Kosan Presents Clinical Results Showing Anti-Tumor Activity of Hsp90 Inhibitors KOS-953 and KOS-1022 at ASCO
Monday June 5, 7:30 am ET
HAYWARD, Calif., June 5 /PRNewswire-FirstCall/ -- Kosan Biosciences Incorporated (Nasdaq: KOSN - News) presented results from three Phase I trials of its two heat shock protein 90 (Hsp90) inhibitors, KOS-953 and KOS-1022, at the 42nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Atlanta, Georgia. Results from these trials demonstrated encouraging clinical activity and safety profiles for both compounds.
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"Kosan's Hsp90 inhibitors have each shown the ability to enhance anti-tumor activity in combination with standard chemotherapies based on their unique mechanism of action," said Robert G. Johnson, Jr., M.D., Ph.D., Kosan's Chief Executive Officer. "We are excited by KOS-953's demonstrated clinical activity in patients with resistant HER2-positive breast cancer and relapsed refractory multiple myeloma. These data suggest that our compounds can re-induce anti-tumor activity after relapse or synergize initial activity of existing cancer therapies. We are also encouraged by the promising activity of KOS-1022, our second-generation Hsp90 inhibitor. We expect to see a significant maturation of our cancer clinical programs in the coming months."
KOS-953: Interim Data from Phase I/II Combination Trial with Trastuzumab (Herceptin®)
KOS-953 is an Hsp90 inhibitor that has demonstrated the potential to disrupt the activity of multiple oncogenes and cell signaling pathways implicated in tumor growth, including HER2, a key pathway in breast cancer. In the Phase I portion of the trial, KOS-953 was administered in combination with trastuzumab (Herceptin) to 25 patients with refractory solid tumors, 17 of whom had HER2-positive metastatic breast cancer. The dosing schedule was a weekly intravenous infusion (dose escalating from 225-450 mg/m2). Out of the 17 patients with HER2-positive metastatic breast cancer:
-- One patient experienced a partial response (59 percent decrease in lung
metastases).
-- Four patients experienced tumor shrinkage (20 percent or greater),
including two patients with complete responses by World Health
Organization (WHO) criteria.
-- All patients who experienced tumor regression had radiographically
documented tumor progression on a Herceptin regimen immediately prior
to entering the study.
In addition, four patients in the Phase I portion of the study experienced stable disease (four months or longer).
Adverse events were generally mild. The only dose-limiting toxicity at the highest dose of 450 mg/m2 was a dose delay in a patient with Grade 2 thrombocytopenia. There was no drug-drug interaction between KOS-953 and Herceptin. Induction of Hsp70 (an indicator of Hsp90 inhibition) was observed at all dose levels.
The data were presented in an oral session on Saturday, June 3, by Shanu Modi, M.D., of Memorial Sloan-Kettering Cancer Center.
"We are excited by the demonstration of anti-tumor activity of KOS-953 in metastatic breast cancer patients whose disease is resistant to treatment with Herceptin," said Dr. Modi. "These encouraging results indicate that use of an Hsp90 inhibitor in combination with Herceptin may have the potential to reinstitute or extend the efficacy of Herceptin, without adding significant toxicity, and could represent a meaningful benefit to breast cancer patients."
The Phase II portion of this KOS-953 clinical trial was initiated in early 2006 with a dosing regimen of 450 mg/m2 weekly along with the standard dose of Herceptin to patients with HER2-positive metastatic breast cancer. Preliminary results presented by Dr. Modi indicated that out of the first five patients enrolled in the Phase II portion, there was one unconfirmed partial response and one unconfirmed minor response. Both patients are still on study. Kosan expects to announce further results from this Phase II clinical trial near the end of 2006.
KOS-953: Interim Results of Phase Ib Combination Trial with Bortezomib (Velcade®)
The primary objective of the Phase Ib dose-escalating clinical trial of KOS-953, administered in combination with bortezomib (Velcade) in patients with relapsed refractory multiple myeloma, was to define the recommended Phase II dose. Of 21 evaluable patients who received increasing doses of both KOS-953 and Velcade, anti-myeloma activity was observed in:
-- Two of six patients refractory to Velcade (33 percent; one partial
response and one minor response); these patients either progressed on
Velcade immediately prior to study or had never responded to prior
Velcade-containing regimen(s);
-- Five of ten patients previously treated with Velcade (50 percent; one
near complete response and four minor responses); and
-- Four of five patients not previously treated with Velcade (80 percent;
one near complete response, one partial response and two minor
responses).
