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Lonafarnib Shows Durable Response in Breast Cancer Patients, When Used in Combination With Paclitaxel and Trastuzumab: Presented at AACR-NCI-EORTC

By Crina Frincu-Mallos, PhD

SAN FRANCISCO, CA -- October 31, 2007 -- The combination of lonafarnib, paclitaxel, and trastuzumab results in durable partial breast tumour remissions and disease stabilisation, researchers reported here at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Lonafarnib is a potent farnesyl transferase inhibitor that is able to inhibit Ras farnesylation.

Lead author, Jan H. M. Schellens, MD, PhD, Group Leader, Department of Medical Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands, discussed the results in a poster presentation on October 24. Dr. Schellens and colleagues aimed to test the toxicity profile of the drug combination.

For this phase 1 study of lonafarnib plus paclitaxel and trastuzumab, Dr. Schellens and colleagues accrued 23 patients with metastatic breast cancer overexpressing HER-2.

Lonafarnib was administered orally, twice daily continuously throughout the 21-day cycle, at one of three doses (150, 200, 250 mg/day); patients on the 300-mg/day dose received it on the first and last week of the 21-day cycle, to prevent severe haematological toxicity. Patient's median age was 49 years (range, 34-68 years); 14 of the 23 patients had prior exposure to anthracycline.

Trastuzumab 2 mg/kg was given intravenously (IV) for 30 minutes on days 1, 8, and 15 of the cycle; the loading dose was 4 mg/kg IV for 90 min on day 1 of cycle 1.

Paclitaxel was administered on day 1 of each cycle as an IV infusion for 3 hours, at two dose levels, 135 or 175 mg/m².

Five dose level combinations were investigated and a total of 266 cycles of chemotherapy were administered to date, according to the researchers.

A significant number of patients experienced haematological adverse events (AEs): grade 3 white blood cells and grades 3 and 4 neutrophils.

A total of 22 patients discontinued the therapy, half of the patients because of toxicity; the rest due to disease progression or withdrawal of consent. Patients went off protocol due to adverse events: six due to neutropaenia; two due to neuropathy; one due to allergic reaction; and one due to increased QTc interval.

Of the nonhaematological adverse events observed, the most common were fatigue, myalgia, nausea, sensory neuropathy, diarrhoea, and arthralgia.

One dose-limiting toxicity, a grade 3 allergic reaction, was observed in eight patients taking lonafarnib 300 mg/day.

Based on these results, Dr. Schellens and colleagues selected a combination of paclitaxel 175 mg/m², trastuzumab 2 mg/kg, and lonafarnib 250 mg/day as the recommended phase 2 dose.

A total of 17 patients were evaluable for responses: one complete response; 10 partial responses; and five patients with stable disease.

Dr. Schellens and colleagues noted that the progression-free survival at 6 months was 85%, with a median follow-up of 8 months at the time of the presentation.

Lonafarnib in combination with paclitaxel and trastuzumab will be tested further in phase 2/3 trials.

Dr. Schellens presented the study on behalf of the European Organisation for Research and Treatment of Cancer (EORTC) New Drug Development Group & Breast Group (EORTC Protocol 16023-10051).

Funding for this study was provided by Schering-Plough Research Institute.


[Presentation title: A Phase I Study of Lonafarnib, A Farnesyl Transferase Inhibitor in Combination With Herceptin Plus Paclitaxel in Her 2 /Neu Overexpressing Breast Cancer. Abstract B116]

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