| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER-2 positive locally recurrent or metastatic breast cancer |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER-2 positive breast cancer |
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| 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 |
| To assess the effect (objective response rate) of i.v. and oral panobinostat monotherapy using RECIST criteria as per investigator assessment. |
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| E.2.2 | Secondary objectives of the trial |
• To assess the effect (objective response rate) of i.v. and oral panobinostat monotherapy as per independent central review
• To assess the progression-free survival, the time to response, the duration of response, the disease control rate and the overall survival of i.v. and oral panobiostat monotherapy
• To evaluate the safety and tolerability profile of i.v. and oral panobinostat monotherapy, with careful monitoring of the QTcF interval.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
- Exploratory biomarker studies - finale version 1.0 dated 19 June 2008 - to evaluate changes in pharmacodynamic, proliferation and apoptosis markers and for exploratory pharmacogenomics analysis.
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| E.3 | Principal inclusion criteria |
• Women ≥ 18 years old
• Patients with an ECOG performance status of ≤ 2 assessed within 2 weeks (14 days) prior to randomization
• Histologically or cytologically confirmed invasive breast carcinoma with locally recurrent or radiological evidence of metastatic disease. Locally recurrent disease must not be amenable to resection with curative intent.
• Measurable disease per RECIST guidelines
• HER2-positive breast cancer patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive).
• Prior trastuzumab-containing regimen (in neoadjuvant and/or adjuvant and/or metastatic settings) regardless of whether trastuzumab was given as monotherapy or in combination with chemotherapy. Any number of prior trastuzumab regimens is acceptable. Additional treatment with lapatinib after or before trastuzumab treatment is permitted, but not mandatory.
• Radiological evidence of relapse or disease progression while on trastuzumab (or lapatinib) or within 12 months of the last dose of adjuvant trastuzumab.
• Complete radiology and tumor assessment within 4 weeks (28 days) prior to randomization:
Chest: CT scan with intravenous contrast if the contrast is not medically contraindicated or MRI
Abdomen: CT scan with intravenous and oral contrast if the contrast is not medically contraindicated or MRI
Brain: CT scan or MRI
Bone: Whole body Bone Scintigraphy
• Up to 2 prior cytotoxic chemotherapy regimens, in addition to neo-adjuvant and adjuvant, for treatment of metastatic or locally recurrent breast cancer (including those cyctotoxic chemotherapy treatments in combination with trastuzumab and/or lapatinib)
• Patients must meet the following laboratory criteria within 2 weeks (14 days) prior to randomization:
• Hematology
• Neutrophil count of > 1200/mm3
• Platelet count of > 100,000/mm3
• Hemoglobin ≥ 90 g/L
• 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
• Serum potassium, sodium, magnesium, phosphorus, total calcium (corrected for serum albumin) or ionized calcium within normal limits for the institution
• Serum albumin ≥ LLN or 30g/L
• Clinically euthyroid function (TSH and free T4). (Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism).
• LVEF assessment (2-D echocardiogram or MUGA scan) performed within 6 weeks prior to randomization, showing a LVEF value > 50%
• Electrocardiogram performed within 1 week prior to randomization (details about findings on the Electrocardiogram that are not acceptable for participating in the study are reported in the Exclusion criteria section)
• Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization and agree to appropriate method of pregnancy prevention
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|
| E.4 | Principal exclusion criteria |
• Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer
• Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment
• Patients who have received prior chemotherapy or investigational agent within the last 4 weeks prior to randomization (6 weeks for nitrosoureas and mitomycin; 2 weeks for capecitabine)
• Patients who have received prior radiotherapy to ≥ 25% of the bone marrow within the last 4 weeks prior to randomization; local radiotherapy is allowed however all recently irradiated lesions should not be included in the measurable disease assessment
• Patients who have received prior investigational agents within the last 4 weeks prior to randomization
• Patients with unresolved diarrhea ≥CTCAE grade 1
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat
• History of cardiac dysfunction including any one of the following:
• Complete left bundle branch block or necessasity for a permanent cardiac pacemaker or congenital long QT syndrome or history or presence of ventricular tachyarrhythmias or clinically significant resting bradycardia (<50 beats per minute) or QTcF > 450 msec on screening ECG or right bundle branch block and left anterior hemiblock (bifasicular block)
• 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 of randomization
• Congestive heart failure (New York Heart Association functional classification III-IV)
• Other clinically significant heart disease (e.g. 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 untreated 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 treatments cannot be discontinued or switched to a different medication prior to starting study drug
• Brain metastases, unless patient randomized on study at least 90 days from completion of brain radiotherapy and / or surgery without radiologic or functional evidence of progressive brain metastases, and off corticosteroids above the dose of 7.5 mg prednisone or equivalent; No concurrent radiotherapy for brain metastasis is allowed
• Clinically significant third space fluid accumulation
• Concurrent bisphosphonates unless if initiated prior to study entry (at least 4 weeks before study randomization)
• Pregnant (i.e., positive beta-human chorionic gonadotropin test) or breast feeding
• Unable to swallow oral medications
• Not willing to use a double barrier method of non-hormonal birth control. Contraception must be used during the study and for 90 days after last dose of study treatment.
• Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate (as determined by the investigator): the percentage of patients assigned to a treatment arm with a confirmed best response of CR or PR. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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