E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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. |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Dose escalation arm: To determine the MTD of AUY922 as a single agent when administered IV on a once a weekly schedule to adult pts with advanced solid tumors despite standard therapy or for whom no standard therapy exists. Breast cancer dose expansion arm: At the MTD two further arms will be expanded to assess response in the following breast cancer pt: 1. Pts with HER2+ inoperable locally advanced or metastatic breast cancer: • History of trastuzumab resistance • Received up to 3 prior anti HER2 based regimens (ie trastuzumab and/or lapatinib in combination with other agents) and up to 2 lines of cytotoxic therapy for advanced disease. • Pts who develop metastases while receiving adjuvant or neoadjuvant trastuzumab 2. Pts with ER+ inoperable locally advanced or metastatic breast cancer whose disease has progressed on at least 1 and received up to 3 lines of standard sequence endocrine therapy and who received up to 2 lines of cytotoxic theraoy for advanced disease |
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E.2.2 | Secondary objectives of the trial |
• Characterize the safety, tolerability, PK profiles of AUY922, assess safety and preliminary anti-tumor activity and explore potential PK and PD correlation • Assess changes in pre and post AUY922 dosing in: -target and downstream PD markers in PBMCs and in tumor tissue biopsies -relevant client proteins and in cellular response markers in biopsies of tumor tissue -cellular response markers in peripheral blood •Quantitate the nb of CTC • Assess: -changes in the HER2 extracellular domain in pre and post AUY922 dosing in peripheral blood in HER2+ and ER+(including HER2-) locally advanced or metastatic breast cancer pts -genetic variants of the UGT1A1 gene and their potential impact on the PK profiles -the original status of the HER2 and ER HSP90 client proteins in archival tumor tissue, the mutational status of specific genes of client proteins in tumor tissue, and their potential association with response -changes in cellular physiology • Evaluate the biomarkers |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
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. Females patients with 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 (ie trastuzumab and/or lapatinib in combination with other agents) for advanced disease. • Received 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 sequence 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 patientsmust 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. |
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E.4 | Principal exclusion criteria |
1. Patients with CNS metastasis. which 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. Patients 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 2 weeks • 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 not recovered frfom 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). • Clinically significant resting bradycardia (< 50 beats per minute). • Patients who are currently receiving treatment with any medication which has a relative risk or prolonging the QTcF interval or inducing Torsades de Pointes (as listed in Post-text supplement 2) and cannot be switched or discontinued to an alternative drug prior to commencing AUY922 dosing. • Obligate use of a cardiac pacemaker. 15. Known diagnosis of HIV infection (HIV testing is not mandatory). 16. Patients with known disorders due to a deficiency in bilirubin glucuronidation (e.g Gilbert’s syndrome). 17. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention. 18. Patients unwilling or unable to comply with the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1: Dose escalation arm - Determination of the MTD • Incidence rate of Dose Limiting Toxicities (DLT) Phase 2: Breast cancer dose expansion arm - HER2 positive and ER positive • Efficacy: For locally advanced or metastatic breast cancer expansion arms patients only; categorical endpoint with categories responders (CR and/or PR), non-responders with stable disease for at least 6 months (SD ≥ 6 months), progressive disease within 6 months from study start or other (PD) according to a multinomial design. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Information not present in EudraCT |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
determine the maximum tolerated dose |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Information not present in EudraCT |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |