| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed high risk multiple myeloma |
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| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the bone marrow. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Information not present in EudraCT |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine whether a combination of four novel agents bortezomib (Velcade), lenalidomide (Revlimid), Daratumumab (Darzalex) & dexamethasone in combination with low-dose cyclophosphamide is sufficiently active in a high risk population of myeloma patients, to take forward into a phase III trial compared to standard treatment. |
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| E.2.2 | Secondary objectives of the trial |
To determine the safety and toxicity profile of the treatment arm
To further summarise clinical activity with regards to the following:
o Progression-free survival at 100 days post-ASCT (autologous stem cell transplant)
o Minimal residual disease (MRD) at the end of induction therapy, 100 days post-ASCT and 1 year post-ASCT
o Overall survival
o Maximum response at the end of induction therapy, 100 days post-ASCT and post- consolidation part 1
o Overall response at the end of induction therapy, 100 days post-ASCT and post- consolidation part 1
o Time to progression
o Time to maximum response
o Second progression-free survival (PFS2)
To summarise compliance with treatment
To summarise overall treatment benefit (as defined in Appendix 3) and clinician assessment of treatment benefit at the end of induction therapy and 100 days post-ASCT, and to compare these two measures
To determine quality of life
Imaging sub-study (exploratory)
1. To explore the association of “imaging MRD” sta |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Target participants:
• Confirmation of High Risk status from ICR following bone marrow and blood sample processed through the screening protocol. Participants with confirmed plasma cell leukaemia with >20% circulating plasma cells, do not need confirmation of High Risk status from ICR to proceed on MUKnine b.
• Confirmation of receipt by CTRU of baseline bone marrow, at HMDS and blood and urine samples at University of Birmingham at MUKnine a baseline.
• Previously untreated participants, although participants may have received up to 2 cycles of CTD (Cyclophosphamide, thalidomide, dexamethasone), CVD (Cyclophosphamide, velcade, dexamethasone), CRD (cyclophosphamide, revlamid, dexamethasone) or VTD (velcade, thalidomide, dexamethasone) pre-trial induction chemotherapy while awaiting the results of the laboratory analysis from the MUK nine a Protocol.(In addition, non-systemic therapy such as therapeutic plasma exchange, dexamethasone up to a maximum of 160mg or radiotherapy sufficient to alleviate or control pain or local invasion is permitted).
• Measurable disease with at least one of the following or willing to undergo further bone marrows for assessment:
- Paraprotein ≥ 5g/L or ≥ 0.5 g/L for IgD subtypes.
- Serum free kappa or lambda light chains ≥ 100 mg/L with abnormal ratio (for light chain only myeloma).
- Urinary Bence Jones protein ≥ 200 mg/L.
• Non measurable participants providing they accept a 3 monthly bone marrow during induction and a 6 monthly bone marrow assessment during consolidation and maintenance.
• Aged 18 years or over.
• Fit for intensive chemotherapy and autologous stem cell transplant (at clinician’s discretion).
• ECOG Performance Status (Eastern Cooperative Oncology Group) ≤2.
• The Celgene Pregnancy Prevention Plan must be followed and participants must agree to comply with this:
• Females of childbearing potential (FCBP) must agree to utilise two reliable forms of contraception simultaneously or practice complete abstinence for at least for 28 days prior to starting trial treatment, during the trial and for at least 28 days after trial treatment discontinuation, and even in case of dose interruption, and must agree to regular pregnancy testing during this timeframe.
• Males must agree to use a latex condom during any sexual contact with FCBP during the trial, including during dose interruptions and for 28 days following discontinuation from this trial even if he has undergone a successful vasectomy
• Males must also agree to refrain from donating semen or sperm while on trial treatment including during any dose interruptions and for 4 months after discontinuation from this trial
• All participants must agree to refrain from donating blood while on trial drug including during dose interruptions and for 28 days after discontinuation from this trial.
- Calculated creatinine clearance ≥ 30mL/min (using Cockcroft-Gault formula).
