the National Cancer Institute (NCI) web site to learn general information about clinical trials, what they are, how they work, and other educational materials for patients and professionals.

Patients should be aware that participation in some trials will prevent their entry into some of the other trials.

NOTE: For patients that do not qualify for the AMN107 phase III trial trial, Novartis has established a compassionate use program. See details of the AMN107 (Nilotinib) compassionate use program (PDF) .

When Gleevec is not tolerated, or resistance to Gleevec develops, the following are some options:

Sutent (Sugen/SU11248)

NOTE: On January 26, 2006 Sutent was approved in the United States for GIST patients that have failed Gleevec. It is also approved in Canada, the United Kingdom and Europe. It is available in many other countries through the Treatment Use Protocol. Most of the information presented in this section still applies for GIST patients outside of the United States, Canada, the United Kingdom and Europe.

SU11248 works, trial ends 7 months early, however, the drug is still available via a treatment use protocol (see below).
 

Sutent (SU11248) is manufactured by Pfizer. It is similar to Gleevec in its mechanism of action. SUGEN’s (SU11248) lead tumor targeted compound, is a small molecule inhibitor of the receptor tyrosine kinases PDGFR, VEGFR, KIT, and FLT3.

For patients with KIT or PDGFRA mutations, the main targets of this drug are still KIT and PDGRFA, respectively. SU11248 also inhibits VEGFR. This provides an anti-angiogenic effect in addition to the primary anti-tumor effect. All tumors require the growth of new blood vessels (angiogenesis) in order for tumor growth to occur. Treatments that block the growth of these new blood vessels are called "anti-angiogenesis" treatments.

VEGF is one of the most promising of the anti-angiogenesis targets.

The Pfizer Oncology SU11248 development team has contracted with EmergingMed to offer free, confidential  clinical trial matching  & referral services to patients, families and health care professionals looking for SU11248 clinical trials.

A "treatment use" study is still available for GIST patients in many countries.

Please call the EmergingMed toll-free Clinical Trial Information Service at 1-800-620-6104 (Monday to Friday, 8:30 am to 6:00 pm eastern time) for assistance identifying and getting access to GIST clinical trials and GIST treatment use programs.  We ask that our international members use 1-877-416-6248 as a temporary number. For problems with that number use email: sutent@emeringmed.com.  Please check the site for any changes for international callers.  You can also complete a GIST questionnaire at http://www.emergingmed.com.

A "treatment use" study; A Treatment Protocol for Patients with Gastrointestinal Stromal Tumor (GIST) who May Derive Benefit from Treatment with SU011248, is still available for GIST patients with progressive disease (in many countries where Sutent has not yet been approved).

Visit the ASCO web site for presentations on SU11248 by Dr. George Demetri and Dr. Robert Maki:

Results from the (phase 1/2) Continuation Trial of SU11248 in Patients with Imatinib-resistant Gastrointestinal Stromal Tumor (GIST)

- 2005 ASCO presentation by Dr. Robert Maki:

- Fact sheet

(Results) Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of SU11248 in Patients Following Failure of Imatinib for Metastatic GIST

- 2005 ASCO presentation by Dr. George Demetri

- Fact sheet

SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GIST)
 

Follow this link for a short look at why SU11248 might work if Gleevec fails. For the original source data and a more thorough review by Dr. George Demetri, follow the link in the preceding paragraph.
 

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BAY 43-9006

BAY 43-9006 ( The approved drug name is Nexavar, the generic name is sorafenib tosylate) is a tyrosine kinase inhibitor that is being produced by Bayer Pharmaceuticals Corporation in a partnership with Onyx Pharmaceuticals Inc. BAY 43-9006 is perhaps best known as a potent inhibitor of RAF kinases. RAF is an important kinase in the MAPK pathway. BAY 43-9006 also inhibits several other kinases including KIT, VEGFR-2, VEGFR-3, PDGRF-β, FLT3, and RET.

Inhibition of KIT signaling provides a direct anti-tumor effect in most GIST tumors and inhibition of VEGF receptors and PDGFR-β provide antiangiogenesis effects (similar to Sutent). Since RAF is downstream of KIT, inhibition of RAF might also contribute an anti-tumor effect. While inhibition of PDGRF-β has been reported, inhibition of PDGFRα, an alternative target in about 5% of GISTs has NOT BEEN reported.

NOTE: On December 21, 2005, the FDA approved Nexavar for the treatment of patients with advanced renal cell carcinoma (RCC), or kidney cancer.

