Patients with Relapsed or Relapsed-Refractory Multiple Myeloma MedDRA version: 16.1 Level: HLT Classification code 10028229 Term: Multiple myelomas System Organ Class: 100000004851
Conditions
Interventions
Product Name: Melflufen
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: melphalan fulfenamide hydrochloride
CAS Number: 380449-54-7
Other descriptive name: J1
Concentration
Sponsors
Oncopeptides AB
Eligibility
Sex/Gender
All
Inclusion criteria
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/24 hours 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, or is a female not of child-bearing potential, or the patient is a male 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 required 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), or 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 – Melflufen + Daratumumab and Dexamethasone B1 Must have had a prior IMiD and a 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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 20 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 60
Exclusion criteria
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 or internal bleeding and/or 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 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 monoclonal antibodies (mAb) within 4 weeks of initiation of therapy. Prednisone up to but no more than 10 mg orally once daily (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 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. 17. Prior treatment with melflufen. Regimen specific exclusion criteria Regimen A – Melflufen + Bortezomib and Dexamethasone A1 Refractory to a PI in the last line of therapy prior to enrollment in this trial; 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 App
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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 therapy in patients with relapsed or relapsed-refractory MM. Each treatment regimen and dose 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 as well as in all treated patients. Each treatment regimen and dose will be evaluated separately. ;Secondary Objective: Secondary Objectives To evaluate the best response including the complete response/stringent complete response (CR/sCR), very good partial response (VGPR), partial response (PR) and clinical benefit rate (CBR: proportion of patients with = minimal response (MR)), , time to response (TTR), duration of response (DOR; PR or better), duration of clinical benefit (CB), , progression free survival (PFS) and overall survival (OS) up to a minimum of 2 years in efficacy evaluable patients as well as in all treated patients. IMWG-URC guidelines will be used. Each treatment regimen and dose will be evaluated separately. To further explore the safety and tolerability of the combination regimens. Each treatment regimen and dose will be evaluated separately. Exploratory Objectives Pharmacokinetics will be evaluated in patients enrolled at selected sites only. To evaluate minimal residual disease (MRD) in patients achieving a CR. ;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 and dose will 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 and dose will be eval | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 selected 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 and dose will be evaluated separately. ;Timepoint(s) of evaluation of this end point: During the course of the study. | — |
Countries
Czechia, Czech Republic, France, Poland, Spain, United States
Contacts
Public ContactClinical Trials Information Desk
Oncopeptides AB
Outcome results
None listed