| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 | 10028228 |
| E.1.2 | Term | Multiple myeloma |
|
| 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 determine the MTD of LBH589 and bortezomib when administered in combination |
|
| E.2.2 | Secondary objectives of the trial |
| To characterize the safety and tolerability of the study treatment To characterize the PK profile of bortezomib in combination with LBH589 To compare the PK profile of LBH589 with and without bortezomib To characterize the PD profile of the study treatment through the analysis of various biomarkers To assess the preliminary efficacy of the study treatment |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
| 1. Patients must have a diagnosis of active multiple myeloma according to the International Myeloma Working Group criteria (IMWG et.al., 2003), and be deemed by the investigator as requiring treatment. 2. Patients must have received at least one prior line of therapy and their disease has relapsed (Durie et. al., 2006). One prior line of therapy may consist of induction followed by autologous stem cell transplantation. 3. Patients must be suitable (according to their local product information) for treatment with bortezomib. Note: patients previously treated with bortezomib are eligible to participate in the trial. 4. Adults ≥ 18 years old 5. ECOG Performance Status ≤ 2 6. Life expectancy > 12 weeks 7. Patients must have the following laboratory values: ANC ≥ 1.5 x 109/L Hemoglobin ≥ 9 g/dl Platelets ≥ 100x 109/L Calculated CrCl ≥ 50 mL/min (MDRD Formula) AST and ALT ≤ 2.5 x ULN Serum bilirubin ≤ 1.5 x ULN Albumin > 3.0 g/dl Serum potassium ≥ LLN Total serum calcium [corrected for serum albumin] or ionized calcium ≥LLN, Serum magnesium ≥ LLN Serum phosphorus ≥ LLN TSH ≤ LLN and free T4 within normal limits. Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism. Baseline MUGA or ECHO must demonstrate LVEF ≥ the lower limit of the institutional normal Patients participating in the dose-expansion phase of the trial must be willing and able to undergo bone marrow aspirates as per protocol, with/without bone marrow biopsy according to their center’s practice Able to sign informed consent and to comply with the protocol |
|
| E.4 | Principal exclusion criteria |
| 1. Prior exposure to a HDAC inhibitor compound used in the treatment of MM 2. Primary refractory MM 3. Patients who have received allogeneic stem cell transplantation < 12 months prior to entering the study 4. Patients who have had prior allogeneic stem cell transplantation and show evidence of active graft-versus-host disease that requires immunosuppressive therapy 5. Peripheral neuropathy ≥ CTCAE grade 1 6. Impaired cardiac function or clinically significant cardiac diseases, including any one of the following: Patients with congenital long QT syndrome History or presence of sustained ventricular tachyarrhythmia. (Patients with a history of atrial arrhythmia are eligible but should be discussed with the Sponsor prior to enrollment) Any history of ventricular fibrillation or torsade de pointes Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if HR ≥ 50 bpm. Screening ECG with a QTc > 450 msec Right bundle branch block + left anterior hemiblock (bifascicular block) Patients with myocardial infarction or unstable angina ≤ 6 months prior to starting study drug Other clinically significant heart disease (e.g., CHF NY Heart Association class III or IV , uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen) 7. Impairment of GI function or GI disease that may significantly alter the absorption of LBH589 8. Patients with diarrhea > CTCAE grade 1 9. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol 10. Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug 11. Concomitant use of CYP3A4 inhibitors 12. Patients who have received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (which ever is longer) and who have not recovered from side effects of those therapies. 13. Patients who have received either immunotherapy within < 8 weeks; chemotherapy within < 4 weeks; or radiation therapy to > 30% of marrowbearing bone within < 2 weeks prior to starting study treatment; or who have not yet recovered from side effects of such therapies. 14. Patients with an active bleeding tendency or is receiving any treatment with therapeutic doses of sodium warfarin (Coumadin) or coumadin derivatives. Low doses of Coumadin (e.g. ≤ 2 mg/day) to maintain line patency (if applicable) is allowed. 15. Patients who have received steroids (e.g. dexamethasone) ≤ 2 weeks prior to starting study treatment or who have not recovered from side effects of such therapy. Concomitant therapy medications that include corticosteroids are allowed if patients receive < 10 mg of prednisone or equivalent as indicated for other medical conditions, or up to 100 mg of hydrocortisone as pre-medication for administration of certain medications or blood products while enrolled in this study. 16. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy 17. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not using an effective method of birth control. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). Women of childbearing potential must have a negative serum pregnancy test within 8 days prior to receiving the first dose of study medication. 18. pls see protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety: The incidence of dose limiting toxicities (DLT) |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| 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 | Yes |
| 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 | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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.8.5 | 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 |
|
| 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
| |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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