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.
- Conditions
- The primary purpose of the phase I dose-escalation component is to determine the maximum tolerated dose (MTD) of AUY922 when administered IV on a once-weekly schedule to adult patients with advanced solid malignancies.The primary purpose of the phase II expansion arms is to assess the response in patients with ER+ inoperable locally advanced or metastatic breast cancer and patients with HER2+ inoperable locally advanced or metastatic BC with a history of trastuzumab resistance.
- Registration Number
- EUCTR2006-002766-20-DE
- Lead Sponsor
- ovartis Pharma Services AG
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 125
1. Dose-escalation and 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 non-operable 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 at least 1 but no more than 2 prior anti HER2 based regimens including at
least 1 regimen containing trastuzumab. (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 non-operable locally advanced or metastatic breast cancer who received standard sequence lines of endocrine therapy and whose disease has progressed on at least one line of endocrine therapy for advanced disease.
c. All patients with locally advanced or metastatic breast cancer (HER2+ or ER+) must have progression of the disease on at least 1 but no more than 2 lines of chemotherapy.
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 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) no
F.1.3.1 Number of subjects for this age range
1. Patients with known CNS metastasis. 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 with the following exception:
• Patients with a diagnosis of GIST who have previously received and benefited from
treatment with retaspimycin are eligible for the study.
3. Patients who received systemic anti-cancer treatment prior to first dose of AUY922 within the following time frames:
• Radiotherapy within 4 weeks
• Palliative radiotherapy: within 2 weeks
• Nitrosureas, mitomycin and monoclonal antibodies, such as 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 not recovered from side effects of previous systemic anticancer therapy to less than grade 2 CTCAE prior to 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
antihypertensiv
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