| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relasped and Refractory Mulitple Myeloma |
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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 | 18.0 |
| 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 evaluate whether ixazomib in combination with cyclophosphamide and dexamethasone (ICD) has improved clinical activity compared to cyclophosphamide and dexamethasone (CD) in patients with RRMM who have relapsed after treatment with thalidomide, lenalidomide and bortezomib. Specifically the study will assess whether ICD provides superior activity in terms of progression-free survival. |
|
| E.2.2 | Secondary objectives of the trial |
• To further evaluate the clinical activity of ICD with regard to additional secondary endpoints
• To determine the safety and toxicity profile of ICD
• To estimate the cost-effectiveness of ICD vs. CD
• To determine quality of life with ICD
• To assess the impact of baseline Charlson index score on outcomes and deliverability of planned treatment
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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 assessments
•Aged 18 years or over
•Participants with confirmed MM based on IMWG criteria, 2009
•Measurable disease with at least one of the following: 1.Paraprotein >5g/L or 0.5 g/l for IgD subtype; 2.Serum free light chains >100mg/L with abnormal radio for light chain only myeloma; 3.Bence Jones protein >200mg/L
•Participants with relapsed or relapsed refractory myeloma and now require further treatment following exposure to thalidomide, lenalidomide and bortezomib regardless of response to these.
•ECOG Performance Status ≤ 2
•Required laboratory values within 14 days prior to Randomisation:
-Platelet count ≥50x109/L. Platelet count of 30-50 is acceptable if bone marrow aspirate shows tumour replacement of >50%. Platelet support is permitted within 14 days prior to randomisation although platelet transfusions to help patients meet eligibility criteria are not allowed within 72 hours prior to the blood sample to confirm protocol eligibility
-Absolute neutrophil count ≥1.0 x 109/L. Growth factor support is not permitted within 14 days prior to randomisation
-Haemoglobin > 9 g/dL. Blood support is permitted
-ALT and / or AST ≤3 x upper limit of normal
-Creatinine clearance ≥ 30 ml/min (using Cockcroft Gault formula)
-Bilirubin ≤1.5 x upper limit of normal
•Female participants should avoid becoming pregnant and male participants should avoid impregnating a female partner. Both non-sterilised and sterilised females and males of reproductive age should use effective methods of contraception during the entire trial treatment (including treatment breaks) and up to 90 days after the last dose of trial treatment.
•Post allograft patients may be included if >12 months from transplant.
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|
| E.4 | Principal exclusion criteria |
•Those with non-measurable disease, a solitary bone or solitary extramedullary plasmacytoma, Plasma cell leukaemia
• Prior malignancy other than those treated with surgery.
• Participants with a known or underlying uncontrolled concurrent illness that, in the investigators opinion, would make the administration of the study drug hazardous 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 participant compliance, or any other condition (including laboratory abnormalities) that in the opinion of the Investigator places the participant at unacceptable risk for adverse outcome if he/she were to participate in the study.
• Patients who have previously received Ixazomib or MLN9708 in a trial. Previous experimental agents or approved anti-tumour treatment within 30 days before the date of randomisation.
• A maximum of 160mg of dexamethasone (in 40mg blocks) may be given between screening and the beginning of treatment if medically required but should be stopped before trial treatment starts. Bisphosphonates for bone disease and radiotherapy for palliative intent are also permitted.
• Participants with a history of a refractory nausea, diarrhoea, vomiting, malabsorption, gastrointestinal surgery or other procedures that might, in the opinion of the Investigator, interfere with the absorption or swallowing of the study drug(s)
• Peripheral neuropathy of ≥ grade 2 (or grade 1 with pain) severity (as per NCI-CTCAEv4.0)
• Gastrointestinal disorders that may interfere with absorption of the study drug
• Active symptomatic fungal, bacterial, and/or viral infection including known active HIV or known viral (A, B or C) hepatitis
• Female patients who are lactating or have a positive pregnancy test during the screening period
• Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
• Systemic treatment, within 14 days before the first dose of Ixazomib, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort
• Major surgery within 14 days prior to the date of randomisation
• Radiotherapy within 7 days for palliative pain control or therapeutic radiotherapy within 14 days prior to randomisation.
• Myeloma involving the Central Nervous System.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint for the proposed trial is progression free survival. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| One interim analysis for superiority of ICD is planned to take place when 70% of the PFS events (139) have been observed. This is estimated to be approximately 24-26 months post-opening the trial. No other formal statistical testing will take place until final analysis. |
|
| E.5.2 | Secondary end point(s) |
•Response to treatment
•Maximum response
•Time to progression
•Time to maximum response
•Response duration
•Overall survival
•Treatment compliance
•Safety and toxicity
•Cost-effectiveness
•Quality of life |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoint analysis will be in accordance with the statistical analysis plan which will be finalised before any data is evaluated. No formal statistical testing will take place until final analysis. The economic analyses will only take place at study end.
•Treatment compliance will be based upon data collected during treatment, at the end of treatment and during follow up.
•Safety and toxicity will be analysed based on SAE, SAR and SUSAR data collected from patient consent until 28 days post the cessation of the trial therapy.
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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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 20 |
| 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 the trial is defined as the last participant's last data item. |
|
| 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 | 1 |
| 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 | 1 |
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