Novel compounds improve the impact of anti-cancer therapy

July 14, 2003

Washington, D.C. - Two new therapies for metastatic cancer are showing significant clinical activity, according to research presented today at the 94th Annual Meeting of the American Association for Cancer Research (AACR). The studies examined the potential anti-tumor benefits of a combination therapy for colorectal cancer and a multi-targeted oral therapy for imatinib-resistant gastrointestinal stromal tumors.

"We are encouraged by the favorable results from such novel therapy methods," said Dr. Judah Folkman, of the Children's Hospital and Harvard Medical School. "The AvastinTM clinical trial establishes proof of principle and validates the concept that inhibiting angiogenesis can slow or stop tumor growth and help patients live longer."

A Phase III Trial Bevacizumab (Avastin, a Monoclonal Antibody to Vascular Endothelial Growth Factor) in Combination with Bolus IFL (Irinotecan, 5-Fluororacil, Leucovorin) as First-line Therapy in Subjects with Metastatic CRC: Efficacy Results in Arm 3 (5-FU/LV/BV) and Other Exploratory Analyses
The addition of the anti-angiogenesis agent bevacizumab (Avastin) to first-line combination chemotherapy with two commonly used treatments for advanced colorectal cancer is safe and effective, according to a study presented by researchers at Duke Comprehensive Cancer Center. Bevacizumab is a recombinant, humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF). The monoclonal antibody was given in addition to the standard combination chemotherapy regimen known as "IFL" (irinotecan, 5-fluorouracil, leucovorin).

"We feel confident that this novel combination will be beneficial for patients with colorectal cancer," said Dr. Herbert Hurwitz, assistant professor of medicine, Duke Comprehensive Cancer Center, and lead investigator of the study. "Continued research is needed to determine whether the benefits of bevacizumab seen in this study will apply to other cancers, and when bevacizumab is combined with other chemotherapy regimens."

The three-arm, phase III, double-blinded trial was designed to investigate the efficacy and safety of bevacizumab (BV) in combination with either 5-FU and leucovorin, being presented today at the AACR meeting, or bolus-IFL versus bolus-IFL with placebo. Results were positive with the addition of bevacizumab, demonstrating increased median survival, progression-free survival, response rate and duration of response as compared with standard chemotherapy alone. The three study arms were: IFL/placebo (101 patients), IFL/BV (103 patients), or FU/LV/BV (110 patients).

After approximately 110 patients were enrolled in the trial, enrollment in arm three was discontinued when members of the independent data monitoring committee determined the safety of IFL/BV was acceptable. Results of the study revealed that the IFL/BV combination therapy was most effective, with a median survival of 20.5 months (versus 18.3 months for FU/LV/BV and 15.1 for IFL/placebo). The combination also resulted in the longest progression-free survival at 10.9 months (versus 8.8 months and 6.7 months IFL/placebo), the highest objective response rate (confirmed and partial responses) at 45.6 percent (versus 40 percent and 36.6 percent) and the best duration of response, at 11.7 months (versus 8.5 months and 7.2 months). The combination of FU/LV/BV was associated with expected chemotherapy related side effects. The most notable bevacizumab related side effect was hypertension, which was easily managed with routine outpatient blood pressure medications.

Results of the addition of bevacizumab to bolus-IFL chemotherapy, which were presented at ASCO 2003, concluded that the combination treatment resulted in increased survival, progression-free survival, response rate and duration as compared to bolus-IFL chemotherapy alone.

Biological activity of the multi-targeted tyrosine kinase inhibitor SU11248 in patients with malignant gastrointestinal stromal tumor (GIST) refractory to imatinib mesylate
The use of SU11248, an oral multi-targeted kinase inhibitor, is effective for many patients with advanced gastrointestinal stromal tumors (GISTs) once the tumors develop resistance to the standard therapy, known as imatinib (Gleevec®), according to a study by researchers at the Dana-Farber Cancer Institute, Boston.

"While imatinib induces objective responses and can control GIST in the majority of patients, the incidence of resistance to imatinib increases over time, and alternative strategies to control this life-threatening disease are needed," according to George Demetri, MD, Associate Professor of Medicine at Harvard Medical School and the Dana Faber Cancer Institute, and lead investigator of the study.

Imatinib has captivated the scientific and medical communities by the impressive ability of this oral drug to shrink and control even the most massive abdominal tumors of GIST patients by inhibiting a specific uncontrolled enzyme known as a kinase.

"SU11248 was developed to target multiple signaling "switches" called kinases within cells, and our data indicate that this agent can molecularly target the cancer cells of GIST differently than imatinib, thereby allowing these resistant patients to be successfully treated."

SU11248 not only targets the tumor cells themselves, but it is also a very powerful anti-angiogenesis agent, blocking the growth of blood vessels that might otherwise feed the tumors.

This phase I study was designed initially to test the best way in which to administer SU11248, as well as to assess the differences in biological activity between SU11248 and imatinib in GIST patients. Groups of patients were treated at starting doses of either 25, 50, or 75 mg per day for 2 to 4 weeks, followed by a 14-day rest period. The molecular mechanisms by which SU11248 affects the tumor cells have been carefully studied and these show important differences in the inhibition of uncontrolled signaling molecules such as the KIT receptor tyrosine kinase and related targets in comparison with the standard therapy, imatinib.

In data presented at this meeting updating the previous summaries of this work, Dr. Demetri reported on the ongoing results from this active trial. Forty-five patients with GIST have been treated with SU11248, with evaluable data from biopsies and correlative imaging studies at early time points for 39 patients. Of these patients, the majority (72 percent) exhibited reductions in tumor-associated metabolic activity by functional imaging using PET scanning while taking the SU11248. After one week of dosing, routine pathology examinations (looking at a tumor biopsy sample under a standard microscope) failed to detect these biological changes; however, by using a more sensitive marker to study the tumors before and after the SU11248 treatment, the researchers were able to see clearly the impact of this therapy: the rate of tumor cell growth (as measured by the Ki-67 proliferation index) decreased in 12 of 17 patients (71 percent) with matched tumor biopsy specimens.

These results have already translated into clinical anti-tumor activity in these imatinib-resistant GIST patients for whom no other therapy existed before. The development of SU11248 as a potential treatment for imatinib-resistant GIST "is an exciting example of the new world of targeted therapy," Demetri remarks. "We can analyze cancer cells to identify mutations, then screen drugs in the laboratory that target those specific mutations. The resulting therapies should be more effective and less toxic than traditional chemotherapy, which attacks normal cells as well as cancerous ones."
Founded in 1907, the American Association for Cancer Research (AACR) is a professional society of more than 20,000 laboratory and clinical scientists engaged in cancer research in the United States and more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication and advocacy. Its principal activities include the publication of five major peer-reviewed scientific journals (Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention). AACR's annual meeting attracts more than 12,000 participants who share new and significant discoveries in the cancer field, and the AACR's specialty meetings throughout the year focus on all the important areas of basic, translational and clinical cancer research. Contact: Warren Froelich/AACR

Aimee Frank/Spectrum Science

In Washington, DC: (7/11-7/14)
Washington Convention Center

American Association for Cancer Research

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