E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 100000004864 |
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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 overall response rate (partial response or better) of patients with relapsed multiple myeloma, after combination treatment with vorinostat, bortezomib and dexamethasone.
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E.2.2 | Secondary objectives of the trial |
Secondary objectives:
• To assess the dose reduction profile of combination treatment with vorinostat, bortexomib and dexamethasone • To assess the safety, toxicity of combination treatment with vorinostat, borrtezomib and dexamethasone • To assess progression free survival • To assess the proportion of patients who attain a very good partial response or better • To assess patients maximum response to treatment and time to maximum response
Exploratory objectives:
• To perform a matched pair analysis of overall response rates, PFS, and toxicity with patient’s randomised in the pivotal MSD Phase III study • To assess overall survival
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Able to give informed consent and willing to follow study protocol and quality of life assessments • Aged 18 years or over • Participants with relapsed multiple myeloma who have received 1-3 prior lines of treatment and now require further treatment • ECOG Performance Status ≤ 2 • Required laboratory values: - Absolute neutrophil count ≥1.0 x 10^9/L - Platelet count ≥75x10^9/L - Haemoglobin > 9 g/dL - Bilirubin ≤1.5 x upper limit of normal - ALT and / or AST ≤2.5 x upper limit of normal - Serum creatinine ≤ 2.0 x upper limit of normal - Corrected calcium ≤ 2.8 mmol/L • Life expectancy of at least 3 months • 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 • Patient is able to swallow capsules and is able to take or tolerate oral medications on a continuous basis. |
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E.4 | Principal exclusion criteria |
• 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 to stop rapid relapse during this period is permitted, but must be stopped 7 days prior to study drug administration. Bisphosphonates for bone disease and radiotherapy for palliative intent are also permitted. • Prior HDAC inhibitor treatment. Participants who have received compounds with HDAC inhibitor like activity, such as valproic acid, as anti-tumour therapy must not be enrolled in this study. (Participants who have received such compounds for other indications e.g. valproic acid for epilepsy, may enrol after a 30 day washout period) • 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. Patients with histories (≥12 months) of other tumours may be entered • Patients considered to be refractory to prior bortezomib treatment, defined as: - Relapse on OR within 60 days after the last dose of a bortezomib containing regimen - No clinical response (≤ SD/NC) on a bortezomib containing regimen. • Peripheral neuropathy of ≥ grade 2 severity • Patients who have received growth factor support or platelet support within 14 days prior to registration • Patient has uncontrolled concurrent illness or circumstances that could limit compliance with the study, including, but not limited to the following: acute or chronic graft versus host disease, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within past 6 months, uncontrolled cardiac arrhythmia, renal failure, psychiatric or social conditions that may interfere with patient compliance, or any other condition (including laboratory abnormalities) that in the opinion of the Investigator places the patient at unacceptable risk for adverse outcome if he/she were to participate in the 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 or with QTC interval > 480 msecs • Active symptomatic fungal, bacterial, and/or viral infection including known active HIV or known viral (A, B, or C) hepatitis. • Pregnant or breast feeding females • Unable to take corticosteroid therapy at study entry • Patient has known hypersensitivity to any components of bortezomib, (such as boron, mannitol), or vorinostat. • Patient has known CNS metastases and/or carcinomatous meningitis. • Patient has a history of a gastrointestinal surgery or other procedures that might, in the opinion of the Investigator, interfere with the absorption or swallowing of the study drug(s)
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of patients who achieve at least a partial response within 8 cycles of treatment with vorinostat, bortezomib and dexamethasone as defined by the modified IWG criteria.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Response to treatment will be assessed every 4 weeks whilst on induction treatment for a maximum of 8 cycles following the Modified IWG Uniform Response Criteria (IMWG). An overall assessment of the primary endpoint will be made at the end of induction therapy. |
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E.5.2 | Secondary end point(s) |
• Proportion of participants receiving dose reductions of vorinostat or bortezomib, or terminating treatment early due to toxicity
• Safety and toxicity
• Progression free survival
• Proportion of patients achieving at least a very good partial response (VGPR) within 8 cycles of treatment
• Maximum response of patients to treatment overall and within 8 treatment cycles
• Time to maximum response
Exploratory endpoints:
• Overall survival
• To perform a matched pair analysis of overall response rates, progression free survival, dose reductions and toxicity with patients randomised in the pivotal MSD phase III study
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Safety, toxicity and tolerability - safety and toxicity is assessed throughout the study and tolerability at the end of each treatment cycle, every 4 weeks during induction therapy and 4 weekly whilst on maintenance • Progression free survival - progression status is assessed at the end of each treatment cycle, every 4 weeks during induction therapy and 4 weekly whilst on maintenance • Proportion of patients achieving at least a VGPR; maximum response to treatment; time to maximum response - response is assessed every three weeks whilst on induction therapy and every 4 weeks during maintenance
• Overall survival - survival status will be assessed prior to final analysis
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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 | 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 | No |
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
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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 | 3 |
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 | 3 |
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 |