April 2009 Clinical Trials Update

United States

Bevacizumab plus Imatinib Phase 3:

This trial continues at over 200 regional cancer centers across the United States. Recently added were major GIST trial sites including Fox Chase Cancer Center, Oregon Health & Science University and the University of Chicago. This first line trial is for patients recently diagnosed with unresectable GIST. The trial exclusion criteria include “No prior imatinib mesylate, Bevacizumab, or other agents targeting KIT, vascular endothelial growth factor (VEGF), VEGF receptor, or platelet-derived growth factor receptor (PDGFR) for advanced disease. These agents may have been used in the adjuvant setting provided no recurrence for ≥ 12 months after completion of therapy.” Bevacizumab is an anti-VEGF agent intended to reduce the ability of the tumor to grow new blood vessels. The trial is intended to answer the question of whether the addition of Bevacizumab to Imatinib will lead to longer progression-free survival. Half the patients will receive Bevacizumab, which is administered intravenously once every three weeks. All patients will receive Imatinib.

US and International

Sunitinib or Imatinib Phase 3:

New sites have opened in Michigan, Nevada, Ohio, Wisconsin, Germany, the United Kingdom and the Republic of Korea. This trial is for patients having progression while on Imatinib at 400 mg. Patients are randomly assigned to receive either 800 mg Imatinib or 37.5 mg Sunitinib daily.

International

IPI-504 Phase 3:

This trial is for patients failing both Imatinib and Sunitinib. It now has multiple new sites in Australia, Belgium, France, Germany, Sweden and the Republic of Korea. IPI- 504 is a HSP-90 inhibitor administered intravenously. Patients are randomized to receive either IPI-504 or a placebo.

Nilotinib Versus Imatinib Phase 3:

This trial for first line patients is now recruiting at two sites in Canada, and one each in Austria and Spain. In the US 19 sites, 11 states are listed in clinicaltrials. gov along with detailed contact information. All are listed as ‘Not yet recruiting’. That could change quickly.

This phase 3 trial will test whether nilotinib (also known as AMN107 and Tasigna) given as initial treatment for metastatic GIST is better than the current initial therapy, imatinib (Gleevec). Nilotinib is a more powerful inhibitor of KIT and PDGFRA than Gleevec. Lab tests also show it is more effective than imatinib against both wild-type GIST and the exon 13 mutant GIST. Nilotinib also showed higher concentrations levels inside GIST tumor cells in the lab.

Patients entering the trial will be randomized to receive either imatinib or nilotinib. Estimated enrollment for the trial will be 736 patients.

Inclusion Criteria include:

1. Histologically confirmed diagnosis of GIST which is unresectable and/or metastatic and either:
● No prior therapy with imatinib or any investigational therapies (e.g. sunitinib). Note: newly diagnosed patients may have received up to 14 days imatinib treatment for disease management while awaiting study start.
● Recurrent GIST after stopping adjuvant treatment with imatinib and no subsequent treatment with any other investigational therapies (for example sunitinib).

2. At least one measurable site of disease on CT/MRI scan

3. Performance status ≤ 2 (capable of self-care but unable to carry out any work)

4. Normal organ, electrolyte and marrow function

Exclusion Criteria include:

1. Prior treatment with nilotinib or any other drug in this class or other targeted therapy agents with the exception of adjuvant imatinib.

2. Disease progression during adjuvant therapy with imatinib

3. Prior or concomitant malignancy that is currently clinically significant or currently requires active intervention.

4. Impaired cardiac function Other protocol-defined inclusion/ exclusion criteria may apply

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