| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Relapsed Refractory Multiple Myeloma who are Refractory to Lenalidomide |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with Multiple Myeloma who are refractory to lenalidomide in the last line of treatment. |
|
| 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 |
|
| 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 compare the PFS of melflufen plus dexamethasone (Arm A) versus pomalidomide plus dexamethasone (Arm B) as assessed by the Independent Review Committee (IRC) according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). |
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary Objectives
- To assess and compare the overall response rate (ORR), i.e., proportion of patients with ≥ PR (stringent complete response [sCR], complete response [CR], very good partial response [VGPR] and partial response [PR]) as best response in Arm A versus Arm B
- To assess and compare duration of response (DOR) in patients with ≥ PR (sCR, CR, VGPR, PR) as best response in Arm A versus Arm B
- To assess and compare overall survival (OS) in Arm A versus Arm B
- To assess and compare the safety and tolerability in Arm A and Arm B
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female, age 18 years or older
2. A prior diagnosis of multiple myeloma with documented disease progression in need of treatment at time of screening.
3. Measurable disease defined as any of the following:
Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP)
≥ 200 mg/24 hours of monoclonal protein in the urine on 24-hour urine electrophoresis (UPEP)
Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain ratio
4. Received 2-4 prior lines of therapy (Appendix D), including lenalidomide and a PI, either sequential or in the same line, and is refractory (relapsed and refractory or refractory) to both lenalidomide in the last line of therapy and to lenalidomide (≥ 10 mg) administered within 18 months prior to randomization. Refractory status to lenalidomide is defined as progression while on lenalidomide therapy or within 60 days of last dose, following at least 2 cycles of lenalidomide with at least 14 doses of lenalidomide per cycle.
5. Life expectancy of ≥ 6 months
6. ECOG performance status ≤ 2. (Patients with lower performance status based solely on bone pain secondary to multiple myeloma may be eligible following consultation and approval of the medical monitor) (Appendix A)
7. Females of child bearing potential (FCBP)* must have a medically supervised negative serum or urine pregnancy test with a sensitivity according to local Risk Evaluation and Mitigation Strategy™ (REMS) or pomalidomide pregnancy prevention plan (PPP) completed within 10 to 14 days prior to planned start of treatment. All FCBP must agree to either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking treatment and as appropriate based on the treatment assignment (See Section 7.7.1). FCBP must also agree to ongoing pregnancy testing. Men must agree to use a condom during sexual contact with a FCBP even if they have had a vasectomy from the time of starting study treatment
through 3 months after the last dose of melflufen (Arm A) or 28 days after the last dose of pomalidomide (Arm B). All patients enrolled in Canada and the USA must be willing to comply with all requirements of the Canadian or USA pomalidomide REMS. All patients enrolled outside of Canada and the USA must be willing to comply with all requirements of the PPP (Appendix J). (Willingness, to comply with the REMS or PPP, must be documented prior to knowledge of randomization but is only required if randomized to Arm B).
8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent.
9. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec (Appendix H).
10. The following laboratory results must be met during screening (within 21 days) and also immediately before study drug 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 prior to first drug administration)
Platelet count ≥ 75,000 cells/mm3 (75 x 109/L) (without required transfusions during the 10 days prior to first drug administration)
Hemoglobin ≥ 8.0 g/dl (red blood cell (RBC) transfusions are permitted)
Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), or patients diagnosed with Gilberts syndrome, that have been reviewed and approved by the medical monitor.
Aspartate transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT) ≤ 3.0 x ULN.
Renal function: Estimated creatinine clearance by Cockcroft-Gault formula ≥ 45 mL/min. (Appendix G).
11. Must be able to take antithrombotic prophylaxis (See Section 7.7.1).
12. Must have, or be willing to have an acceptable central catheter. (Port a cath, peripherally inserted central catheter [PICC] line, or central venous catheter) (Willingness must be documented prior to randomization but insertion only required if randomized to Arm A). |
|
| E.4 | Principal exclusion criteria |
1. Primary refractory disease (i.e. never responded with ≥ MR to any prior therapy)
2. Evidence of mucosal or internal bleeding and/or are platelet transfusion refractory (i.e. platelet count fails to increase by > 10,000 cells/mm3 after 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 conduction system abnormalities, uncontrolled hypertension, ≥ grade 3 thromboembolic event in the last 6 months)
4. Prior exposure to pomalidomide
5. Known intolerance to IMiDs. (≥ Grade 3 hypersensitivity reaction or at the investigators discretion)
6. Known active infection requiring parenteral or oral anti-infective treatment within 14 days of randomization
7. 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
8. Pregnant or breast-feeding females
9. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation
10. Known human immunodeficiency virus or active hepatitis C viral infection.
11. Active hepatitis B viral infection (defined as HBsAg+) are excluded.
Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-HBs+, Anti-HBc-).
Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) may be enrolled at the discretion of the investigator after consideration of risk of reactivation.
12. Concurrent symptomatic amyloidosis or plasma cell leukemia
13. POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes]
14. Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to randomization. The use of live vaccines within 30 days before randomization. IMiDs, PIs or corticosteroids within 2 weeks prior to randomization. Other investigational therapies and monoclonal antibodies within 4 weeks of randomization. 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 randomization.
15. Residual side effects to previous therapy > grade 1 prior to randomization (Alopecia any grade and/or neuropathy grade 2 without pain are permitted)
16. Prior peripheral stem cell transplant within 12 weeks of randomization
17. Prior allogeneic stem cell transplantation with active graft-versus-host- disease.
18. Prior major surgical procedure or radiation therapy within 4 weeks of randomization (this does not include limited course of radiation used for management of bone pain within 7 days of randomization).
19. Known intolerance to steroid therapy |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS (Progression Free Survival) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| During the course of the study |
|
| E.5.2 | Secondary end point(s) |
- ORR (Overeall Response Rate)
- DOR (Duration of Respone)
- OS (Overall Survival)
- Safety and Tolerability
- CBR (Clinical Benefit Rate)
- TTR (Time to Response)
- TTP (Time to Progression)
- Best Response
- Melphalan PK |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During the course of the study. |
|
| 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 | 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 | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 |
| Australia |
| Israel |
| Korea, Democratic People's Republic of |
| Korea, Republic of |
| Russian Federation |
| Taiwan |
| United States |
| Austria |
| Belgium |
| Czechia |
| Denmark |
| Estonia |
| France |
| Greece |
| Hungary |
| Italy |
| Lithuania |
| Norway |
| Poland |
| United Kingdom |
| Netherlands |
| Romania |
| Spain |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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