For further information see the ClinicalTrials.gov web site at: http://www.clinicaltrials.gov/ct/show/NCT00265798?order=10

Unofficial List of BAY 43-9006 Clinical Trial Sites

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XL820

XL820 is manufactured by Exelixis; it inhibits KIT, VEGFR2, and PDGFR-α and -β.  In preclinical studies, XL820 potently inhibited the resistance-associated activation loop mutations in KIT, and mutations in the ATP binding region of KIT including those in the juxtamembrane domain.

Phase I trials were conducted in San Antonio, Texas and in New Brunswick, New Jersey. We have been informed that phase 2 trials are open to subjects with advanced gastrointestinal stromal tumors (GIST) resistant to or intolerant of imatinib and/or sunitinib.

For information about clinical sites and investigators participating in this trial, please visit:

http://www.clinicaltrials.gov

For more information on XL820 please visit:

http://exelixis.hanechow.com/pipeline_xl820.shtml

Links to phase I and preclinical posters:

XL820 Inhibits Mutated Forms of KIT Associated With Drug Resistance

A Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of XL820 Administered Orally Daily (QD) or Twice Daily (BID) to Patients with Solid Malignancies

A Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of a Novel Spectrum Selective Kinase Inhibitor, XL820, Administered Orally to Patients with Solid Tumors
(presented at the EORTC-NCI-AACR conference)

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Imatinib and Pegylated Interferon-a 2B in Imatinib-naïve GIST Patients

This phase II trial combines Gleevec (Novartis) and Pegylated Interferon-a 2B (Schering-Plough) as initial therapy for GIST patients with metastatic GIST as well as patients with primary GIST if the primary tumor is 6cm or greater in size. This study hopes to make Gleevec more effective by combining it with Peg Interferon in hopes of preventing resistance. Other innovative details include dose adjustment based on mutational status, the option for surgery and response measurement by both RECIST and Choi criteria.

Phase II Study of Imatinib and Pegylated Interferon-a 2B in Imatinib-naïve GIST Patients (Clinicaltrials.gov)

LRG Article: Immunotherapy trial strives to improve Gleevec response

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HSP90 Inhibitors

HSP90 1) helps proteins to fold into their correct three dimensional shapes; 2) stabilizes a variety of proteins, among which many are involved in the development of cancer, and; 3) protects them from degradation. Very recent preclinical work by other researchers has shown that some of these mutant proteins, including KIT, can be effectively inhibited by interrupting the HSP90 function.

Patients should be aware that participation in a HSP90 inhibitor trial might make them ineligible for other future HSP90 inhibitor trials.

Resistant GIST may fall to new inhibitor(s) (LRG science article)

IPI-504

IPI-504 is an inhibitor of Heat Shock Protein 90 (HSP90) and is manufactured by Infinity Pharmaceuticals. HSP90 is a member of the “chaperone” family of proteins.
Phase I trials are closed. A phase III registration trial is planned. The anticipated start date is August, 2008 (anticipated clinical trial start dates often slip).

IPI-504-06 is a Phase 3, randomized, double-blind, placebo-controlled, multi-center study to evaluate the efficacy and safety of IPI-504 as compared to placebo in patients with metastatic and/or unresectable GIST following failure of at least imatinib and sunitinib.

Approximately 195 patients will be randomized using a 2:1 ratio to receive either IPI-504 (N=130) or placebo (N=65). Upon unblinding, patients receiving either IPI-504 or placebo may receive IPI-504 in the open-label portion of the study if defined inclusion criteria are met.

Early and frequent imaging timepoints are incorporated into this study to capture progression events and limit patient exposure to ineffective agents.

Interested persons should contact Infinity at 1-366-504-INFI.

More about IPI-504 and how HSP90 inhibititors might work for resistant GIST

Study Evaluating IPI-504 in Patients With Gastrointestinal Stromal Tumors (GIST) Following Failure of at Least Imatinib and Sunitinib (Clinicaltrials.gov)
 
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AUY922

AUY922 is an inhibitor of Heat Shock Protein 90 (HSP90) and is manufactured by Novartis. It is a third-generation HSP90 inhibitor. Phase I trials have started in Boston, St. Louis, Las Vegas and Los Angeles. The phase I portion is open to all advanced solid tumors including GIST. The trial is expected to eventually advance into a phase II trial for breast cancer patients.

