| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed and/or Relapsed-Refractory Multiple Myeloma |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with a type of blood cancer. |
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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 | 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I (completed)
The primary objective of the Phase I portion of the study is to determine the MTD of the combination of melflufen and dexamethasone in patients with relapsed and/or relapsed-refractory multiple myeloma (MM).
Phase IIa
To evaluate the objective response rate ≥ Partial Response (PR) and the clinical benefit (including minimal response [MR]) to the combination of melflufen and dexamethasone and melflufen as single agent at the MTD determined in Phase I. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the overall response including the complete response/stringent complete response (CR/sCR), very good partial response (VGPR), partial response (PR) and clinical benefit (≥ MR) , time to progression, duration of response, progression free survival and overall survival in all evaluable patients.
To further explore the safety and tolerability of the combination at the MTD. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Eligible patients will be considered for inclusion in this study if they meet all of the following criteria:
1. Male or female, age 18 years or older.
2. Patient has a diagnosis of multiple myeloma with documented relapsed and/or relapsed-refractory disease.
3. Patient has measurable disease defined as any of the following:
• Serum monoclonal protein ≥ 0.5 g/dL by protein electrophoresis.
• ≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis
• Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio.
• If no monoclonal protein is detected (non-secretory disease), then ≥ 30% monoclonal bone marrow plasma cells.
4. Patient has had at least 2 or more prior lines of therapy including lenalidomide and bortezomib and has demonstrated disease progression on or within 60 days of completion of the last therapy. (see appendix D for the definition of lines of therapy);
5. Life expectancy of ≥6 months;
6. Patient has an ECOG performance status ≤ 2. (Patients with lower performance status based solely on bone pain secondary to multiple myeloma will be eligible);
7. Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test prior to initiation of therapy;
8. Female patients of child bearing potential and non-vasectomized male patients agree to practice appropriate methods of birth control;
9. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information;
10. The patient has or, accepts to have, an acceptable infusion device for infusion of melflufen (Port A Cath, PICC line or central venous catheter);
11. 12 lead ECG with QTcF interval of ≤470 msec; (see Appendix G)
12. The following laboratory results must be met within 21 days, or as specified in the table of assessments, prior to initiation of therapy:
• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) (Growth factors cannot be used within 14 days prior to initiation of therapy).
• Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (platelet count ≥ 50,000 cells/ mm3 for patients in whom ≥ 50% of bone marrow nucleated cells are plasma cells (without transfusion during the previous 7 days to initiation of therapy).
• Hemoglobin ≥ 8.0 g/dL (RBC transfusions are permitted)
• Total Bilirubin ≤ 1.5 X upper limit of normal (ULN);
• Renal function: Estimated creatinine clearance ≥ 45 ml/min and serum creatinine ≤ 2.0 mg/dL;
• AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN.
† (FCBP) is any sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (not having menstrual cycles due to cancer therapy does not rule out childbearing potential) for at least 24 consecutive months.
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| E.4 | Principal exclusion criteria |
Patients will be ineligible for this study if they meet any one of the following criteria:
1. Patient has evidence of mucosal or internal bleeding and/or is platelet transfusion refractory (i.e., unable to maintain a platelet count ≥50,000 cells/mm3);
2. Any medical conditions that, in the Investigator’s opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study. Examples of such conditions are: a significant history of cardiovascular disease (e.g., myocardial infarction, significant conduction system abnormalities, uncontrolled hypertension, ≥ grade 3 thromboembolic event in the last 6 months), renal insufficiency (unless felt to be secondary to MM);
3. Known active infection requiring parenteral or oral anti-infective treatment;
4. Other malignancy within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix;
5. Other ongoing anti-myeloma therapy. Patients may be receiving concomitant therapy with bisphosphonates and low dose corticosteroids (e.g., prednisone up to but no more than 10 mg PO q.d. or its equivalent) for symptom management and comorbid conditions. Doses of corticosteroid should be stable for at least 7 days prior to prior to initiation of therapy;
6. Pregnant or breast-feeding females;
7. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation;
8. Known HIV or hepatitis B or C viral infection;
9. Patient has concurrent symptomatic amyloidosis or plasma cell leukemia;
10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes);
11. Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy. Biologic, novel therapy (including investigational agents in this class) or corticosteroids within 2 weeks prior to initiation of therapy. Patient has side effects of the previous therapy > grade 1 or previous baseline.
12. Prior peripheral stem cell transplant within 12 weeks of initiation of therapy;
13. Radiotherapy within 21 days prior to initiation of therapy. However, if the radiation portal covered ≤ 5% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy;
14. Known intolerance to steroid therapy.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint for Phase I:
To determine the MTD by monitoring and analyzing the frequency and grade of adverse events occurring at each dose level of melflufen and dexamethasone to be tested.
Phase IIa
The primary end point of Phase IIa is the objective response rate (CR, sCR, VGPR, PR) and clinical benefit (≥ MR) and the rate of SD and PD observed in patients treated at the MTD.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I: Continuously during cycle 1.
Phase II: Continuously during the course of the trial.
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| E.5.2 | Secondary end point(s) |
Secondary Endpoint(s)
The overall response rate (CR/sCR, VGPR, PR) and clinical benefit (≥ MR), time to progression, duration of response, progression free and overall survival in all evaluable patients.
To further evaluate the frequency and grade of all adverse events of the combination of melflufen and dexamethasone and melflufen alone including the rate and type of second primary malignancies.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During the course of the trial. |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Denmark |
| Italy |
| Netherlands |
| Sweden |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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