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Lani · 03-26-2006, 07:55 PM

Abstract 429:
A Phase I, open label, dose-escalating study of the proteasome inhibitor PS-341 (VELCADE®) in combination with two schedules of trastuzumab, in patients with advanced breast cancer (ABC) that overexpresses HER2

Citation: European Journal of Cancer Supplements Volume 4, No. 2, March 2006, page 173

F. Cardoso1, E. Azambuja1, C. Bernard1, L. Dirix2, D. De Becker1, S. Bartholomeus1, V. D'Hondt1, H. van de Velde3, M. Piccart1, A. Awada1

1Jules Bordet Institute, Medical Oncology Clinic, Brussels, Belgium
2General Hospital Sint-Augustinus, Wilrijk, Belgium
3Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium

Background: The ubiquitin proteasome pathway plays an important role in cell cycle regulation, cancer growth and metastatic spread and is a promising novel target for anti-cancer therapy. HER-2 receptor is degraded by the proteasome, which can thus regulate HER-2 levels. Bortezomib (PS-341, VELCADE®) is a highly specific inhibitor of the proteasome and represents the first agent of this class approved for clinical use. We report the preliminary results of a phase I trial initiated to determine the maximum tolerated dose (MTD) and tolerability of bortezomib in combination with trastuzumab as first-line treatment of HER-2-positive ABC.
Methods: Patients (pts) were treated with bortezomib (1.0–1.3 mg/m2; days 1, 4, 8 & 11) and trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly (Group A – Hw) or 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks (Group B – H q3ws)). DLT was defined as febrile neutropenia, grade 4 neutropenia without fever that does not resolve within seven days, grade 4 thrombocytopenia and any ? grade 3 non-hematological toxicity, with the exception of inadequately treated nausea, vomiting and diarrhea.
Results: To date, 11 pts were included and 9 are evaluable. The median age is 51 years (range 35–80 years), median number of metastatic sites 1 (range 1–4; visceral metastases 55.5%), prior anthracycline therapy 55.5% and prior taxane therapy 11.1%.
Treatment: bortezomib 1.0 mg/m2 + Hw (n = 4), bortezomib 1.3 mg/m2 + Hw (n = 3), and bortezomib 1.0 mg/m2 + H q3ws (n = 2). Median number of cycles is 4 (range 2–8 cycles). A DLT (grade 3 muscular pain) was seen in 1 pt treated with Hw and bortezomib 1.3 mg/m2. This cohort is currently extended with 3 extra pts. Grade 2 nausea, vomiting, diarrhea, thrombocytopenia, and liver function alteration were seen in 2 pts. A papular cutaneous rash was seen in 3 pts, which required therapy with steroids and anti-histaminics. The most common side effect was grade 1–2 asthenia (66.6%). No cardiotoxicity was seen. At this time, 1 partial response (PR) and 8 progressive diseases (PD) were seen. Of the 8 pts with PD, 5 received a combination of CT + trastuzumab as 2nd line therapy (3 obtained stable disease-SD, 1 PD, 1 too early to evaluate); 1 received CT alone (with PD), and 1 trastuzumab alone (too early).
Conclusions: So far, data suggest good tolerability of the combination bortezomib + trastuzumab with no cardiotoxicity. Cutaneous rash and asthenia have been the most common side effects. Enrollment is ongoing and an updated data will be presented at the meeting.
Study grant provided by Johnson&Johnson/Millennium Pharmaceuticals.

03-26-2006, 07:55 PM	#3
Lani Senior Member Join Date: Mar 2006 Posts: 4,783	more on a trial of Herceptin and Velcade! Abstract 429: A Phase I, open label, dose-escalating study of the proteasome inhibitor PS-341 (VELCADE®) in combination with two schedules of trastuzumab, in patients with advanced breast cancer (ABC) that overexpresses HER2 Citation: European Journal of Cancer Supplements Volume 4, No. 2, March 2006, page 173 F. Cardoso1, E. Azambuja1, C. Bernard1, L. Dirix2, D. De Becker1, S. Bartholomeus1, V. D'Hondt1, H. van de Velde3, M. Piccart1, A. Awada1 1Jules Bordet Institute, Medical Oncology Clinic, Brussels, Belgium 2General Hospital Sint-Augustinus, Wilrijk, Belgium 3Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium Background: The ubiquitin proteasome pathway plays an important role in cell cycle regulation, cancer growth and metastatic spread and is a promising novel target for anti-cancer therapy. HER-2 receptor is degraded by the proteasome, which can thus regulate HER-2 levels. Bortezomib (PS-341, VELCADE®) is a highly specific inhibitor of the proteasome and represents the first agent of this class approved for clinical use. We report the preliminary results of a phase I trial initiated to determine the maximum tolerated dose (MTD) and tolerability of bortezomib in combination with trastuzumab as first-line treatment of HER-2-positive ABC. Methods: Patients (pts) were treated with bortezomib (1.0–1.3 mg/m2; days 1, 4, 8 & 11) and trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly (Group A – Hw) or 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks (Group B – H q3ws)). DLT was defined as febrile neutropenia, grade 4 neutropenia without fever that does not resolve within seven days, grade 4 thrombocytopenia and any ? grade 3 non-hematological toxicity, with the exception of inadequately treated nausea, vomiting and diarrhea. Results: To date, 11 pts were included and 9 are evaluable. The median age is 51 years (range 35–80 years), median number of metastatic sites 1 (range 1–4; visceral metastases 55.5%), prior anthracycline therapy 55.5% and prior taxane therapy 11.1%. Treatment: bortezomib 1.0 mg/m2 + Hw (n = 4), bortezomib 1.3 mg/m2 + Hw (n = 3), and bortezomib 1.0 mg/m2 + H q3ws (n = 2). Median number of cycles is 4 (range 2–8 cycles). A DLT (grade 3 muscular pain) was seen in 1 pt treated with Hw and bortezomib 1.3 mg/m2. This cohort is currently extended with 3 extra pts. Grade 2 nausea, vomiting, diarrhea, thrombocytopenia, and liver function alteration were seen in 2 pts. A papular cutaneous rash was seen in 3 pts, which required therapy with steroids and anti-histaminics. The most common side effect was grade 1–2 asthenia (66.6%). No cardiotoxicity was seen. At this time, 1 partial response (PR) and 8 progressive diseases (PD) were seen. Of the 8 pts with PD, 5 received a combination of CT + trastuzumab as 2nd line therapy (3 obtained stable disease-SD, 1 PD, 1 too early to evaluate); 1 received CT alone (with PD), and 1 trastuzumab alone (too early). Conclusions: So far, data suggest good tolerability of the combination bortezomib + trastuzumab with no cardiotoxicity. Cutaneous rash and asthenia have been the most common side effects. Enrollment is ongoing and an updated data will be presented at the meeting. Study grant provided by Johnson&Johnson/Millennium Pharmaceuticals.