In addition, five patients experienced stable disease (three or more cycles).
Dose escalation continues with KOS-953; all patients are now receiving the recommended dose of Velcade. The combination of KOS-953 and Velcade was well-tolerated. Isolated dose-limiting toxicities have occurred over the range of doses, including increased liver function tests, pancreatitis and metabolic acidosis. No pharmacokinetic interactions were seen between the two drugs.
These data were presented in a poster session presented on Sunday, June 4, by Asher Chanan-Khan, M.D., of Roswell Park Cancer Institute.
"One of the major challenges in treating multiple myeloma is the large number of patients with either primary or acquired resistance to Velcade," said Dr. Chanan-Khan. "We are encouraged by these early results showing clinical response to the combination of KOS-953 and Velcade in patients previously treated as well as refractory to Velcade."
KOS-1022: Phase I Single-Agent Trial in Refractory Hematological Malignancies
KOS-1022 is a second-generation Hsp90 inhibitor that has shown enhanced potency and ease of formulation with potentially more favorable dosing in hematologic malignancies.
Results from a Phase I clinical trial of 20 patients, who received the intravenous formulation of KOS-1022 in doses ranging from 8 to 32 mg/m2 twice weekly for two out of three weeks, showed evidence of clinical activity:
-- Two patients with refractory acute myelogenous leukemia experienced a
complete response (i.e., clearance of leukemic cells from the bone
marrow) with incomplete hematologic recovery;
-- One additional patient experienced stable disease (nine cycles); and
-- The most common toxicities were manageable and included fatigue,
gastrointestinal effects and arthralgia. Dose-limiting toxicities
(acute myocardial infarcation and elevation of troponin) were observed
at the highest dose of 32 mg/m2 in two patients with significant
co-morbidities.
These results from the company's first Phase I clinical study of KOS-1022 were presented Sunday, June 4, in a poster session by Jeffrey Lancet, M.D., of the H. Lee Moffitt Cancer Center, Tampa, FL. Enrollment in this Phase I trial is continuing at a dose of 24 mg/m2 of KOS-1022.
Kosan also has ongoing clinical trials of KOS-1022 in patients with solid tumors: a Phase Ib study of the intravenous formulation of KOS-1022 in combination with Herceptin and a Phase I study of the oral formulation. Under a collaboration agreement with Kosan, the National Cancer Institute (NCI) is also conducting several Phase I clinical trials evaluating the intravenous formulation of KOS-1022 using various dosing schedules. The NCI has reached the maximum tolerated dose with respect to an intensive daily dosing regimen of KOS-1022, having seen some cases of Grade 3 and Grade 4 shortness of breath that were reversible. Most of these patients had pre-existing pulmonary conditions. Kosan utilizes a less frequent dosing regimen in its clinical trials of the intravenous formulation of KOS-1022 and has not seen any dose-limiting pulmonary toxicities in its intravenous or oral KOS-1022 clinical trials.
About Kosan
Kosan Biosciences is a biotechnology company advancing two new classes of anticancer agents through clinical development -- Hsp90 (heat shock protein 90) inhibitors and epothilones. Kosan is leveraging its proprietary discovery platform to generate a pipeline of potentially significant product candidates, primarily in the area of oncology.
Hsp90 inhibitors have a novel mechanism of action targeting multiple pathways involved in cancer cell growth and survival. KOS-953 is Kosan's proprietary formulation of 17-AAG, a geldanamycin analog. The agent is currently in Phase I and II clinical trials, primarily for multiple myeloma and HER2-positive breast cancer. In addition, intravenous and oral formulations of Kosan's second-generation Hsp90 inhibitor, KOS-1022, are being evaluated in Phase I clinical trials.
Epothilones inhibit cell division with a mechanism of action similar to taxanes, one of the most successful classes of anti-tumor agents. KOS-862 is currently being studied in a Phase II single-agent clinical trial in patients with metastatic breast cancer, as well as a Phase II combination trial with Herceptin. KOS-1584, a second candidate designed to improve pharmacokinetics, is in Phase I clinical trials in patients with solid tumors. Kosan's epothilone program is partnered with Roche through a global development and commercialization agreement.
For additional information on Kosan Biosciences, please visit the company's website at www.kosan.com. |