Phase I-II Study to Determine the Maximum Tolerated Dose (MTD) of AUY922 in Advanced Solid Malignancies, and Efficacy in HER2+ or ER+ Locally Advanced or Metastatic Breast Cancer Patients

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STA-9090

STA-9090 is a third-generation Hsp90 inhibitor manufactured by Synta Pharmaceuticals. Based on pre-clinical data, it appears to be 10 to 100 times as potent than the geldanamycin family of Hsp90 inhibitors (such as 17AAG). Because of the increased potency, it appears to be able to inhibit a broader range of Hsp90 client proteins.
This phase I trial will give STA-9090 twice a week for 3 weeks followed by a one week drug holiday. The current phase I trial is open in Boston and Detroit. A future phase I trial giving STA-9090 once a week for 3 weeks with a one week drug holiday is planned.

Snyta initiates phase I clinical trial of STA-9090, a novel Hsp90 inhibitor (Synta press release).

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SNX-5422

SNX-5422 is an oral third-generation Hsp90 inhibitor and is manufactured by Serenex, Inc. Phase I trials are underway in Scottsdale, AZ and in Nashville, TN. Patients with refractory (advanced) solid tumors, including GIST, are eligible.

Safety and Pharmacology of SNX-5422 Mesylate in Subjects with Refractory Solid Tumor Malignancies (Clinicaltrials.gov)

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BIIB021(CNF-2024)

BIIB021 is an oral third-generation Hsp90 inhibitor and is manufactured by Biogen Idec. Phase II trials have started at Memorial Sloan-Kettering Cancer Center (New York, NY). A second site is pending activation at the Mayo Clinic in Rochester, Minnesota. The phase II trial is specifically for GIST.

Phase I trials are underway in Scottsdale, AZ and in San Antonio, TX.

An Open-Label, 18FDG-PET Pharmacodynamic Assessment of the Effect of BIIB021 in Subjects With Gastrointestinal Stromal Tumors (GIST) Refractory to, Intolerant of, or Not a Candidate for Imatinib and Sunitinib Treatment (Phase II ClinicalTrials.gov)

Study of Oral CNF2024 in Advanced Solid Tumors (Phase I ClinicalTrials.gov)

 

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Perifosine (KRX-0401) is made by KERYX Biopharmaceuticals. Perifosine is an oral drug that inhibits the AKT protein. AKT is an anti-apoptosis protein. It is speculated that inhibition of AKT might enhance therapy.  Apoptosis is a form of controlled cell death, a type of cellular suicide where the cell issues its own death warrant. A phase II trial is now seeking to enroll GIST patients at MD Anderson Cancer Center in Houston, Texas.
University of Texas - MD Anderson Cancer Center
Ph: 713-792-3626; 800-392-1611

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RAD001 and Gleevec

Both RAD001 and Gleevec are manufactured by Novartis. RAD001 is an mTOR inhibitor that may improve the effectiveness of Gleevec. Phase I/II trials are underway. It has long been speculated that treatment of GIST (and most cancers in general) will eventually be comprised of a "cocktail mixture" of drugs. This is the first such combination to come to clinical trials for GIST.

mTOR is a downstream target in the AKT pathway. AKT is a survival pathway that is activated by KIT and many other receptors. It is hoped that inhibition of KIT and mTOR at the same time will result in increased effectiveness over Gleevec alone.

Note: All, or almost all of the current sites for this trial are in Germany.

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AZD2171

This drug is manufactured by AstraZeneca. It is a tyrosine kinase inhibitor of all of the VEGF receptors (VEGFR1, VEGFR2 and VEGFR3), as well as KIT and (less potently) PDGFRA and PDGFRB.

The phase II clinical trial will evaluate the biological activity of AZD2171 as Measured by FDG-PET Response, in Patients With Metastatic GIST resistant or intolerant to imatinib (Gleevec). Trial sites are in London, United Kingdom (recruiting) and Manchester, United Kingdom (not yet recruiting). Contact AstraZeneca Cancer Support Network 1-866-992-9276 information.center@astrazeneca.com for more information.

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OSI-930

This drug is manufactured by OSI pharmaceuticals. It is a potent inhibitor of the VEGF receptors and KIT. A phase I trial is open at Dana-Farber Cancer Center (Boston, MA.) and activation is pending in London, United Kingdom ((Michelle Scurr – PI, John DeBono, Stan Kay) and the University of Colorado (Denver, CO.). OSI-930 has previously completed phase I testing in healthy volunteers.

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MP-470

This drug is manufactured by SuperGen Pharmaceuticals. A phase I trial opened in July of 2007. MP-470 is a tyrosine kinase inhibitor of KIT (including forms of mutated KIT), PDGFR, c-Met, c-RET and AXL. MP-470 may inhibit some of the secondary mutations that cause resistance to Gleevec. In addition, AXL may be activated in some GISTs and inhibition of AXL may be beneficial to some GIST patients.

