A phase I dose escalation, multi-center, open-label study of AUY922 administered IV on a once-weekly schedule in adult patients with advanced solid malignancies including phase II expansion arms in patients with either HER2 positive or ER positive locally advanced or metastatic breast cancer. - N/A
- Conditions
- Dose-expansion study to assess safety, tolerability & efficacy:-One arm (MTD expansion) will enroll advanced cancer patients (other than breast carcinoma).-Two arms (phase II) to assess response in following breast cancer patients:1. HER2+ inoperable locally advanced or metastatic breast cancer.2. ER+ inoperable advanced/metastatic breast cancer progressed on at least 1 and received up to 3 lines of standard seq. endocrine therapy and who received up to 2 lines of cytotoxic therapy.
- Registration Number
- EUCTR2006-002766-20-GB
- Lead Sponsor
- ovartis Pharma Services AG
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- Female
- Target Recruitment
- Not specified
1. MTD dose expansion arm: Patients with histologically confirmed, advanced malignant solid tumors whose disease has progressed on standard therapy or for whom no standard therapy exists.
Breast cancer phase II expansion arms only
a. Female patients with ER positive HER2 positive inoperable locally advanced or
metastatic breast cancer must have:
• History of trastuzumab resistance, defined as either local or systemic disease
progression on treatment with at least 8 weeks of a trastuzumab containing regimen.
• Received up to 3 prior anti HER2 based regimens (i.e. trastuzumab and/or lapatinib in combination with other agents) for advanced disease.
• Recieved up to 2 lines of cytotoxic therapy for advanced disease.
Patients who develop metastases while receiving adjuvant or neo-adjuvant trastuzumab are eligible.
HER2 positive patients, tumor/s must demonstrate HER2 over-expression based on either:
• Immunohistochemistry (IHC) at the 3+ level, or
• IHC 2+ confirmed by fluorescence in-situ hybridization (FISH). Tumors tested by FISH must be positive by the specific FISH assay for the amplification of HER2.
b. Female patients with ER positive inoperable locally advanced or metastatic breast cancer whose disease has progressed on at least one and up to 3 lines of std squence endocrine therapy and who have received up to 2 lines of cytotoxic therapy for advanced disease.
2. All patients must have at least one measurable lesion as defined by RECIST. Irradiated lesions are only evaluable for disease progression.
3. All patients must have progressive disease before entering to the study.
4.Patients who fulfill the following criteria will be eligible for PET assessments:
Indications: tumor types expected to have a high FDG uptake, such as breast, lung, GIST, melanoma & colorectal cancer.
• At least one lesion must be measurable (>2cm).
• To be eligible for follow-up scans, patients should have uptake of the tracer in at least one lesion with a tumor-muscle ratio =2.
• Able to lie still and flat on the PET table.
5. Age = 18 years.
6. World Health Organization (WHO) Performance Status of = 2.
7. Life expectancy of = 12 weeks.
8. Patients must have the following laboratory values:
• Absolute Neutrophil Count (ANC) = 1.5 x 109/L
• Hemoglobin (Hgb) = 9 g/dl
• Platelets (plt) = 100 x 109/L
• Potassium within normal limits or correctable with supplements
• Total calcium (corrected for serum albumin) within normal limits or correctable with
supplements
• Magnesium within normal limits or correctable with supplements
• Phosphorus within normal limits or correctable with supplements
• AST/SGOT and ALT/SGPT = 2.5 x Upper Limit of Normal (ULN) or = 5.0 x ULN if
liver metastases are present
• Serum bilirubin = 1.5 x ULN
• Serum albumin = 2.5g/dl
• Serum creatinine = 1.5 x ULN or 24-hour clearance = 50 ml/min
• Negative serum pregnancy test. The serum pregnancy test must be conducted prior to the first administration of AUY922 (=72 hours prior to dosing) in all pre-menopausal women and women < 2 years after the onset of menopause.
9. Able to sign informed consent and to comply with the protocol.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range
1. Patients with CNS metastasiswhich are symptomatic or require ttt for symptom control and/or growing. Note: patients without clinical signs or symptoms of CNS involvement are not required to have a CT/MRI of the brain.
2. Prior treatment with any HSP90 or HDAC inhibitor compound.
3. Patient who received systemic anti-cancer treatment prior to the first dose of AUY922 within the following time frames:
• Chemotherapy within 4 weeks
• Wide-field radiotherapy within 4 weeks
• Localized palliative radiotherapy: within 2weeks
• Trastuzumab ttt within 4 weeks
• Nitrosoureas, mitomycin and monoclonal antibodies (except trastuzumab): within 6 weeks
• Any continuous-dosing (i.e. daily dosing, every-other-day dosing, Monday- Wednesday-Friday dosing, weekly etc) of systemic anticancer treatment for
which the recovery period is not known, or investigational drugs (i.e. targeted agents) within a duration of = 5 half lives of the agent and their active metabolites (if any)
4. Patients who have recovered from side effects of previous systemic anticancer therapy to less than grade 2 CTCAE prior to the first dose of study treatment
5. Treatment with therapeutic doses of sodium warfarin (Coumadin). Low doses of
Coumadin (e.g. = 2mg/day for line patency) are permitted.
6. Patients using medications that are substrates, inhibitors or inducers of CYP3A4,
CYP2C8, CYP2C9 and CYP2C19 and cannot be switched or discontinued to an
alternative drug prior to commencing AUY922 dosing need special consideration (please refer to Post-text supplement 2 and see Section 6.6.7 for further details).
7. Unresolved diarrhea = CTCAE grade 2.
8. Patients who do not have either an archival tumor sample available or are unwilling to have a fresh tumor sample collected at baseline.
9. Pregnant or lactating women.
10. Fertile women of childbearing potential (WCBP) not using adequate 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 adequate contraception.
11. Acute or chronic liver disease.
12. Acute or chronic renal disease.
13. Other concurrent severe and/or uncontrolled medical conditions (e.g. uncontrolled
diabetes, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol.
14. Cardiac exclusion criteria:
• History (or family history) of long QT syndrome.
• Mean QTc = 450 msec on screening ECG.
• History of clinically manifest ischemic heart disease including myocardial infarction,
stable or unstable angina, coronary arteriography or cardiac stress testing/imaging
with findings consistent with coronary occlusion or infarction, = 6 months prior to
study start.
• History of heart failure or left ventricular (LV) dysfunction (LVEF = 45%) by MUGA
or ECHO.
• Clinically significant ECG abnormalities including one or more of the following: left
bundle branch block (LBBB), right bundle branch block (RBBB) with left anterior
hemiblock (LAHB). ST segment elevations or depressions > 1mm, or 2nd (Mobitz II)
or 3rd degree AV block.
• History of atrial fibrillation, atrial flutter or ventricular arrhythmias including
ventricular tachycardia or Torsades de Pointes.
• Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled
hypertension, history of labile hypertension, or history of poor compliance with an
antihypertensive regimen).
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Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method