| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Multiple myeloma in the relapsed and relapsed/refractory stage |
|
| E.1.1.1 | Medical condition in easily understood language |
| Multiple myeloma is a form of blood cancer; specifically a cancer of the plasma cells |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 the dose escalation phase, the purpose of the study is to determine the
maximum tolerated dose (MTD) of panobinostat, administered in combination with VTD, in subjects with relapsed and relapsed/refractory multiple myeloma.
In the dose expansion phase the purpose of the study is to estimate the response rate (partial response or better) within 16 cycles of VTD-pano at the RD identified in the dose escalation phase.
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|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives
To confirm the safety profile of panobinostat in combination with VTD
To estimate the proportion of participants with each maximum response category within 16 cycles of therapy
To estimate time to maximum response to therapy
To estimate progression-free survival
To assess compliance to therapy
To determine the feasibility of panobinostat maintenance
Exploratory Objectives
To estimate overall survival
To estimate the proportion of participants mobilising sufficient stem cells for transplant (out of those undergoing mobilisation)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Patients with a previous diagnosis of multiple myeloma based on IMWG 2003 definitions:
o Monoclonal immunoglobulin (M component) on electrophoresis, and on immunofixation of serum or of total 24 hour urine
o Bone marrow (clonal) plasma cells ≥10% or biopsy proven plasmacytoma
o Related organ or tissue impairment (CRAB symptoms, anemia, hypercalcemia, lytic bone lesions, renal insufficiency, hyperviscosity, amyloidosis or recurrent infections)
• Relapsed or relapsed-and-refractory myeloma who have received 1-4 prior lines and now require further treatment
• Able to give informed consent and willing to follow study protocol
• Aged 18 years or over
• ECOG Performance Status ≤ 2
• Required laboratory values within 14 days of registration:
o Absolute neutrophil count ≥ 1.0 x 109/L. Growth factor support is not permitted within 14 days prior to eligibility assessment
o Platelet count ≥ 100 x 109/L. Platelet support is not permitted within 14 days prior to eligibility assessment
o Haemoglobin ≥ 8.0g/dL. Blood transfusion support is permitted
o Bilirubin ≤ 2 x upper limit of normal (ULN)
o AST and/or ALT ≤ 2.5 x ULN; except in subjects with known hepatic involvement, where AST and/or ALT ≤ 5.0 x ULN
o Serum creatinine ≤ 2.0 x ULN
o Corrected calcium ≤ 2.8 mmol/L.
• Anticipated survival of at least 3 months
• Evaluable disease per modified IWG criteria, utilising the following assessments as appropriate:
o Serum M protein ≥ 10g/l.
o Urine M protein ≥ 200mg/24 hours
o Serum free light chain assay: involved FLC level ≥ 100mg/l. Provided serum FLC ratio is abnormal
• Female subjects of child-bearing potential must have a negative pregnancy test at baseline and agree to use dual methods of contraception for the duration of the study and must continue to do so for 3 months after the end of treatment. Male subjects must agree to use a barrier method of contraception for the duration of the study if sexually active with a female of child-bearing potential and must continue to do so for 3 months after the end of treatment.
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|
| E.4 | Principal exclusion criteria |
• Pregnant (positive pregnancy test) or breastfeeding women.
• Non-secretory multiple myeloma
• Previous anti-tumour therapies, including prior experimental agents or approved anti-tumour small molecules and biologics, within 28 days before the start of protocol treatment. Steroid therapy is permitted (maximum 160mg dexamethasone or equivalent), but must be stopped 48 hours prior to study drug administration. Bisphosphonates for bone disease and radiotherapy for palliative intent are also permitted.
• Concurrent or previous malignancies (<12 months post end of treatment) at other sites with the exception of appropriately treated localised epithelial skin or cervical cancer, or incidental histologic findings of prostate cancer (TMN stage T1a or 1b). Patients with histories (≥12 months) of other tumours may be entered.
• Poorly controlled or serious medical or psychiatric illness that, in the Investigator’s opinion, is likely to interfere with participation and/or compliance in this clinical study
• Patients with significant cardiovascular disease (e.g. history of congestive heart failure requiring therapy, presence of severe valvular heart disease, presence of an atrial or ventricular arrhythmia requiring treatment, uncontrolled hypertension, a history of QTc abnormalities)
• Active symptomatic fungal, bacterial, and/or viral infection including known active HIV or known viral (A, B, or C) hepatitis.
• Gastrointestinal disorders that may interfere with absorption of the study drug
• Patients who have been refractory to prior bortezomib, i.e. did not achieve at least an MR, or who have progressed on therapy or within 60 days of last dose
• Participants with peripheral neuropathy CTC grade 2 or higher or grade 1 with pain within 14 days prior to registration
• Any history of known hypersensitivity to any of the study medication or excipients
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
In the dose escalation phase, the number of participants experiencing DLTs within the first cycle of VTD-pano is the primary outcome.
In the dose expansion phase, the primary outcome will be the proportion of participants achieving at least a partial response within 16 cycles of VTD-pano. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
During the dose escalation phase, at the end of each cohort.
Final analysis will be carried out when all participants have been followed up for at least 12 months and had response data observed. |
|
| E.5.2 | Secondary end point(s) |
Safety and toxicity
Proportion of participants with each maximum response category within 16 cycles of therapy
Time to maximum response to therapy
Progression-free survival
Compliance to therapy
Feasibility of panobinostat maintenance
Overall survival
Proportion of participants mobilising sufficient stem cells for transplant (out of those undergoing mobilisation)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Final analysis will be carried out on all but the feasibility of panobinostat maintenance endpoint when all participants have been followed up for at least 12 months and had response data observed.
The long-term endpoint, feasibility of panobinostat maintenance, will be analysed after the last participant has had their last active trial treatment at which point the progression-free and overall survival endpoints will be updated. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| The ‘end of trial’ will be defined as the end of the period of serious adverse event notification, that is 30 days after the last participant has had their last active trial treatment. At this point, the ‘end of trial notification’ will be submitted to the relevant regulatory authorities (e.g. UK MHRA) and ethics committees. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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