SuperGen press release

This phase I trial is open at Scottsdale Healthcare in Scottsdale, Arizona and at South Texas Accelerated Research Therapeutics (START) in San Antonio, Texas.

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Gleevec + Sutent

This phase I study will study the side effects the best dose for the combination of Gleevec (Novartis) and Sutent (Pfizer). This study is open at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

Imatinib Mesylate and Sunitinib in Treating Patients with GIST (Clinicaltrials.gov)

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BMS-354825

This drug is manufactured by Bristol-Myers Squibb. It is a tyrosine kinase inhibitor of Src, abl, KIT, and PDGFR. Phase II trials are open as front-line therapy (for patients that have never taken Glivec) in Switzerland.

NOTE: The phase I trial is now closed.

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PTK787

PTK787/ZK22584 is a joint collaboration between Novartis and Schering AG. It is a multi-tyrosine kinase inhibitor and inhibits all three VEGF receptors as well as KIT and PDGFR. The investigators for this phase II trial are Heikki Joensuu, M.D., from Helsinki, Finland; Paolo G. Casali, M.D., from Milan, Italy; and Filippo DeBraud, M.D., Milan, Italy.

PTK787/ZK222584 in the Treatment of Metastatic Gastrointestinal Stromal Tumors Resistant to Imatinib

Note: This trial is now listed as closed in the ClinicalTrials.gov database (11/27/07)

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PI3K Inhibitors

PI3K proteins have been identified in crucial signaling paths of multiple cancers. They can become over-active via a variety of mechanisms including upstream signaling. PI3Ks have recently been identified as active downstream signal points in the c-KIT pathway in GIST. A number of PI3K inhibitors have now entered phase I clinical trials. The PI3K inhibitor trials that we are aware of are listed below: Note: To see the listing in Clinicaltrials.gov, click the NCT#.

BEZ235: This oral drug from Novartis targets Class I PI3Ks and mTOR. It is one of two PI3K inhibitors from Novartis currently in phase I. This is a combined Phase I/I trial, with an accrual goal of 80 patients. The trial design will admit solid tumors in Phase I. However, Phase II is limited to breast cancer patients. It is currently available at The Nevada Cancer Institute, Las Vegas, Nev. and at Sarah Cannon Research Institute in Nashville, Tenn. NCT00620594

SF1126: Semafore Pharmaceuticals, a small company in Indianapolis, Ind. has developed a broad spectrum PI3K inhibitor based on the lab drug LY294002. SF1126 is a Prodrug that inhibits Class IA PI3Ks and DNA-PK and mTOR. A Prodrug is given in one form and converted into a different, active form by metabolic action in the body. Semafore has designed SF1126 to have an affinity for the vascular forming areas of tumors. This design is intended to concentrate the effect of a broad spectrum inhibitor within the tumor. Of the six PI3K inhibitors listed here, SF1126 is the only one administered intravenously. Current trial sites include Arizona Cancer Center, Tucson, Ariz. and Indiana University, Indianapolis, Ind. Clinical trials at Tgen

XL147: A second PI3K inhibitor from Exelixis. XL147 is a more selective PI3K inhibitor. It inhibits Class IA and IB PI3Ks. It is also administered orally. Trial sites currently include Dana Farber (under Jeffrey Shapiro, MD), Mary Crowley Medical Research Center, Dallas, T.X. and Hospital Universitario Vall d’Hebron in Barcelona, Spain. NCT00486135

XL 765: Exelixis is a drug development company based in San Francisco, Calif.. Exelixis has 13 drugs in Phase II or earlier stages of development. XL765 is one of two oral PI3K targeted drugs in development. XL765 inhibits Class 1A and 1B PI3Ks as well as DNA-PK and mTOR and is administered orally. Trial sites currently include Karmanos in Detroit, Mich., South Texas Accelerated Research therapeutics (START) in San Antonio, T.X. and Hospital Universitario Vall d’Hebron in Barcelona, Spain. NCT00485719

BGT226: This is a second PI3K inhibitor from Novartis, which inhibits Class I PI3Ks. This trial is classified as a combined Phase I/II. Initially patients with solid tumors will be accepted, but the phase II expansion part will enroll only advanced breast cancer patients and Cowden syndrome patients. Cowden syndrome is an inherited disease in which the PTEN gene is defective leaving the survival signal from the PI3K pathway un-attenuated. The only current trial site is Nevada Cancer Institute, Las Vegas, Nev. NCT00600275

GDC-0941: This drug was initially developed by Piramed in the United Kingdom. GDC-0941 selectivity has not yet been published, so this information is unknown. We have been told informally that this oral drug inhibits multiple class I PI3K’s. It is currently in trial at Dana Farber in Boston, Mass. under George Demetri, MD. Translational Pharmacology and Early Therapeutic Trials at Dana-Farber and TGEN Clinical Trials

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AMN107 - Phase III - This trial is no longer accruing patients

AMN107 is manufactured by Novartis. AMN107 is a newer and possibly more potent tyrosine kinase inhibitor. Like Gleevec, it also inhibits KIT, PDGFRA, and BCR/ABL. Phase III trials began in late April of 2007 and as of 4/7/08 have reached accrual goals.

