A multicenter, open-label, randomized phase II study to evaluate the efficacy of AUY922 vs pemetrexed or docetaxel in NSCLC patients with EGFR mutations who have progressed on prior EGFR TKI treatment (CAUY922A2207)

Lung cancer is the leading cause of cancer deaths in the US with 215.000 new
cases and 160.000 deaths in 2008. Non-small cell lung cancer (NSCLC) accounts
for roughly 85% of all lung cancer cases. Epidermal growth factor receptors
(EGFR) have been shown to be over-expressed in an approximately 40 to 90% of
NSCLC patients. 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 PI3K/AKT pathway, and even
some mutations in EGFR, are insensitive to targeted therapy, 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. 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.
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.
The purpose of this phase II trial is to evaluate the safety and efficacy of
treatment with AUY922 in comparison with pemetrexed and docetaxel in NSCLC
patients who progressed on prior EGFR-TKI treatment.

Primary: Progression Free Survival (PFS) in patients treated with AUY922 versus
pemetrexed or docetaxel.
Secondary: Overall response rate, disease control rate, overall survival,
safety and tolerability, PK.

Multicenter randomized open-label placebo controlled parallel group phase II
study.
Randomization (1:1) to treatment with:
* AUY922 IV infusion 70 mg/m2 of 1 h every week
* Pemetrexed IV infusion 500 mg/m2 of 1 h every 3 weeks or docetaxel IV
infusion 75 mg/m2 of 1 h every 3 weeks . The investigator will make the choice
between pemetrexed and docetaxel on a patient by patient basis.
Treatment until progression or unacceptable toxicity.
108 patients.

Treatment with AUY922, docetaxel or pemetrexed.

Risk: Adverse events of study medication.
Burden: Study duration in principle until disease progression. Thereafter
follow-up for survival. AUY-group: weekly visits (course 1: 5 visits), control
group every 3 weeks.
I.v. infusions weekly (AUY, 500 ml in 1 h) or every 3 weeks (control group, 500
ml in 1 h).
Physical examination day 1 of every course.
Blood draws screening approx. 40 ml, every course 25 ml, final visit 20 ml.
Pregnancy test at screening.
ECG every visit (AUY) of at start and end.
Echocardiography or MUGA-scan start and end.
Tumor evaluations conform regular treatment.
Eye examination in AUY group 3 times.
Tumor biopsy at screening (if no archived tumor material available).
Optional tumor biopsy at the end of treatment.
Optional donation of left-over tumor tissue for future testing.