December 2006 clinical trial updates
By Jim Hughes
Member of LRG Science Team
XL820 (Exelixis)
This drug inhibits c-Kit, PDGFRb and VEGFR. It is similar to the OSI-930 drug below. Data presented by Exelixis in a poster at EORTC in October 2006 showed results for 23 evaluable patients in phase I, including one GIST patient. The GIST patient had stable disease after 3.5 months on XL820. Exelixis has a phase I trial listed in the clinicaltriials. gov database to assess “the safety and tolerability of XL820 when given orally.” The listing says it is not open but we checked with one of the sites (Texas) and understand that it is now open. The sites are: The Cancer Institute of New Jersey, New Brunswick, N.J.- Mark Stein, M.D., and the Cancer Therapy and Research Center, San Antonio, Texas- Kyriakos P. Papadopoulos, M.D. This trial is open to patients with solid tumors failing standard therapy.
AZD2171 (AstraZeneca International)
This investigational drug is in early trials for a number of cancers. It inhibits KIT and VEGFR-1, VEGFR-2 and VEGFR-3. This phase II trial is being sponsored by AstraZeneca in the United Kingdom. The clinicaltrials.gov website lists a site recruiting in London. GIST patients progressing on Gleevec are given AZD2171 45mg daily without Gleevec. Biologic tumor activity is evaluated by FDG/PET response at eight days and four weeks.
OSI-930
OSI Pharmaceuticals has begun a phase I trial of the compound OSI-930 at two locations in the United States and one in Europe. The trial is for patients with advanced solid tumors, but will admit GIST patients. Locations include:
• Dana-Farber Cancer Institute- Boston, Mass. (Dr. George Demetri, Principal Investigator)
• Colorado University- Denver, Colo.
• Royal Marsden Hospital- London, UK (Dr. Michelle Scurr, Principal Investigator)
OSI-930 is a new small molecule tyrosine kinase inhibitor. It inhibits c-Kit, VEGFR and PDGFRb. The trial began in August. Up to 60 patients are expected to be accrued.
Sutent
In the United States, Canada, the United Kingdom and the European Union countries Sutent is now approved for patients failing Gleevec or those who cannot tolerate Gleevec. In addition, Sutent continues to be available to patients via the “Treatment Use Protocol,” which is “four weeks on/two weeks off” (50 mg). There are many sites open throughout the world. Site information changes frequently; for the most current information, contact EmergingMed at 1-877- 416-6248 (outside the United States) or at 1-800-620-6104 (inside the United States). If international patients have problems with the listed number, use email at: sutent@emergingmed.com.
In September Pfizer posted a new phase III trial on the NIH website. This study will compare 37.5mg daily of Sutent with 800mg daily of Gleevec for patients progressing on 400mg of Gleevec. Anticipated enrollment is 212. Site information has not yet been announced. According to the listing this trial is not yet recruiting and is scheduled to start November 2006. It had not yet started when we last checked on November 17.
AMN107 + Gleevec
The combination of AMN107 and Gleevec may have a broad spectrum of activity against primary and secondary mutations in GIST. The generic name for AMN107 is nilotinib and our understanding is that the brand name will be Tasigna. The phase I trial is now closed at all sites. A phase III trial is planned. In the meanwhile, access to AMN107 is available through a compassionate use process.
IPI-504
The IPI-504 phase I trial is open for patients resistant to prior therapies and is accruing patients at Dana-Farber Cancer Institute. It undergoes fairly frequent start/stop periods as cohorts accrue.
IPI-504 is an inhibitor of Heat Shock Protein 90 (HSP90) and has been the subject of articles in the November 2005 and January 2006 editions of the Life Raft Group newsletter. This is an intravenous drug which is administered twice a week for two weeks followed by a one week off period. HSP-90 is administered without Gleevec. We understand that a second schedule of treatment without a one week off period is beginning.
Genasense + Gleevec
A phase II trial testing the combination of Genasense plus Gleevec in patients with Gleevec-resistant GIST recently opened.
Genasense (Genta Inc.) is an antisense drug that inhibits bcl-2. Bcl-2 is a protein involved in cellular survival. This drug is administered intravenously. It is hoped that Genasense may help Gleevec kill tumor cells by making them more sensitive to Gleevec.
This trial is currently open only at M.D. Anderson. Several other trial sites are planned including: Dana-Farber Cancer Institute, Boston, Mass.; University of Michigan Comprehensive Cancer Center, Ann Arbor, Mich.; Mayo Clinic Cancer Center, Rochester, Minn.; and Memorial Sloan-Kettering Cancer Center, New York, N.Y.
Perifosine (Keryx Biopharmaceuticals)
Keryx Biopharmaceuticals has perifosine (KRX-0401) is an oral drug that inhibits the AKT protein. AKT is an antiapoptosis 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.