The phase III trial is for patients that are resistant (or intolerant) to both Gleevec and Sutent. Patients were randomized to receive either AMN107 or best supportive care. For every patient that received best supportive care, two patients received AMN107. Best supportive care allows the treating physician to continue administering Gleevec, Sutent, or other supporting care. Patients receiving best supportive care will be allowed to cross over to receive AMN107 at the time of progression. Patients receiving AMN107 will be given 400 mg twice a day (800 mg total).

Efficacy and Safety of AMN107 Compared With Current Treatment Options in Patients With GIST Who Have Failed Both Imatinib and Sunitinib (clinicaltrials.gov)

Unofficial List of AMN107 Clinical Trial Sites

NOTE: For patients that do not qualify for the phase III trial, Novartis has established a compassionate use program. See details of the AMN107 (Nilotinib) compassionate use program (PDF) .

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CCI-779

CCI-779 (Temsirolimus)is a mTOR inhibitor manufactured by Wyeth Pharmaceuticals. The Phase II trial testing CCI-779 in GISTs and other soft tissue sarcomas is now closed. Results have not yet been reported.

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Sarcoma Trials that Allow GIST patients

FR901228

This is a phase II trial for Sarcoma patients, including GIST patients, with metastatic or unresectable disease. FR901228 belongs to a new class of chemotherapy drugs called histone deacetylase inhibitors (HDAC inhibitors). This is a class of drugs that works at a higher level within the cell-acting on the genome, which is like the master control room for all of the genes in a cell.

Patients must be at least 18 and have a Performance status of ECOG 0-2 or Karnofsky 60-100%. Projected accrual is 18 to 36 patients.

The principal investigator is Paul D. Savage, MD, Comprehensive Cancer Center of Wake Forest University.

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Doxorubicin + Flavopiridol

This is a phase I trial to determine the maximum tolerated dose of the combination of doxorubicin (a traditional cytotoxic chemotherapy) with flavopiridol (an inhibitor of the cell cycle and an inhibitor of transcription). This trial is for sarcoma patients, including GIST patients, that are 18 years old or older. Patients must have a Performance status of ECOG 0-2 or Karnofsky 60-100%. Projected accrual is 3 to 36 patients.

The trial is being conducted at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, N.Y. U.S.A. The principal investigator is Dr. David D’Adamo.
 
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Trial Phases

The following definitions of different phases of clinical trials are provided by the NCI:

Phase I trials are the first step in testing a new approach in humans. In these studies, researchers evaluate what dose is safe, how a new agent should be given (by mouth, injected into a vein, or injected into the muscle), and how often. Researchers watch closely for any harmful side effects. Phase I trials usually enroll a small number of patients and take place at only a few locations. The patients are divided into smaller groups, called cohorts. Each cohort is treated with an increased dose of the new therapy or technique. The highest dose with an acceptable level of side effects is determined to be appropriate for further testing.

Phase II trials study the safety and effectiveness of an agent or intervention, and evaluate how it affects the human body. Phase II studies usually focus on a particular type of cancer, and include fewer than 100 patients.

Phase III trials compare a new agent or intervention (or new use of a standard one) with the current standard therapy. Participants are randomly assigned to the standard group or the new group, usually by computer. This method, called randomization, helps to avoid bias and ensures that human choices or other factors do not affect the study’s results. In most cases, studies move into phase III testing only after they have shown promise in phases I and II. Phase III trials may include hundreds of people across the country.

Phase IV trials are conducted to further evaluate the long-term safety and effectiveness of a treatment. They usually take place after the treatment has been approved for standard use. Several hundred to several thousand people may take part in a phase IV study. These studies are less common than phase I, II, or III trials.

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1. Ronald P. Dematteo, MD, Michael C. Heinrich, MD, Wa'El M. El-Rifai, MD and George Demetri, MD. Clinical Management of Gastrointestinal Stromal Tumors: Before and After STI-571