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)