A phase II, multi-center, open-label study of AUY922 administered i.v. on a once-weekly schedule in patients with advanced non-small-cell lung cancer who have received at least two lines of prior chemotherapy

Lung cancer is the leading cause of cancer deaths in the US with 215,020 new
cases and 161,840 deaths in 2008 (Jemal, et al 2009). Non-small cell lung
cancer (NSCLC) accounts for roughly 85% of all lung cancer cases (Alvarez 2007,
Ruiz 2008). Epidermal growth factor receptors (EGFR) have been shown to be
overexpressed in an approximately 40 to 90% of NSCLC patients (Zakowski, et al
2009). Recent development of targeted agents such as EGFR tyrosine kinase
inhibitors erlotinib and gefitinib have opened up new treatment options in
NSCLC. However, a large majority of NSCLC patients, including patients with
certain KRAS mutations, and a constitutively active
phosphatidylinositol-3-kinase (PI3K)/AKT pathway, and even some mutations in
EGFR, are insensitive to targeted therapy (Sos, et al 2009), necessitating
development of newer agents. Heat shock protein 90 (HSP90) is an ATP-dependent
molecular chaperone that assists in the structural folding and stabilization of
a wide range of cellular proteins including IGF-1R, EGFR, AKT, and RAS (Pratt
and Toft 2003). AUY922, an isoxazole, is one of the most potent
non-geldanamycin HSP90 inhibitors currently under clinical development. AUY922
exerts its activity by binding to the ATP-ase domain of the HSP90 N-terminus
preventing HSP90 from forming the closed conformation, and performing its
functions on client proteins (Jensen, et al 2008). Pre-clinical studies have
shown AUY922 to be active in a wide range of NSCLC cell lines, including cell
lines with EGFR and K-ras mutations. As a majority of the oncogenic proteins
involved in NSCLC proliferation such as IGFR-1, c-Met, KRAS and EGFR are HSP90
client proteins AUY922 treatment may have significant therapeutic potential in
patients with advanced NSCLC.

Primary objective
* To estimate efficacy for each study stratum at 18 weeks as assessed by RECIST

Key Secondary objectives:
* To estimate overall survival (OS) and progression free survival (PFS) in
patients with advanced NSCLC
* To determine safety and tolerability of AUY922 i.v. monotherapy in patients
with advanced NSCLC
* To further characterize the PK profile of AUY922 in NSCLC patient population

Exploratory objective:
* To use [18F]-FDG PET imaging as early indicator of pathway inhibition and
cellular response.

This is a global, multi-center, open-label phase II study. Patients will be
assigned retrospectively, or prospectively later during the study (see below),
to three strata based on their molecular characteristics. The three strata
will be: 1. EGFR mutant (30 patients), 2. KRAS mutant (30 patients),and 3.
EML4-ALK translocation (30 patients) 4. KRAS wt and EGFR wt (30 patients) 5.
EGFR mutant modified (30 patients). For purposes of this study, patients
exhibiting both mutations will be stratified to the EGFR mutation stratum, as
these tumors appear to respond to EGFR TKI treatment. Determination of the
mutation status is not required prior to enrolment, but will be determined as
soon as teh fresh of archival tissue is received at the Novartis designeed
laboratory. Once one stratum has enrolled 26 patients, the enrollment strategy
will be based on prospective selection into the remaining strata. All patients
will receive AUY922 i.v. at 70 mg/m2 weekly in a 21 day cycle. Treatment
duration will continue until disease progression (defined by RECIST),
unacceptable toxicity, patient withdrawal, death, or discontinuation from the
study for any other reason. Patients who discontinue treatment should have a
follow-up visit 28 (±7) days after the end of treatment visit. Any patient who
discontinued from study treatment for any reason other than disease progression
or withdrawal of consent will continue to have tumor assessments every 12 weeks
(±1 week) until the patient starts another antineoplastic therapy. All patients
will be followed for PFS and OS for a duration of up to a year after last
patient last visit.

AUY922 will be given i.v. over 60 minutes weekly at 70 mg/m2 in a 21 day
treatment cycle. Patient treatment will continue until disease progression,
unacceptable toxicity, patient refusal or until investigator decision.

Study assessments will be performed at baseline, C1D1, C1D2, C1D3, C1D8, C1D15
and CXD1, CXD8, CxD15 of every consecutive cycle. All patients will receive
AUY922 i.v. at 70 mg/m2 weekly in a 21 day cycle.Treatment duration will
continue until disease progression (defined by RECIST), unacceptable toxicity,
patient withdrawal, death, or discontinuation from the study for any other
reason, whereupon all patients will complete the End of Treatment visit. Any
patient who discontinued from study treatment for any reason other than disease
progression or withdrawal of consent will continue to have tumor assessments
every 12 weeks (±1 week) until the patient starts another antineoplastic
therapy. All patients will be followed for PFS and OS for a duration of up to a
year after last patient last visit.

Please refer to Table 7-1, page 56.

Risks:
* Toxicity due to the use of AUY922 (especially cardiac toxicity, diarrhea and
visual adverse events).
* Reaction to the use of contrast fluid (used for CT scans)
* Side effects of blood sampling and taking of the biopsies