E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with relapsed and refractory multiple myeloma. |
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E.1.1.1 | Medical condition in easily understood language |
Patients with Multiple Myeloma. |
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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 | 16.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10028229 |
E.1.2 | Term | Multiple myelomas |
E.1.2 | System Organ Class | 100000004851 |
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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 |
- To evaluate and compare the pharmacokinetic (PK) variables Cmax, AUC(0-t) and AUC(0-∞) of melflufen and melphalan after central and peripheral intravenous infusion of melflufen.
- To assess the local tolerability of peripheral intravenous administration of melflufen |
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E.2.2 | Secondary objectives of the trial |
- To evaluate and compare the PK variables Cmax, AUC(0-t) and AUC(0-∞) of desethylmelflufen and elimination half-life (t½) for melflufen, melphalan and desethylmelflufen after central and peripheral intravenous infusion of melflufen.
- To assess safety and general tolerability of melflufen
- To evaluate efficacy:
• Best response during the study
• Overall response rate (ORR)
• Clinical benefit rate (CBR)
• Duration of response (DOR)
• Duration of Clinical Benefit (DOCB)
• Time to response (TTR)
• Time to progression (TTP)
• Time to next treatment (TTNT)
• Progression Free Survival (PFS)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female, age 18 years or older;
2. Capable of giving signed informed consent
3. A prior diagnosis of MM with documented disease progression in need of treatment at time of screening;
4. Measurable disease defined as any of the following:
• Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP)
• ≥ 200 mg/24hr of monoclonal protein in the 24hour urine collection by electrophoresis (UPEP)
• Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain (FLC) ratio
5. Received at least 2 prior lines of therapy and is refractory to an IMiD and a PI. The definition of refractory includes intolerance to an IMiD/PI after at least two 28-day cycles of therapy;
6. Adequate peripheral arm veins for repeated intravenous infusions
7. Life expectancy of ≥ 6 months;
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; Patients with ECOG performance status > 2 solely based on bone pain secondary to MM may be eligible following consultation and approval of medical monitor;
9. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec;
10. Adequate organ function with the following laboratory results during screening (within 21 days) and immediately before study treatment administration on Cycle 1 Day 1:
• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) (Growth factors cannot be used within 10 days (14 days for pegfilgrastim) prior to initiation of study treatment)
• Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (without transfusions during the 10 days prior to initiation of therapy)
• Hemoglobin ≥ 8.0 g/dL (Red blood cell [RBC] transfusions are permitted)
• Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), except patients diagnosed with Gilbert’s syndrome that have been reviewed and approved by the Medical Monitor
• AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN
• Renal function: Estimated glomerular filtration rate (eGFR) by CKD-EPI formula of ≥ 45 mL/min;
11. Must have or be willing to have an acceptable central catheter (Port a Cath, peripherally inserted central catheter [PICC] line, or central venous catheter [CVC]) and a PVC;
12. a) Male patients: A male patient is eligible if he agrees to use contraception as detailed in the protocol during the treatment period and for at least 3 months after the last dose of study treatment and refrain from donating sperm during this period
b) Female patients: A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
i. Not a woman of childbearing potential (WOCBP)
or
ii. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 28 days after the last dose of study treatment. |
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E.4 | Principal exclusion criteria |
1. Primary refractory disease (i.e. never responded with at least MR to any prior therapy);
2. Evidence of mucosal and/or internal bleeding or platelet transfusion refractory (platelet count fails to increase by > 10,000 cells/mm3 after a transfusion of an appropriate dose of platelets);
3. 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 cardiac conduction system abnormalities, uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the last 6 months);
4. Known active infection that is uncontrolled or has required intravenous systemic therapy within 14 days of randomization. Patients that have required oral anti-infective treatment within 14 days of randomization should be discussed with the Medical Monitor;
5. Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active surveillance;
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. Human immunodeficiency virus (HIV) or active hepatitis B or C viral infection;
9. Concurrent known or suspected amyloidosis or plasma cell leukemia;
10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes);
11. Known central nervous system (CNS) or meningeal involvement of myeloma;
12. Any of the following treatments, within the specified timeframe
• Previous cytotoxic therapies, including cytotoxic investigational agents, for MM within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy.
• The use of live vaccines within 30 days before initiation of therapy.
• IMiDs, PIs and or corticosteroids within 2 weeks prior to initiation of therapy.
• Other investigational therapies and monoclonal antibodies within 4 weeks of initiation of therapy.
• Prednisone up to but no more than 10 mg orally q.d. or its equivalent for symptom management of comorbid conditions is permitted but dose should be stable for at least 7 days prior to initiation of therapy.
Other washout times may be considered following consultation with the medical monitor.
13. Residual side effects to previous therapy > Grade 1 prior to initiation of therapy (Alopecia any grade and/or neuropathy Grade 1 without pain are permitted);
14. Prior stem cell transplant (autologous and/or allogenic) within 6 months of initiation of therapy;
15. Prior allogeneic stem cell transplantation with active graft-versus-host-disease;
16. Prior major surgical procedure or radiation therapy within 4 weeks of the initiation of therapy (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of therapy);
17. Known intolerance to the required dose and schedule of steroid therapy, as determined by the investigator;
18. Known hypersensitivity reaction to melphalan, melflufen or its excipients
19. Prior treatment with melflufen
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E.5 End points |
E.5.1 | Primary end point(s) |
• Maximum observed concentration (Cmax)
• Area under the concentration-time profile from 0 hours to end of drug infusion (AUC(0-t))
• Area under the concentration-time profile from 0 hours to infinity (AUC(0-∞))
• Frequency and Grade of local reactions including phlebitis at infusion site after peripheral intravenous administration.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
During the course of the study. |
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E.5.2 | Secondary end point(s) |
• Cmax
• AUC(0-t)
• AUC(0-∞)
• Elimination half-life t½
• Frequency and Grade of Treatment Emergent Adverse Events (TEAEs)
• Best Response (stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD) or progressive disease (PD)
• ORR (including CR/sCR, VGPR and PR)
• CBR proportion of patients with ≥ MR as best response
• DOR (time from the first confirmed response of sCR, CR, VGPR or PR to first confirmed disease progression, or death due to any cause.
• DOCB (time from first evidence of confirmed assessment of sCR, CR, VGPR, PR, or MR to first confirmed disease progression, or to death due to any cause.)
• TTR (time from randomization to the date of the first documented confirmed response in a patient that has responded with ≥ PR (sCR, CR, VCPR or PR))
• TTP (time from the date of randomization to the date of the first documented confirmed PD)
• TTNT (time from randomization to the date of next anti-myeloma treatment)
• PFS (time from the date of randomization to the date of first documentation of confirmed PD or death due to any cause).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During the course 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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability of peripheral intravenous administration |
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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 | 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 | Yes |
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 | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 |
Bulgaria |
Czech Republic |
Hungary |
Ukraine |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |