| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with relapsed or relapsed-refractory multiple myeloma. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with Multiple Myeloma. |
|
| 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 show superiority of progression free-survival (PFS) in patients treated with melflufen and dexamethasone in combination with daratumumab compared to daratumumab alone. |
|
| E.2.2 | Secondary objectives of the trial |
- to evaluate and compare Overall Response Rate (ORR) in patients treated with melflufen and dexamethasone in combination with daratumumab compared to daratumumab alone
- to evaluate and compare Duration of Response (DOR) in patients treated with melflufen and dexamethasone in combination with daratumumab compared to daratumumab alone
- to assess the safety and tolerability of melflufen and dexamethasone in combination with daratumumab compared to daratumumab alone
- to evaluate and compare efficacy endpoints in patients treated with melflufen and dexamethasone in combination with daratumumab compared to daratumumab alone:
• Best response during the study
• Clinical benefit rate (CBR)
• Duration of Clinical Benefit (DOCB)
• Time to response (TTR)
• Time to progression (TTP)
• Time to next treatment (TTNT)
• Overall survival (OS) |
|
| 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 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol;
3. A prior diagnosis of multiple myeloma with documented disease progression in need of treatment at time of screening;
4. Double refractory to an IMiD and a PI (regardless of the number of prior lines of therapy), or have received at least 3 prior lines of therapy including an IMiD and a PI (the definition of refractory includes intolerance to an IMiD/PI after at least two 28-day cycles of therapy);
5. Prior treatment with daratumumab or another anti-CD38 antibody is allowed if the patient has:
• Achieved at least PR and is not refractory to previous anti-CD38 antibody treatment
• At least 6 months since last dose of anti-CD38 antibody prior to Cycle 1/Day 1 (C1/D1)
• Not discontinued anti-CD38 antibody treatment due to related Grade ≥3 toxicity
6. 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 24-hour urine collection by electrophoresis (UPEP)
• Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain (FLC) ratio
7. Life expectancy of ≥ 6 months;
8. 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);
9. Ability to understand the purpose and risks of the study, ability to participate in all the procedures required by the protocol and provide signed and dated informed consent;
10. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (Q-TcF) interval of ≤ 470 msec;
11. 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 (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
• Aspartate transaminase/Aspartate aminotransferase (AST, also known as Serum Glutamic Oxaloacetic Transaminase (SGOT)) and Alanine transaminase/Alanine aminotransferase (ALT, also known as Serum Glutamic Pyruvic Transaminase (SGPT)) ≤ 3.0 x ULN
• Renal function: Estimated creatinine clearance by Cockcroft- Gault formula of ≥ 45 mL/min
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);
13. a) Male patients: Male patient who agrees to use contraception 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:
iii. Not a woman of childbearing potential (WOCBP)
or
iv. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 3 months after the last dose of study treatment |
|
| E.4 | Principal exclusion criteria |
1. Primary refractory disease (i.e. never responded with at least MR to any prior therapy);
2. Prior treatment with CD38 CAR-T cell therapy or CD38/CD3 bispecific antibodies;
3. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) less than 50% of predicted normal;
4. Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification;
5. 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);
6. 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., heart failure class III or IV according to New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, significant cardiac conduction system abnormalities, uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the last 6 months);
7. Known active infection that is uncontrolled (including symptomatic or asymptomatic COVID-19) or has required intravenous systemic therapy within 14 days of randomization. Patients who has required oral antiinfective treatment within 14 days of randomization should be discussed with the Medical Monitor;
8. 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;
9. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation;
10. Human immunodeficiency virus (HIV) or active hepatitis C viral infection, either known or if detected during screening;
11. Hepatitis B: both active (defined as HBsAg+) or non-active hepatitis B (defined as HBsAg-, Anti-HBs+, Anti-HBc+):
• Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-HBs+, Anti-HBc-).
12. Concurrent known or suspected amyloidosis or plasma cell leukemia;
13. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes);
14. Known CNS or meningeal involvement of myeloma:
15. Any of the following treatments, within the specified timeframe:
• Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma 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 mAb 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;
16. 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);
17. Prior stem cell transplant (autologous and/or allogenic) within 6 months of initiation of therapy;
18. Prior allogeneic stem cell transplantation with active graft-versushost-disease;
19. 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);
20. Known intolerance to the required dose and schedule of steroid therapy, as determined by the investigator;
21. Known hypersensitivity to any of the agents in this study including hyalonuridase
22. Prior treatment with melflufen |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS (time from the date of randomization to the date of first documentation of confirmed progressive disease (PD) or death due to any cause). |
|
| 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 (proportion of patients who achieve a best confirmed response of stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR))
- DOR (time from the first evidence of confirmed assessment of sCR, CR, VGPR or PR to first confirmed disease progression, or death due to any cause. DOR is defined only for patients with a confirmed PR or better)
- frequency and Grade of treatment emergent adverse events (TEAE)
- Best Response (proportion of patients with sCR, CR, VGPR, PR, Minimal Response (MR), Stable Disease (SD), PD or non-evaluable)
- CBR (the proportion of patients who achieve a best confirmed response of sCR, CR, VGPR, PR or MR)
- 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.) DOCB is defined only for patients with a confirmed MR or better
- TTR (time from randomization to the date of the first documented confirmed response in a patient who has responded with ≥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 or until death)
- OS (time from date of randomization to death due to any cause) |
|
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| 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 |
| Georgia |
| Russian Federation |
| Serbia |
| Ukraine |
| United States |
| Bulgaria |
| Finland |
| Germany |
| Greece |
| Hungary |
| Norway |
| Poland |
| Slovakia |
| Spain |
| United Kingdom |
| Czechia |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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