| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Relapsed or Relapsed-Refractory Multiple Myeloma |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients in which the disease, Multiple Myeloma returns after treatment or is not responded to treatment |
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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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objective(s)
Phase 1
To determine the optimal dose of melflufen, up to a maximum of 40 mg,given every 28 days, in triple drug combination therapies in patients with relapsed or relapsed-refractory MM. Each treatment regimen will be evaluated separately.
Phase 2a
To evaluate the overall response rate (≥ PR) of melflufen, in each combination Regimen, at the dose levels and schedules determined in Phase 1 in efficacy evaluable patients. Each treatment Regimen will be evaluated separately.
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives
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 rate (CBR) (≥ MR), duration of response (DOR), time to response (TTR), time to progression (TTP), time to next treatment (TTNT), progression free survival (PFS) and overall survival (OS) up to a minimum of 2 years according to the SAP. IMWG-URC guidelines will be used. Each treatment regimen will be evaluated separately.
To further explore the safety and tolerability of the various combination regimens. Each treatment regimen will be evaluated separately.
Exploratory Objectives
Pharmacokinetics will be evaluated in patients enrolled at select sites only.
To evaluate minimal residual disease (MRD) in patients achieving a CR.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients will be considered eligible for inclusion in this study if they meet all of the following 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. One to four prior lines of therapy (Appendix D)
4. Measurable disease defined as any of the following:
• Serum monoclonal protein ≥ 0.5g/dL by serum protein electrophoresis (SPEP)
• ≥ 200 mg of monoclonal protein in the urine on 24-hour electrophoresis (UPEP)
• Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain (FLC) ratio
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);
7. Patient is a female of childbearing potential (FCBP)* with a negative serum or urine pregnancy test prior to initiation of therapy and agrees to practice appropriate methods of birth control, is a female not of child bearing potential, or is a male patient and agrees to practice appropriate methods of birth control.
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. Adequate organ function with the following laboratory results during screening (within 21 days) and 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 (14 days for pegfilgrastim) prior to initiation of therapy)
• Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (Without transfusions required 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
• AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN
• Renal function: Estimated creatinine clearance by Cockcroft- Gault formula of ≥ 45 mL/min and serum creatinine ≤ 2.0 mg/dL(Appendix G);
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).
Regimen Specific Inclusion criteria:
Regimen A - Melflufen + Bortezomib and Dexamethasone
A1 Must be intolerant or refractory to a prior IMiD; refractory defined as failure to respond (MR or better) or progression while on therapy or within 60 days of last dose.
Regimen B - Melfufen + Daratumumab and Dexamethasone
B1 Must have had a prior IMiD and proteasome inhibitor (PI); alone or in combination and must be refractory or intolerant to an IMiD, PI or both.
*(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. Primary refractory disease (i.e. never responded with ≥ 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 cardiac history of cardiovascular disease (e.g., myocardial infarction, significant conduction system abnormalities, uncontrolled hypertension ≥ Grade 3 thromboembolic event in the last 6 months);
4. Known active infection requiring parenteral or oral anti-infective treatment within 14 days of initiation of therapy;
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. Known human immunodeficiency virus or active hepatitis B or C viral infection (see criterion B5 for additional requirements for Regimen B);
9. 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. 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;
12. 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);
13. Prior peripheral stem cell transplant within 12 weeks of initiation of therapy;
14. Prior allogeneic stem cell transplantation with active graft-versus-host-disease);
15. 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);
16. Known intolerance to the required dose and schedule of steroid therapy, as determined by the investigator.
Regimen specific exclusion criteria
Regimen A – Melflufen + Bortezomib and Dexamethasone
A1 Refractory to a PI; refractory defined as failure to respond (MR or better) or progression while on therapy or within 60 days of last dose;
A2 History of allergic reaction/hypersensitivity attributed to compounds containing boron, mannitol, polysorbate 80 or sodium citrate dihydrate (See Apendix K).
Regimen B – Melflufen + Daratumumab and Dexamethasone
• Prior exposure to daratumumab or other antiCD-38 mAb;
• Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) less than 50% of predicted normal;
• Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification;
• Grade 3 conduction system abnormalities unless patient has a pacemaker.
• Active hepatitis B (defined as HBsAg+).
• 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 only be enrolled following approval by the sponsor after consideration of risk of reactivation (Additional screening and monitoring for hepatitis B and consultation with a liver disease specialist may be required) (See Table B-1, footnote u).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint
Phase 1
The primary endpoint of Phase 1 is to analyze the frequency and grade of AE occurring during Cycle 1 at each dose level to be tested. Each Regimen to be evaluated separately.
Phase 2a
The primary endpoint of Phase 2a, is the overall response rate (CR, sCR, VGPR, PR) observed in patients treated at the optimal dose of melflufen in combination therapy according to IMWG -URC. Each treatment regimen to be evaluated separately.
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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) |
Secondary Endpoints
• Best response during the study (sCR, CR, VGPR, PR, MR, stable disease [SD], PD or non-evaluable)
• CBR (≥ MR)
• DOR
• PFS
• OS
• Frequency and grade of AE’s
• TTR
• TTP
• TTNT
• Duration of clinical benefit
Exploratory Endpoint
• PK parameters of melphalan at select time points.
• Assessment of MRD status in patients that achieve a CR.
*All tumor response and progression-dependent endpoints are as assessed by the investigator according to the IMWG-URC (Rajkumar et al. 2011, Appendix C). Oncopeptides will implement an independent review of the response and progression assessments performed by the investigator. The investigator will be notified of any discrepancies in the form of a data query.
Each Regimen to be evaluated separately.
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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 | 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 | 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 | 14 |
| 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 |
| Czech Republic |
| France |
| Spain |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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