E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER positive metastatic breast cancer |
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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 |
• During dose escalation, to determine the MTD of panobinostat that can be combined with trastuzumab, in patients with HER2-positive MBC whose disease has progressed on or after trastuzumab: Arm I - Determine the MTD of panobinostat i.v. given on D1, D8 as part of a 21 day cycle, combined with standard doses of trastuzumab in patients with HER2-positive MBC Arm II - Determine the MTD of oral panobinostat given as part of a 21 day cycle, combined with standard doses of trastuzumab in patients with HER2-positive MBC • During expansion of the MTD, to preliminarily explore the anti-tumor activity of i.v. and oral panobinostat at their respective MTDs when combined with trastuzumab using RECIST criteria
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E.2.2 | Secondary objectives of the trial |
•To evaluate: -the safety and tolerability profile of i.v. / oral panobinostat when in combination with trastuzumab -the preliminary efficacy of i.v./oral panobinostat when in combination with trastuzumab using RECIST criteria •To characterize the PK profile of i.v. & oral panobinostat after single and multiple doses when given in combination with trastuzumab (dose escalation only) •To monitor the QTc interval in patients receiving i.v. and oral panobinostat when combined with trastuzumab •To characterize potential biological factors, such as serum HER2 ECD, circulating tumor cells and apoptosis markers, that could correlate with efficacy and response (additional exploratory and/or optional biomarkers may be evaluated.) See Biomarker section •At the end of dose expansion phase, a risk-benefit analysis will be performed in the population evaluable for efficacy, to assess both risk (safety) and benefit (efficacy) for both the oral and iv arms of panobinostat
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Female patients ≥ 18 years old • Patients with an ECOG performance status of ≤ 2 • Histologically or cytologically confirmed breast cancer with radiological evidence of metastatic disease. • During dose escalation metastatic disease can be non-measurable or measurable. • During recruitment of the additional patients for dose expansion, only measurable disease is acceptable • History of HER2-positive MBC patients (ICH 3+ staining or FISH (+ve) or ICH 2+ only if FISH (+ve). Whenever it is feasible HER2 status should be confirmed at metastatic stage of the disease at baseline and post-treatment • Prior trastuzumab-containing regimen (in neoadjuvant and/or adjuvant and/or metastatic setting) regardless of whether trastuzumab was given as monotherapy or in combination with chemotherapy. Any number of prior trastuzumab regimens is acceptable • Radiological evidence of progression while on trastuzumab or within 6 months of last dose of trastuzumab • Radiological evidence of progression on or following most recent therapy within three months of study entry • Up to 2 prior chemotheraphy regimens for treatment of MBC (including chemotherapy treatment in combination with trastuzumab) • Hormone receptor status: HR (ER/PR) positive or negative (or indeterminate) • Patients must meet the following laboratory criteria: • Hematology • Neutrophil count of ≥1500/mm3 • Platelet count of > 100,000/mm3L • Hemoglobin ≥ 9 g/dL • Biochemistry • AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if the transaminase elevation is due to disease involvement • Serum bilirubin ≤ 1.5 x ULN • Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min • Total serum calcium (corrected for serum albumin) or ionized calcium ≥ LLN and ≤ULN • Serum potassium > LLN and ≤ULN • Serum sodium ≥ LLN and ≤ULN • Serum albumin ≥ LLN or 3g/dl • Serum magnesium ≥ LLN and ≤ULN • Serum phosphatase ≥ LLN and ≤ULN • Serum phosporus ≥ LLN and ≤ULN • Patients with any elevated Alkaline Phosphatase due to bone metastasis can be enrolled • Clinically euthyroid (patients may be on thyroid hormone replacement) • Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of the first administration of study treatment and must be willing to use two methods of contraception, one of them being a barrier method, during the study and for 3 months after last study drug administration.
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E.4 | Principal exclusion criteria |
• Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer • Patients who need valproic acid for any other medical condition during the study or within 5 days prior to first LBH589 treatment • Patients who have received prior chemotherapy within the last 4 weeks (6 weeks for nitrosoureas and mitomycin: 2 weeks for capecitabine) • Patients who have received prior radiotherapy within the last 4 weeks • Patients who have received prior investigational agents within the last 4 weeks • Patients who have received prior radiotherapy to >30% of the bone marrow • Patients with unresolved diarrhea > CTCAE grade 1 • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat • Impaired cardiac function, including any one of the following: • LVEF < 50% as determined by ECHO or MUGA • Complete left bundle branch block or obligate use of a cardiac pacemaker or congenital long QT syndrome or history or presence of ventricular tachyarrhythmias or clinically significant resting bradycardia (<50 beats per minute) or QTc > 450 msec on screening ECG or right bundle branch block and left anterior hemiblock (bifasicular block) • Medical history of long QTc syndrome • Family history of sudden death • Medical history of unexplained syncope • Presence of unstable atrial fibrillation (ventricular response rate >100 bpm). Patients with stable atrial fibrillation are allowed in the study provided they do not meet the other cardiac exclusion criteria • Previous history angina pectoris or acute MI within 6 months • New York Heart Association functional classification III-IV • Other clinically significant heart disease (e.g. congestive heart failure, cardiomyopathy, cardiac artery disease, uncontrolled hypertension, or history of poor compliance with an antihypertensive regimen) • Acute or chronic liver or renal disease • Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes mellitus, active or uncontrolled infection, chronic obstructive or chronic restrictive pulmonary disease including dyspnoea at rest from any cause) that could cause unacceptable safety risks or compromise compliance with the protocol • Concomitant use of drugs with a risk of causing torsades de pointes where such treatment cannot be discontinued or switched to a different medication prior to starting study drug • Concomitant use of CYP3A4/5 inhibitors • Active bleeding diathesis or on any treatment with therapeutic doses of sodium warfarin or any other anti-vitamin K • Uncontrolled or symptomatic brain metastasis (No concurrent radiotherapy for brain metastasis) • Symptomatic pleural effusion • Clinically significant third space fluid accumulation • Concurrent biphosphonates allowed if initiated prior to study entry ( at least 4 weeks before study entry) • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/ml • Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable written informed consent
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoints: MTD of panobinostat i.v. and oral in combination with trastuzumab, overal anti-tumor response rate at the MTDs during dose expansion
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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 | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Information not present in EudraCT |
E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
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.8.6 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 | No |
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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |