A phase Ib, open-label, two arm study of i.v. and oral panobinostat (LBH589) in combination with i.v. trastuzumab (Herceptin®) and i.v. paclitaxel as treatment for adult female patients with HER2 overexpressing metastatic breast cancer (MBC)

HER2-positive breast cancer accounts for approximately 20 to 30% of all cases
of breast cancer. In the setting of HER2 gene amplification or high levels of
HER2 expression, the HER family of receptors and their associated
signal-transduction pathways play a dominant role in cell growth and survival.
These tumors have a distinct natural history that, in the absence of
HER2-directed therapy, is characterized by short disease-free survival and an
aggressive course in the metastatic setting.

Trastuzumab is a monoclonal antibody directed against HER2. Its anti-tumor
activity is likely attributable to several different effects including the down
regulation of HER2 expression on cell surfaces and activation of p27 and p130.
Trastuzumab also sensitizes tumor cells to TNF and inhibits tumor angiogenesis
by decreasing the production of VEGF.
Taxanes are among the most active chemotherapy agents used in the management of
metastatic breast cancer (Ghersi 2005). Paclitaxel in combination with
trastuzumab is indicated for the treatment of patients with metastatic breast
cancer whose tumors overexpress HER2 and who have previously not received
chemotherapy for MBC (Herceptin® US PI).
Combining two or more agents has been shown to improve survival in advanced
breast cancer (Carrick 2006). Studies indicate that triplet combinations can
provide improved survival if over-lapping toxicities can be avoided or
adequately managed.

Panobinostat is a multi-targeted agent which inhibits deacetylase (DAC) enzyme
activity, activates the p21 tumor suppressor gene and inhibits proliferation of
tumor cell lines at nanomolar concentrations. In vivo experiments have
demonstrated the single agent anti-tumor activity of panobinostat against both
ER positive and HER2 positive tumors. Other pre-clinical data suggests that the
anti-tumor effects of panobinostat occur in part through the increased
acetylation and consequent loss of HSP90 function. Both ER and HER2 are HSP90
client proteins, and are degraded in cell lines exposed to panobinostat in
vitro.

In-vitro data has shown that panobinostat inhibits the function of HSP90 and
causes degradation of HER2 and/or ER in molecularly defined breast cancer cell
lines
induces highly potent single agent death of all HER2/neu driven breast cancer
cell lines tested in vitro.
induces the death of most ER positive cell lines with high potency
causes re-expression of ER in hormone receptor negative breast cancer cell
lines and sensitizes them to tamoxifen (receptor antagonist) synergizes with
the HER2/neu tyronsine kinase inhibitor lapatinib and AEE788 and has additive
activity with the EGFRi Gefitinib.

In-vivo data has shown a profound synergistic anti-tumor effect when
panobinostat is combined with trastuzumab or taxotere in the HER2/neu-driven
BT474 in vivo model.

The purpose of this phase Ib study is to determine the maximum tolerated dose
(MTD) of i.v. and oral panobinostat when given in combination with trastuzumab
and paclitaxel. Additional patients will be enrolled at the MTD to further
evaluate the safety and tolerability of this treatment combination.

Primary objective
* Arm I: to determine the maximum-tolerated dose (MTD) based on dose-limiting
toxicities (DLT) of i.v. panobinostat given weekly for two weeks on treatment,
one week off treatment (e.g. D1, D8 as part of a 21 day cycle) when given in
combination with weekly paclitaxel and weekly trastuzumab in patients with HER2
positive MBC
Arm II: to determine the maximum-tolerated dose (MTD) based on dose-limiting
toxicities (DLT) of oral panobinostat given on days 1, 3 and 5 every week as
part of a 21 day cycle) when given in combination with weekly paclitaxel and
weekly trastuzumab in patients with HER2 positive MBC

Secondary objectives
* To characterize the safety and tolerability of i.v. and oral panobinostat
when given in combination with paclitaxel and trastuzumab
* To evaluate the effect on QTc interval in patients receiving i.v. and oral
panobinostat when given in combination with paclitaxel and trastuzumab
* To characterize the disposition (pharmacokinetics) of panobinostat following
i.v. and oral administration of panobinostat when given at the MTD in
combination with paclitaxel and trastuzumab
* To describe the disposition (pharmacokinetics) of paclitaxel alone and
following the co-administration of panobinostat at the MTD and trastuzumab
* To explore preliminary antitumor activity of panobinostat when given
intravenously (Arm I) and orally (Arm II) in combination with weekly paclitaxel
and weekly trastuzumab

Exploratory objectives
* To explore the effect of i.v. and oral panobinostat at the MTD when given in
combination with i.v. trastuzumab and i.v. paclitaxel on circulating tumor
cells and other biomarkers during treatment

This is a phase Ib open label, multi-centre, two-arm, international study of
i.v. panobinostat and oral panobinostat given in combination with weekly
paclitaxel and weekly trastuzumab in women with HER2-positive MBC.
In this study patients screened successfully will be randomly allocated to one
of the two arms (i.v. or oral panobinostat) after assignment of a unique
patient identification number according to a prearranged sequence provided by
Novartis. During the dose escalation phase an arm maybe temporarily *closed*
for evaluation. If so then all patients will be enrolled to the *open* arm.

