A Phase Ib/randomized phase II study of BEZ235 and trastuzumab versus lapatinib and capecitabine in patients with HER2-positive locally advanced or metastatic breast cancer who failed prior to trastuzumab.

Breast cancer, after skin carcinomas, is the most common malignancy and the
leading cause of cancer mortality in women worldwide. In the US, it is
estimated that approximately 207,090 new cases of invasive breast cancer were
diagnosed in 2010. For the same year about 40,230 women died from their disease
(American Cancer Society 2010). Approximately 40% of diagnosed patients will
eventually develop metastatic breast cancer (MBC). Metastatic breast cancer is
still considered incurable, and treatment is palliative. Despite the variety of
agents available for the treatment of MBC, the median survival time for women
with MBC is about 2 to 3 years, and only 20% of women will be alive 5 years
after diagnosis (Gennari 2005, Miles 2009). As a result, the goals of treatment
are to optimize quality of life, manage symptoms and prolong survival.

Over the past years, progress has been made in understanding the molecular
biology and genetics of breast cancer which are central to the development of
novel therapies. Among others, the phosphatidylinositol-3-kinase (PI3K) pathway
has been identified as an important target. The PI3K pathway is a key signal
transduction system linking multiple oncogenes, tumor suppressors and receptor
classes to essential cellular functions such as cell growth, survival, motility
and metabolism (reviewed in (Courtney et al 2010)). Important components of the
signaling cascade include pAKT, mTOR, and PTEN as a negative regulator of PI3K


In HER2-positive breast cancer, it is estimated that up to 25% of tumors have
aberrant PI3K signaling due to mutations in the PIK3CA or PTEN genes leading to
constitutive pathway activation (Kalinski 2009, Stemke 2008). In addition, the
pathway can be activated by HER2-overexpression itself which likely contributes
to tumorigenesis and clinical behavior in patients with HER2-positive breast
cancer (Holbro et al 2003).
Moreover, the PI3K pathway seems to be involved in resistance to
anti-neoplastic treatments. Preclinical studies have shown that aberrant PI3K
signaling can render cell lines resistant to endocrine, HER2-targeted and
cytotoxic therapy. For example, PTEN deficiency, PIK3CA mutation and/or
activation of other pathways such as IGF1R or members of the growth factor
receptor family have been associated with resistance to trastuzumab treatment
(Nagata 2004, Berns 2007, Nahta 2005). However, these findings together with
the observation that sensitivity may be restored or its effect potentiated by
co-administration of PI3K or mTOR inhibitors (Yu 2001, West 2002) provide a
rationale for PI3K targeted therapy setting. In fact, recent results from
clinical studies with everolimus indeed suggest that the PI3K pathway may be
involved in treatment resistance and that targeting the pathway can play a
therapeutic role in overcoming resistance to endocrine or HER2-targeted therapy
in breast cancer (Bachelot 2010, Andre 2010).

Primair
To determine the MTD and/or RP2D of oral twice daily (BID) BEZ235 in
combination with trastuzumab in patients with HER2-positive breast cancer

Secondair
To assess the preliminary activity of the combination
To assess the safety and tolerability of the combination
To describe the pharmacokinetics (PK) of BEZ235 and trastuzumab

Exploratory
To assess pharmacodynamic markers in the context of a BID administration in
combination with trastuzumab
To identify molecular profiles relevant to PI3K signaling

Open-label, dose-finding Phase Ib study followed by an open-label, randomized,
active-controlled Phase II study.
Phase Ib will investigate the MTD/RP2D of oral BID dosing of BEZ235 in
combination with weekly trastuzumab.

Once the MTD/RP2D has been established, Phase II of the study will start in
which patients will be randomized to receive either lapatinib + capecitabine or
weekly trastuzumab in combination with BEZ235 BID at the recommended dose for
phase II.

BEZ235 will be administered twice daily andTrastuzumab infusion will be
administered weekly

In Phase two the control group will receive Lapatinib (once daily from D1-D21
of each cycle) and Capecitabine( twice daily from D1-D18 of each cycle)

Toxicity of the combination-therapy BEZ 235 and trastuzumab
- Radiation exposure of MUGA ( Fase II ook CT/MRI/Botscan)
-Frequent visits and blood sampling
- (optional) tumorbiopsy (Phase II)


An overview of all visits during the procedure are given in Appendix B of the
patient information.
The side effects can be found in Appendix C of the patient information.
It is not certain that participation in the study will directly benefit the
patient, the data can be useful for the future.
The burden on the patients is as expected for a Phase 1 study.