| 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] - Blood and lymphatic diseases [C15] |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary hypothesis of this study is that six cycles of melflufen and dexamethasone re-induction as an adjunct to continued daratumumab in subjects that have become refractory to daratumumab will recapture and potentiate the clinical efficacy of daratumumab by suppressing the daratumumab-refractory myeloma sub-clones. |
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| E.2.2 | Secondary objectives of the trial |
Clonality
• The clonal architecture of myeloma cells in patients at the time of inclusion in this study is dominated by an emerging daratumumab-refractory clone.
• Reduction of the dominant clone is associated with efficacy of the study treatment
Gene expression
• Specific gene expression patterns are associated with treatment efficacy
Positron emission tomography
• Positron emission tomography positive lesions at baseline are associated with reduced treatment efficacy
• Reduction of positron emission tomography after re-induction treatment is associated with better treatment efficacy
Humoral immunodeficiency
• Baseline anti-pneumococcal polysaccharide IgG concentrations are reduced in the majority of patients in the study population
• The level of humoral immunodeficiency estimated by anti-pneumococcal polysaccharide IgG concentrations is associated with susceptibility to infections
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male or female, age 18 years or older;
• A prior diagnosis of multiple myeloma;
• Previously exposed to a proteasome inhibitor (bortezomib, carfilzomib or ixazomib) and an immunomodulatory drug (thalidomide, lenalidomide or pomalidomide);
• Two to eight prior lines of therapy
• Refractory to daratumumab in the last line of therapy, defined as progressive disease
o during treatment with daratumumab monotherapy or a daratumumab containing regimen, or
o within 60 days of the last dose of daratumumab as monotherapy or part of a daratumumab containing regimen;
• Prior response to daratumumab, defined as at least minimal response achieved during daratumumab monotherapy or a daratumumab containing regimen;
• Measurable disease defined as any of the following:
o Serum monoclonal protein ≥ 10 g/L by serum protein electrophoresis
o ≥ 200 mg of monoclonal protein in the urine on 24-hour electrophoresis
o Serum free light chain ≥ 100 mg/L and abnormal serum kappa to lambda free light chain (FLC) ratio
• Life expectancy of ≥ 6 months;
• ECOG performance status ≤ 2. (Patients with performance status > 2 based solely on bone pain secondary to multiple myeloma may be eligible following approval of the sponsor);
• A negative serum or urine pregnancy test if the subject is a female of childbearing potential, defined as any sexually mature female who:
o has not undergone a hysterectomy or bilateral oophorectomy and
o has not been naturally postmenopausal for at least 24 consecutive months
A sexually mature female who stopped having menstrual cycles due to cancer therapy cannot be considered naturally postmenopausal
• Patient agrees to practice appropriate methods of birth control;
• Ability to understand the purpose and risks of the study and provide signed and dated informed consent;
• Adequate organ function with the following laboratory results:
o Absolute neutrophil count ≥ 1,000 cells/mm3 (1.0 x 109/L)
o Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (without transfusions required within 10 days prior to initiation of study treatment)
o Hemoglobin ≥ 5 mmol/l; red blood cell transfusions are permitted
o Total Bilirubin ≤ 1.5 x upper limit of normal, except patients diagnosed with Gilbert’s syndrome that have been approved by the sponsor
o Alanine transaminase ≤ 3.0 x upper limit of normal
o Renal function: Estimated creatinine clearance by Cockcroft- Gault formula of ≥ 45 mL/min and serum creatinine of ≤ 175 µmol/l
• Patient must have or be willing to have an acceptable central catheter (port a cath, peripherally inserted central catheter, or central venous catheter)
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| E.4 | Principal exclusion criteria |
• Any somatic or psychiatric condition that in the investigator’s opinion would impose excessive risk to the patient or would adversely affect the patient’s participation in this study;
• Severe ongoing infection that in the investigator’s opinion would impose excessive risk to the patient
• Known intolerance to the required dose and schedule of study treatment;
• Evidence of platelet transfusion refractory thrombocytopenia (defined as platelet counts not increasing at least 10.000 cells/ mm3 [10 x 109/L] after a transfusion of an appropriate dose of platelets);
• Evidence of mucosal or internal bleeding that requires platelet transfusion within 10 days prior to initiation of study treatment;
• Pregnant or breast-feeding females;
• Known human immunodeficiency virus or active hepatitis B or C viral infection;
• The use of live vaccines within 30 days before initiation of study treatment;
• The use of any of the following therapies prior to initiation of study treatment in the time intervals specified below:
o cytotoxic agents within 3 weeks,
o proteasome inhibitors within 2 weeks,
o immunomodulatory agents within 2 weeks,
o monoclonal antibodies other than daratumumab within 4 weeks
o Corsticosteroids more than a dosis equivalent to Prednisolone 10 mg per day (unless administered as part of a pre- or post-infusion schedule for daratumumab.) Corticosteroids up to an equivalent dose to Prednisolone 10 mg per day are allowed for symptom management of comorbid conditions, but dose should be stable for at least 7 days prior to initiation of therapy
o Peripheral stem cell transplant within 12 weeks prior to initiation of study treatment;
o other investigational therapies within five halflives of the involved drugs
• Prior allogeneic stem cell transplantation with active graft-versus-host-disease;
• ≥ Grade 3 cardiac conduction system abnormalities unless patient has a pacemaker
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary end-point
• Overall response rate
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Best achieved response during 30 cycles of 28 days. |
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| E.5.2 | Secondary end point(s) |
Secondary end-points
• Progression-free survival
• Clinical benefit rate
• Time to next treatment
• Overall survival
• Time to response
• Duration of response
• Safety and tolerability
• Discontinuation rate
• Quality of life
Exploratory end-points
• Analysis of genomic changes of myeloma clones over time
• Analysis of myeloma cell gene expression patterns and correlation to response
• Assessment of humoral immunodeficiency at baseline and its relation to infections
• Assessment of the effect of positron emission tomography positive lesions at baseline on treatment efficacy
• Correlation of changes in positron emission tomography positive lesions with response
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| When every participant completed participation in 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) | 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 | 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) | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 54 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 54 |
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