Hsp90 Inhibitor AUY922 and Erlotinib Hydrochloride in Treating Patients With Stage IIIB-IV Non-Small Cell Lung Cancer

This is a phase I, dose-escalation study of Hsp90 inhibitor AUY922 followed by a phase II
study. Patients receive Hsp90 inhibitor AUY922 IV over 1 hour once weekly and oral erlotinib
hydrochloride once daily. Courses repeat every 4 weeks in the absence of disease progression
or unacceptable toxicity. After completion of study treatment, patients are followed up
periodically.

Inclusion Criteria:

- All patients must have pathologic evidence of advanced lung adenocarcinoma (stage IIIB
or stage IV) confirmed histologically/cytologically at NU, MSKCC, or DFCI and EITHER
previous RECIST-defined response (CR or PR) to an EGFR-TKI (erlotinib or gefitinib) or
an investigational EGFR TK inhibitor OR a documented mutation in the EGFR gene (G719X,
exon 19 deletion, L858R, L861Q)

- Radiographic progression by RECIST during treatment with erlotinib/gefitinib

- Received treatment with erlotinib/gefitinib throughout the one month prior to
enrollment and at least six months at any time

- Measurable (RECIST) indicator lesion not previously irradiated

- Must have undergone a biopsy after the development of acquired resistance

- Karnofsky Performance Status >= 70% OR ECOG/WHO Performance Status 0-1

- Signed informed consent

- Effective contraception and negative serum pregnancy test obtained within two weeks
prior to the first administration of AUY922 in all pre-menopausal women (ie., last
menstrual period =< 24 months ago) and women < 2 years after onset of menopause;
menopause is defined as the time at which fertility ceases, where a woman has had no
menstruation for > 24 months

- Total bilirubin =< 1.5 x Upper Limit of Normal (ULN)

- AST/SGOT and ALT/SGPT =< 3.0 x ULN, or =< 5.0 x ULN if liver metastasis present

- Absolute neutrophil count (ANC) >= 1.5 x10^9/L

- Hemoglobin (Hgb) >= 9g/dL

- Platelets (plts) >= 100 x 10^9/L

- Serum creatinine =< 1.5 x ULN or 24 hour clearance >= 50 mL/min

Exclusion Criteria:

- Symptomatic CNS metastases which are symptomatic and /or requiring escalating doses of
steroids

- Prior treatment with any HSP90 inhibitor compounds

- Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks
(erlotinib/gefitinib therapy within the past 4 weeks IS allowed)

- Palliative radiation within 2 weeks

- Unresolved diarrhea >= CTCAE grade 2

- Pregnant or lactating women

- Women of childbearing potential (WCBP) (i.e. women able to become pregnant) not using
double-barrier methods of contraception (abstinence, oral contraceptives, intrauterine
device or barrier method of contraception in conjunction with spermicidal jelly, or
surgically sterile); male patients whose partners are WCBP not using double-barrier
methods of contraception

- Acute or chronic liver or renal disease

- Other concurrent severe and/or uncontrolled medical conditions that could cause
unacceptable safety risks or compromise compliance with the protocol

- Major surgery =< 2 weeks prior to randomization or who have not recovered from such
therapy

- History (or family history) of long QT syndrome

- Mean QTc >= 450 msec on baseline ECG

- History of clinically manifested ischemic heart disease =< 6 months prior to study
start

- History of heart failure or left ventricular (LV) dysfunction (LVEF =< 45%) by MUGA or
ECG

- Clinically significant resting bradycardia (< 50 beats per minute)

- Clinically significant ECG abnormalities including 1 or more of the following: left
bundle branch block (LBBB), right bundle branch block (RBBB) with left anterior
hemi-block (LAHB); ST segment elevation or depression > 1mm, or 2nd (Mobitz II), or
3rd degree AV block

- History ventricular tachycardia

- Other clinically significant heart disease including congestive heart failure (New
York Heart Association class III/IV) or uncontrolled hypertension (> 160/90 despite
intensive medical management)

- Patients who are currently receiving treatment with any medication which has a
relative risk of prolonging the QTcF interval and cannot be switched or discontinued
to an alternative drug prior to commencing AUY922

- Known diagnosis of HIV infection (HIV testing is not mandatory)

- Patients with a history of another primary malignancy that is currently clinically
significant or currently requires active intervention

- Patients who are receiving warfarin (Coumadin®) will be excluded unless =< 2 mg/d,
with an INR < 1.5

- Patients with known disorders due to a deficiency in bilirubin glucuronidation (e.g.
Gilbert's syndrome)