- ALT and/or AST ≤ 2.5 times upper limit of normal (ULN).
- Bilirubin ≤ 2.0 x ULN, except in participants with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin ≤2.0 times ULN
- Platelet count ≥ 75 x 109/L. (≥ 50 x 109/L if myeloma involvement in the bone marrow is >50%). Platelet support is permitted.
- Absolute neutrophil count (ANC) ≥ 1.0 x 109/L. Growth factor support is permitted.
- Haemoglobin ≥ 80 g/L. (Participants may be receiving red blood cell (RBC) transfusions in accordance with institutional guidelines.
- Corrected serum calcium ≤ 3.5 mmol/L.
Eligibility criteria for ASCT
• Minimum stem cell harvest of 2 x 106 CD34+ cells/kg body weight.
• Received a minimum of 4, unless CR has been achieved with a lesser number, or a maximum of 6 Induction (CVRDd - cyclophosphamide, bortezomib, lenalidomide, daratumumab, dexamethasone) cycles.
• Achieved a response of SD or better.
Eligibility Criteria for Consolidation Part 1 (VRDd - bortezomib, lenalidomide, daratumumab, dexamethasone)
• Undergone autologous transplant with HDM-V (high dose melphalan-bortezomib) conditioning (Participants must have received a minimum of 100 mg/m2 Melphalan in order to proceed with consolidation).
• Neutrophils ≥ 1.0 x 109/L. Growth factor support is permitted.
• Platelet count ≥ 75 x 109/L. Platelet support is permitted.
Eligibility Criteria for Consolidation Part 2 (VRD - bortezomib, lenalidomide, daratumumab)
• Received 6 cycles of Consolidation Part 1 (VRDd) or 1 cycle of VRd pre-harvest plus 5 cycles of Consolidation Part 1 (VRDd).
• Neutrophils ≥ 1.0 x 109/L. Growth factor support is permitted.
• Platelet count ≥ 75 x 109/L. Platelet support is permitted.
Eligibility Criteria for Maintenance (RD - lenalidomide, daratumumab)
• Received 12 cycles of Consolidation Part 2 (VRD).
• Neutrophils ≥ 1.0 x 109/L. Growth factor support |
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| E.4 | Principal exclusion criteria |
Exclusion Criteria
• Participants that have progressive disease
• Solitary bone/solitary extramedullary plasmacytoma.
• Primary diagnosis of amyloidosis, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma or Waldenstrom’s Disease.
Medical history and Concurrent disease:
• Prior or concurrent invasive malignancies except the following:
o Adequately treated basal cell or squamous cell skin cancer.
o Incidental finding of low grade (Gleason 3+3 or less) prostate cancer.
o Any cancer from which the subject has been disease free for at least 3 years.
• Known/underlying medical conditions that, in the investigator’s opinion, would make the administration of the study drug hazardous (e.g uncontrolled diabetes or uncontrolled coronary artery disease).
o Any clinically significant cardiac disease, including:
o myocardial infarction within 1 year before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV.
o uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4 Grade ≥2) or clinically significant ECG (Electrocardiogram) abnormalities.
o screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >470 msec.
• Known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume [FEV] in 1 second <60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (intermittent asthma is allowed). Participants with known or suspected COPD or asthma must have a FEV1 test during screening.
• Known to be seropositive for history of human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C.
• Any known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure), or known sensitivity to mammalian-derived products.
• Clinically significant allergies or intolerance to cyclophosphamide, lenalidomide, velcade, daratumumab or dexamethasone.
• Previous treatment with daratumumab or any other anti-CD38 therapies.
• Participants with contraindication to thromboprophylaxis.
• Grade 2 or greater peripheral neuropathy (per NCI-CTCAEv4.0).
• Participants with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
• Any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
• Known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). Participant has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
• Participant is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this trial, 4 months after the last dose of trial treatment. Or, participant is a man who plans to father a child while taking part in this trial, within 4 months after the last dose of trial treatment.
• Major surgery within 2 weeks before treatment protocol registration or has not fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study. Kyphoplasty or vertebroplasty is not considered major surgery.
• Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before treatment protocol registration or is currently enrolled in an interventional investigational study.
Imaging study:
If the participant is taking part in the imaging study the following will exclude the participant form the imaging study only. They may continue to take part in all other aspects of the MUKnine b study if they have any of these exclusions.
• MRI incompatible metal implants
• Claustrophobia
• Not received a DWI-MRI scan as part of the trial during MUKnine a
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint to assess efficacy of the treatment arm (if the trial is not stopped early for futility) is progression-free survival at 18 months post-registration.
Progression-free survival (PFS) is defined as the time from registration in MUK nine a study until first documented evidence of disease progression or death. Participants who have not progressed or died at the time of analysis will be censored at the last date they were known to be alive and progression-free, whichever is soonest.
Note that interim assessments of futility are performed throughout the trial, after groups of 10 patients have been followed up to 100-120 days post-ASCT. The primary endpoints to determine whether to terminate the trial early for futility are
• Minimal residual disease (MRD) at 100 days post-ASCT
• Progression-free survival at 100 days post-ASCT
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoints as described above.
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| E.5.2 | Secondary end point(s) |
• Safety will be reported based on the occurrence of SAEs, SARs and SUSARs.
• Toxicity will be reported based on adverse reactions, as graded by CTCAE V4.0, and determined by routine clinical assessments at each centre.
• Progression-free survival at 100 days post-ASCT is used to determine whether the treatment schedule should be dropped for futility. This is expressed as a binary outcome, defined as whether a participant has progressed or died before this time-point or not. If a participant does not receive an ASCT, the 100 days post-ASCT time-point becomes 12 months post registration to treatment as this is approximately equivalent.
• MRD negative disease is defined as the absence of aberrant phenotype plasma cells as assessed by multi-parameter flow cytometry (sensitivity 0.01%). MRD status (positive or negative) will be determined centrally. For MRD status at 100 days post-ASCT, if a participant does not receive an ASCT, the 100 days post-ASCT time-point becomes 12 months post registration to treatment as this is approximately equivalent.
• Overall survival is defined as the time from registration to MUK nine a until death. Participants who are alive at the time of analysis will be censored at the last date they were known to be alive.
• Maximum response is defined as the proportion of participants achieving each of the response categories sCR, CR, VGPR, PR, MR or SD as their maximum response to treatment
• Overall response is defined as the sum of sCR, CR, VGPR and PR, determined according to the Modified IMWG Uniform Response Criteria. If a participant achieves at least PR but subsequently progresses, the participant will be classed as achieving at least PR.
• Time to progression is defined as the time from registration to MUK nine a until first documented evidence of disease progression. Participants who have not progressed at the time of analysis will be censored at the last date they were known to be alive and progression-free. Participants who have died with no previous evidence of disease progression will either be classed as having had a competing risk or censored at the date of death.
• Time to maximum response is defined as the time from registration to MUK nine a until the participant achieves any of the categories sCR, CR, VGPR, PR, MR or SD as their maximum response. Participants who do not achieve a maximum response will either be classed as having had a competing risk or censored at the time of disease progression or death, whichever is earlier.
• Second progression-free survival (PFS2) is defined as the time from registration to MUK nine a until documented evidence of second disease progression or death, whichever is soonest. Participants who have not died or experienced a second progression at the time of analysis will be censored at the last date they were known to be alive and without second progression.
• Overall treatment benefit. Clinician assessment of treatment benefit will be obtained using one simple question to understand whether, in the opinion of the treating clinician, the participant has benefitted from the treatment they have received.
• Quality of life is based on the EQ-5D, EORTC QLQ-C30 and EORTC QLQ-MY20 questionnaires, completed at baseline, end of Induction treatment, 100 days post-ASCT and then 3-monthly until progression. Appropriate scoring manuals will be used for each questionnaire.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints as described above. |
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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 | 30 |
| 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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| The end of the trial is defined as the date of the last participant’s last data item. |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 | 31 |
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