A Phase I/II Trial of Hsp 90 Inhibitor AUY-922 in Patients With Lung Adenocarcinoma With "Acquired Resistance" to EGFR Tyrosine Kinase Inhibitors
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)