Letrozole Plus Oral Cyclophosphamide Plus/Minus Sorafenib as Primary Systemic Treatment in Breast Cancer Patients
Recruitment status was Active, not recruiting
Endocrine therapy is the mainstay of systemic treatment in patients with endocrine responsive breast cancer. Aromatase inhibitors are the most active agents in post-menopausal women. Randomized comparisons either in primary/adjuvant setting or in metastatic disease setting have demonstrated the superiority of these drugs over tamoxifen.
Primary systemic treatment administered to breast cancer patients is a useful model to identify baseline features able to predict which patients are most likely to benefit from cytotoxic treatment and is a way to study new biological markers in relation to the predictive information they provide.
This treatment modality represents therefore the best way to explore new treatment strategies in particular treatment strategies involving target therapies.
We have conducted a randomised phase II trial in which the activity of Letrozole plus/minus oral metronomic cyclophosphamide as primary systemic treatment has been investigated in a patient population of elderly breast cancer patients. The conclusions were that the combination of letrozole with metronomic cyclophosphamide was a very active scheme. In addition this was the first study demonstrating in vivo the antiangiogenic effect of metronomic scheduling. This study suggests that chemotherapy administered on a metronomic schedule, targeting therefore the neo-angiogenesis, could be synergistic with endocrine therapy with aromatase inhibitors.
Sorafenib is a multi-kinase inhibitor targeting Raf, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alfa, Flt-3, c-Kit, and p38.
There is a strong rationale of combining different anti-angiogenic agents. At the ASCO 2007 meeting the data of a phase I study exploring the toxicity of a combination of sorafenib and bevacizumab have been presented. The results showed an increased toxicity being dose limiting in some patients. To our knowledge there are no data un activity and toxicity of adding sorafenib to metronomic chemotherapy.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Letrozole Plus Oral Cyclophosphamide Plus/Minus Sorafenib as Primary Systemic Treatment in Post-menopausal, Estrogen Receptor Positive, Breast Cancer Patients|
- Progression free survival [ Time Frame: six years ] [ Designated as safety issue: No ]
- Overall survival [ Time Frame: six years ] [ Designated as safety issue: No ]
|Study Start Date:||September 2007|
|Estimated Study Completion Date:||December 2010|
|Estimated Primary Completion Date:||June 2010 (Final data collection date for primary outcome measure)|
|Active Comparator: letrozolo+cyclophosphamide||
Letrozole 2,5 mg/daily + metronomic cyclophosphamide 50 mg/daily for 6 months
Letrozole (2,5 mg/daily) + "metronomic" cyclophosphamide (50 mg/daily) + Sorafenib (400 mg/bid/daily) for 6 months
To compare the activity of the 2 regimens The primary end point will be the clinical complete response rate of each treatment arm among all registered cases (intent to treat analysis).
To compare the 2 treatment arms with respect to:
- Progression Free Survival
- Overall survival
Ancillary studies To evaluate before and after treatment a number of markers of hypoxia, neoangiogenesis, apoptosis, EGFR activating pathways.
|Breast Unit Azienda Ospedaliera Istituti Ospitalieri|
|Azienda Ospedaliera S.Luigi Orbassano|
|Study Chair:||Alfredo Berruti, MD||Medical Oncology, Department of clinical and biological sciences Univerity of Turin|
|Principal Investigator:||Daniele Generali, MD||Breast Unit Azienda Ospedaliera Istituti Ospitalieri Cremona|
|Study Director:||Alberto Bottini, MD||Breast Unit Azienda Ospedaliera Istituti Ospitalieri Cremona|