A minimum of 3 patients will be enrolled into a cohort. In each successive
cohort patients will receive an increased dose of panobinostat with standard
doses of trastuzumab and paclitaxel until the MTD is reached. The starting
doses of i.v. and oral panobinostat for this study have been chosen on the
basis of their safety in the preceding single-agent phase I trials. The
starting dose for i.v. panobinostat (Arm I) will be 10mg/m2 given once a week
(e.g. D1 and D8) for two weeks on treatment with one week off treatment as part
of a 21 day treatment cycle. The starting dose for oral panobinostat (Arm II)
will be 10mg given three times every week (e.g. D1, D3, and D5 weekly) given as
part of a 21 day treatment cycle
Data from the ongoing [CLBH589C2204] study combining i.v. and oral panobinostat
with trastuzumab will provide supporting dosing and toxicity data.

In arm I, additional panobinostat doses or intermediate panobinostat doses, if
needed, may be evaluated to better define the safety, pharmacokinetics and/or
pharmacodynamics of the study treatment combination.

During the dose escalation phase, an adaptive Bayesian logistic regression
model (Thall, et al 2003) and dose escalation criteria similar to that proposed
by Babb (Babb, Rogatki, and Zacks 1998) will be used separately for Arms I and
II. The statistical model for the combination treatment will be based on a
6-parameter logistic model with overdose control.
Each cohort will consist of a minimum of 3 newly enrolled evaluable patients.
If * 1 patient in the cohort experiences a DLT before the completion of
enrollment to that cohort, the model will be re-evaluated and additional
patients enrolled as determined necessary.

The patient population used for the determination of MTD will consist of
patients who have experienced DLT and/or who have met the minimum safety
evaluation requirements for their first cycle of treatment. Once a dose cohort
has been identified as the potential MTD, a minimum of 9 patients must be
treated at the given dose before it can be declared the MTD. It is anticipated
that at least 15 patients from each arm will be required during dose escalation
of the study to determine the MTD. This estimate assumes that the third dose
level in each arm will be the MTD. Once the MTD is declared an additional 11
patients will be enrolled into each arm during an expansion phase.
After completion of a given dose cohort, the decision to dose escalate and the
selection of the next dose to evaluate will depend on a calculated risk of DLT
using the Bayesian logistic regression models and the medical review of
available clinical and laboratory data by Novartis and the treating
investigators.

A DLT is defined as an AE or laboratory abnormality that is considered to be
related to the study treatment (see Table 6-6). During the dose escalation
phase of the study the MTDs of panobinostat given i.v. and orally will be
principally determined from DLTs occurring during the first cycle of therapy.
However toxicities occurring in subsequent cycles of treatment may also be
considered at the time of dose escalation discussions/decisions.
Hypersensitivity or infusion reactions to paclitaxel or to trastuzumab will not
be considered DLTs (Section 6.6.1.7). Should a toxicity be considered
specifically related to paclitaxel, the paclitaxel dose may be modified and/or
interrupted as per the locally approved PI. Toxicities be considered
specifically related to trastuzumab the trastuzumab infusion will be
interrupted and/or delayed as per the locally approved PI (See Section 6.6.2.1).

Study treatment will be repeated every 21 days unless there is evidence of
progression or occurrence of unacceptable toxicities. For a patient to be
followed within the context of this study, the patient needs to continue to
receive panobinostat treatment.
Pharmacokinetic assessments will be performed in the patients treated at the
MTD during the expansion phase.

If a patient participates in this study, he/shewill be asked to sign the
informed consent before any tests are performed specifically for this study.
After the patient sign the informed consent but before starting therapy, the
study doctor will ask the patient about his/her health and medical history to
determine if the patient is eligible to take part in the study. The patient
will undergo a series of tests to evaluate the present state of health and the
state of the disease.

If these tests show that the patient is eligible to enter the study, and if the
patient chooses to enter the study, he/she will be assigned to one of two
groups which will determine whether he/she will receive panobinostat as an
intravenous infusion once a week (usually on Mondays) for two weeks out of
three weeks or panobinostat as capsule(s) he/she will take by mouth three times
a week (usually on Mondays, Wednesdays and Fridays) every week. No matter what
group a patient is assigned to, he/she will receive trastuzumab and paclitaxel
as intravenous infusions once a week (usually on Mondays). The patient will
return to the doctor*s office at regular intervals so that his/her condition
can be checked. The study doctor will ask the patient how he/she is feeling.
The patient may continue to receive treatment provided that tests show the
disease is not getting worse, and the patient is not experiencing unacceptable
side effects and the doctor thinks that the patient is benefiting from
treatment. The patient will continue to have tests on a regular schedule while
he/she is in this study.

All patients in this study will receive the investigational drug panobinostat
with an infusion of trastuzumab and infusion of paclitaxel.

Risks are the possible side-effects of the study medication and side-effects of
the study procedures, like blood- and urine sampling.

An more extensive description of the risks has been described in Paragraph 1.3
(on page 40) of the study protocol.