Perifosine + Gleevec Phase II
A phase II trial, which combines Perifosine with Gleevec, is open at M.D. Anderson Cancer Center, Houston, Texas; Oncology Specialists, Park Ridge, Ill.; and under Dr. Sant Chawla at the Cancer Center at Century City in Los Angeles, Calif. This trial is accruing Gleevec-resistant GIST patients.
Perifosine + Sutent Phase I
This phase I trial is primarily for renal cell cancer and GIST patients. It has two parts. The first part will determine the maximum tolerable dose (MTD) in a four week “on,” two week “off,” six week cycle. The second part of the phase I trial will use the MTD to determine if a larger group of patients can remain on the drug for two six week cycles. The inclusion criteria includes the following caution:
“The physician must believe that the patient’s course and the growth rate of the tumor are such that the patient would feel comfortable continuing treatment for 12 weeks even if there is a transient period of modest tumor growth during the first weeks following the initiation of perifosine and sunitinib malate treatment.”
It is not stated that tumor growth or failure on a current treatment is a necessary condition for entry into this trial. Patients who have received prior Sorafinib or Sutent are eligible for this trial.
Sites currently open include: Tower Hematology and Oncology, Beverly Hills, Calif., and Oncology Specialists, Park Ridge, Ill.
RAD001 + Gleevec
RAD001 is an mTOR inhibitor. We have been informally advised that the RAD001 plus Gleevec phase II trial for GIST patients has completed accrual. We are awaiting word from Novartis on the outcome of the trial and on future plans for this drug. RAD001 is available outside the United States as Certican® for heart and kidney transplant patients. A similar mTOR inhibitor from Wyeth called Rapamune ® is available in the United States for kidney transplant patients. We have received reports from GIST patients who have been prescribed Rapamune “off-label” with Gleevec.
PTK787/ZK222584
This is a phase II study being conducted at the University of Helsinki in Finland and in Milan, Italy. This trial is for patients progressing on Gleevec. PTK787 is administered without Gleevec. A seven day washout period is required.
PTK787/ ZK222584 was synthesized and developed by Novartis AG and Schering AG. It is a tyrosine kinase inhibitor and inhibits VEGF receptors as well as KIT and PDGFRB. See the July 2006 Life Raft Group newsletter for an article about this trial.
BMS-354825 (Dasatinib)
BMS-354825 is a tyrosine kinase inhibitor of Src, abl, KIT, and PDGFR.
Dasatinib is available in a phase I trial at Dana-Farber and Glasgow, Scotland. In June the Karmanos Cancer Center in Detroit, Mich. also began recruiting patients. Future plans include a SARC phase II trial. We will update trial sites and the scope of the trial as this information becomes available.
This trial is for patients with progression on Gleevec. The BMS drug is administered without Gleevec.
BAY 43-9006 (known as Sorafenib and by trade name Nexavar)
This drug was approved in December 2005 for kidney cancer. BAY 43-9006 inhibits several kinases including KIT, VEGFR-2, VEGFR-3, PDGRF-β, RAF, FLT3, and RET.
The phase II trial for BAY 43-9006 is open and recruiting patients. Three trial sites are open in Illinois and one in New York:
• University of Chicago- Chicago, Ill.
• Decatur Memorial Hospital- Decatur, Ill.
• Oncology/Hematology Associates of Central Illinois- Peoria, Ill.
• Memorial Sloan-Kettering Cancer Center-New York, N.Y.
Several sites are also pending.
This trial is for patients progressing on Gleevec. BAY 43- 9006 s administered without Gleevec. A fourteen day washout period is required before trial drug start.
Sarcoma trials that also allow GIST patients:
The last two trials listed are sarcoma trials that allow GIST patients. There are several ways to attack GIST tumor cells with drugs. The most common method is to inhibit KIT and/or PDGFRA signaling. The protein is still present; it is just inhibited by the drug. This is the method used by Gleevec, Sutent and most of the other new inhibitors being developed (dasatinib, AMN107, etc). Another way to target GIST is to destroy the KIT or PDGFRA protein. IPI- 504 targets GIST tumors in this manner.
A third way to target GIST is to try to prevent (or reduce) the formation of KIT or PDGFRA proteins. The following two trials take the approach of inhibiting the formation of a large number of proteins including KIT and PDGFRA.
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 percent. Projected accrual is 3 to 36 patients.
The trial is being conducted at Memorial Sloan-Kettering Cancer Center in New York, N.Y.
FR901228
This is a phase II trial for sarcoma patients, including GIST patients, with metastatic or unresectable disease. FR901228 (depsipeptide) 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 percent. Projected accrual is 18 to 36 patients.
Trial locations include: Phoenix, Ariz.; Oakland, Calif.; Rome, Ga.; Decatur, Ill.; Louisville, Ky.; Columbus, Ohio; Greenville, S.C.; Spartanburg, S.C.; Danville, Va.; Burlington, N.C.: Greenville, N.C.; Goldsboro, N.C.; Winston Salem, N.C.; High Point, N.C.; Elkin, N.C.; Goldsboro, N.C.
