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SECTION V: Novel Therapies

Satellite Symposium
Docetaxel in Combination with Molecular-Targeted Therapies: A Promising New Strategy for the Treatment of Breast Cancer
Martine J. Piccart, MD, Jules Bordet Institute, Brussels, Belgium

"We are fortunate in having several systemic treatments for breast cancer. These include endocrine therapy, biological therapy, and chemotherapy. There is some overlap with use of these therapies. Our best hope for improving response and prolonging remission is to combine biological therapies with chemotherapy or endocrine therapy," Dr. Martine Piccart told attendees at the 38^th annual ASCO meeting.

Speaking at a satellite symposium entitled "Beyond Chemotherapy 2002: Emerging Targeted Therapies for the Treatment of Breast Cancer" Dr. Piccart presented three novel therapies that may be combined with Taxotere (docetaxel) chemotherapy, the standard of care for patients who fail anthracycline therapy:

anti-Ras compound R115777 (Zarnestra).
anti-Raf compound BAY 43-9006.
proteasome inhibitor PS-341/MLN341 (formerly LDP-341, MG-341).

R115777
Studies have shown single-agent R115777 is active in advanced breast cancer and an abstract presented at the 38^th ASCO meeting suggests that further study of R115777 is warranted (Abstract 138).

The phase II study involved 76 patients who failed endocrine therapy plus one or two chemotherapies. In the first cohort of patients, the drug was given continuously at 300 mg or 400 mg twice daily. The second cohort received 300 mg twice daily in a cyclic regimen of 21 treatment days followed by seven days off treatment. This intermittent dosing strategy showed similar clinical efficacy to the continuous dosing regimen, but significantly improved the tolerability profile.

Dr. Piccart said that this study and others by the same group encouraged her research team to study Taxotere in combination with R115777.

"Taxotere is an attractive agent to use in combination with these novel therapies," Dr. Piccart said. In patients with minimum exposure to anthracyclines, Taxotere improved response rates and time to progression.

A phase II study is currently underway to determine the optimal dose and schedule of the Taxotere-R115777 combination, she said. The study involves 32 patients (19 with breast cancer) who were heavily pretreated. Preliminary results showed a dose- limiting toxicity of myelosuppression, with rates of other adverse events being low. No pharmacokinetic interactions were observed between Taxotere and R115777, and the combination had significant antitumor activity. Of the 32 patients, there was one complete response (a patient with breast cancer and liver metastases) and seven partial responses (four in patients with breast cancer). A phase III study is planned to compare Taxotere plus R115777 versus Taxotere alone.

BAY 43-9006
Phase II studies with another novel oral compound, the anti-Raf agent BAY 43-9006, are underway at Jules Bordet Institute in Belgium. Thus far, they suggest this drug should be given twice a day, with or without food.

Thirty-eight patients (seven with breast cancer) were enrolled in a dose-finding study of BAY 43-9006 (50 to 800 mg twice daily given for three weeks with a one week break). All 38 patients are evaluable for safety and 34 for tumor response, she said. The dose-limiting toxicity was skin rash, which was seen at 600 mg/day. The drug had clear activity, with stable disease being seen in six patients and a partial response in one patient.

A phase I/II study will compare other investigational schedules of Taxotere given in combination with BAY 43-9006.

PS-341
PS-341 is a potent selective proteasome inhibitor that has been shown to enhance the antitumor activity of Taxotere, doxorubicin (Adriamycin, Adiblastine, Adriablatina, Doxil, and others), 5-fluorouracil (5-FU; Adrucil, Efudex, Fluroplex), gemcitabine (Gemzar), irinotecan (Camptosar), and radiotherapy, Dr. Piccart said. The main toxicity of this agent is gastrointestinal disturbance.

Phase I trials demonstrated antitumor activity in hematologic malignancies, as well as cancers of the prostate, lung, kidney, breast, head and neck, and melanoma. The main side effects were grade 1 and 2 fatigue, myelosuppression, gastrointestinal disturbance, thrombocytopenia, and peripheral neuropathy. Additional studies are planned to look at the combination of Taxotere plus PS-341 in breast, prostate, and lung cancer. PS-341 will be combined with other cytotoxic drugs as well, Dr. Piccart observed.

PS-341 stabilizes p27 activity, therefore Taxotere should be given first in sequence to capitalize on this activity, she explained. An ongoing phase I/II study will evaluate investigational schedules of Taxotere in combination with PS-341. No toxicity has been observed in the first three patients started on the combination, Dr. Piccart reported.

"In 20 years, we will be giving targeted drugs to help us control metastatic breast cancer for much longer than we can today," Dr. Piccart concluded.

Key Points In Focus:

Drugs aimed at novel targets have promising activity in metastatic breast cancer.
Three novel agents are R115777, a farnesyl transferase (or anti-Ras) inhibitor; BAY 43-9006, an anti-Raf compound; and PS-341, a proteasome inhibitor.
Phase I and II studies suggest that these drugs can be combined with Taxotere to enhance antitumor activity.

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