| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed Multiple Myeloma (MM) |
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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 | 21.0 |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The principle objective is to determine the percentage of patients achieving minimal residual disease (MRD) negativity on bone marrow (BM) at day 100 post-transplant. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to compare safety and toxicity of the addition of daratumumab to the peripheral blood stem cell (PBSC) harvest and ASCT with the control arm, specifically;
- to compare the rate of graft failure between the two arms
- to compare time to engraftment between the two arms
- to assess the proportion of patients completing treatment as per protocol
- to assess the proportion of patients achieving a satisfactory stem cell harvest yield in each arm
- to compare toxicity collected in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) criteria version 5.0
To assess the proportion of patients in each arm achieving a greater or equal to 10 fold reduction in disease burden comparing pre-ASCT bone marrow (BM) aspirate and day 100 post-ASCT BM aspirate; to compare progression free survival (PFS) and PFS-2 between the two arms;
To compare overall survival (OS) between the two arms;
To measure the effect of anti-CD |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Confirmed diagnosis of symptomatic MM, both those with; measurable secretory disease according to IMWG criteria and patients with non-secretory myeloma may enter the trial
•Received only 1st line induction therapy (i.e., undergoing or completed first line therapy at the time of enrolment).*
•Induction with either VCD or VTD**
•Received Bortezomib-containing induction treatment for at least 4 cycles
•Achieving at least PR following induction treatment
•Considered suitable for ASCT at the time of entering the trial as clinically judged by the local Investigator
•ECOG ≤2, (Appendix 3) unless related to myeloma
•Age ≥18
•Creatinine clearance ≥30ml/min
•Adults of reproductive potential must agree to use effective contraception or maintain abstinence for 6 months after therapy
•Willing and able to participate in all required evaluations and procedures in this study.
*This trial will adopt the general definitions for a cycle of chemotherapy proposed by [1], whereby a line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens (e.g., 3 - 6 cycles of initial therapy with bortezomib-dexamethasone (VD) followed by stem cell transplantation (SCT), consolidation, and lenalidomide maintenance is considered 1 line). However, since standard practice in many UK centres includes an adaptive approach whereby VCD or VTD is started, but a swap to VTD or VCD respectively is planned depending on response and tolerability, these two combinations (i.e. VCD changing to VTD or VTD changing to VCD) will be considered a single line of therapy and patients will be eligible for this trial.
**This study will recruit patients who have received either VCD or VTD induction therapy. However, since standard practice in many UK centres includes switching from one regimen to the other, we will therefore allow enrollment into the study of patients who have swapped from VCD to VTD or from VTD to VCD.
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| E.4 | Principal exclusion criteria |
•Previous treatment with Daratumumab or other anti-CD38 therapies
•Demonstrating evidence of progressive disease according to IMWG criteria
•Peripheral neuropathy above grade 2 as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
•Current or prior malignancy within 5 years from enrolment (other than multiple myeloma, adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or prostate cancer <Gleason Grade 6 with stable Prostate Specific Antigen (PSA))
•Bilirubin >2 x upper limit of normal (ULN)
•ALT/AST >3 x ULN
•Known chronic obstructive pulmonary disease (COPD), persistent asthma or pulmonary function tests showing Forced Expiratory Volume (FEV1) <60%
•Known cardiac impairment with Left Ventricular Ejection Fraction (LVEF) <50%
•Pregnant or breast-feeding women. (Women of child-bearing potential and men who are sexually active will be required to undergo the standard testing prior to chemotherapy, which we will not list here for brevity)
•POEMS syndrome, plasma cell leukaemia, amyloidosis (AL), smouldering multiple myeloma, Waldenstroms macroglobulinaemia.
•Known or suspected central nervous system (CNS) involvement by myeloma
•Radiation therapy within 4 weeks of trial entry
•Participation in an investigational therapeutic study within the 4 weeks prior to first dose of Daratumumab
•Acute active infection requiring systemic antibiotics, antivirals or antifungals within 2 weeks prior to trial entry
•Known or suspected human immunodeficiency virus (HIV) infection or subjects who are HIV seropositive
•Active hepatitis A, B (surface antigen or core antibody positive), or C infection (patients with no detectable virus by PCR may be entered into the study with ongoing monitoring and therapy for viral reactivation as per local practice)
•Serious psychiatric or medical conditions that could, in the investigator’s opinion, interfere with treatment, protocol adherence or a subject's ability to give informed consent
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The percentage of patients with MRD negative bone marrow aspirate (malignant plasma cells <1 in 105 total cells by multiparameter flow cytometry) on day 100 after an ASCT in each arm |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 100 days post autologus stem cell transplant to assess the percentage of MRD negativity. |
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| E.5.2 | Secondary end point(s) |
| Safety and toxicity of addition of dataumumab to peripheral blood stem cell harvest which included; Rate of graft failure, time to engraftment, proportion of patients completing treatment as per protocol, proportion of patients achieving a stem cell harvest yield of >4 (underlined)x 10 to the 6 CD34+ cells/kg, toxicity collected accordance with CTCAE criteria 5.0; proportion of patients achieving a > (underlined) 10 fold reduction in disease burden (by multiparameter flow cytometry)comparing pre ASCT bone marrow (BM) aspirate and day 100 post ASCT BM aspirate, progression free survival (PFS) and progression free survival 2 (PFS2), time to next treatment, overall survival (OS), level of residual myeloma in BM pre-and post-ASCT. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Patients will be followed up clinically in the transplant centre until D 100 post-ASCT and then remotely by 'virtual follow-up' for 10 years to assess the secondary endpoints of the study. |
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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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 22 |
| 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 will be 12 months after the last data capture following 10 years of long-term follow-up.This will allow sufficient time for the completion of protocol procedures, data collection and data input. The Trials Office will notify the MHRA and main REC that the trial has ended at the appropriate time and will provide them with a summary of the clinical trial report within 12 months of the end of 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 | 10 |
| 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 | 10 |
| 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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