RRMM
Conditions
Keywords
central intravenous administration, peripheral intravenous administration, central venous catheter (CVC), peripheral venous catheter (PVC)
Brief summary
This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy.
Interventions
DRUGMelphalan
Peripheral versus central administration
DRUGDexamethasone
Oral tablets
Sponsors
Oncopeptides AB
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female, age 18 years or older 2. Capable of giving signed informed consent as described in Appendix 1 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 (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 immunomodulatory drug (IMiD) and a proteasome inhibitor (PI). The definition of refractory includes intolerance to an IMiD/PI after at least two 28-day cycles of therapy, see Appendix 10 and Appendix 8. 6. Adequate peripheral arm veins for repeated intravenous infusions 7. Life expectancy of ≥ 6 months; 8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, see Appendix 6. 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, see Appendix 11; 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 * Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) ≤ 3.0 x ULN * Renal function: Estimated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula of ≥ 45 mL/min, see Appendix 12. 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 Appendix 4 of this protocol during the treatment period and for at least 3 months after the last dose of study treatment and refrains 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) as defined in Appendix 4 or II. A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 during the treatment period and for at least 28 days after the last dose of study treatment
Exclusion criteria
1. Primary refractory disease (i.e. never responded with at least minimal response \[MR\] 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Plasma Concentration for Melphalan | Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | To evaluate and compare the pharmacokinetic (PK) variable Cmax of melphalan after central and peripheral intravenous infusion of melflufen. |
| Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melphalan | Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of melphalan after central and peripheral intravenous infusion of melflufen. |
| Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melphalan | Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | To evaluate and compare the pharmacokinetic (PK) variable AUC(0-inf) of melphalan after central and peripheral intravenous infusion of melflufen |
| Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | 15 minutes and 4 hours after peripheral intravenous administration, pre- and post-infusion on Day 1 and Day 8 | Assessment of the local tolerability of peripheral intravenous administration of melflufen using the Visual Infusion Phlebitis (VIP) scale. The VIP scale provides a score from 0 to 5, noting an ascending order of severity of inflammation. A score of 0 is the lowest possible score, meaning no inflammation detected, and 5 is the highest score, indicating the most severe reaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Plasma Concentration for Melflufen and Desethyl-melflufen | Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle) | To evaluate and compare the pharmacokinetic (PK) variable Cmax of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen. |
| Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melflufen and Desethyl-melflufen | Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle) | To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen |
| Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melflufen and Desethyl-melflufen | Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle) | To evaluate and compare the pharmacokinetic (PK) variable AUC(0-inf) of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen |
| Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen | Cycle 1 Day 1 and Cycle 2 Day 1 - 13 measurements during and post infusion (28 days cycle) | To evaluate elimination half-life (t½) for melflufen, melphalan and desethyl-melflufen after central and peripheral intravenous infusion of melflufen. |
| Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Median treatment durations for Arm A and Arm B were 29.14 weeks and 12.14 weeks, respectively. The AE reporting period is estimated to be 30 days longer. | To assess safety and general tolerability of melflufen by collecting non-serious Adverse Events (AEs) from the start of study treatment until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first. Serious AEs (SAEs) were collected from the time the subject signed the ICF until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first. |
| 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) | From initiation of therapy until disease progression. Median treatment durations for Arm A and Arm B were 29.14 weeks and 12.14 weeks, respectively. | To assess best response during the study with the criteria established by the International Myeloma Working Group Uniform Response Criteria (IMWG-URC) for sCR, CR, VGPR, PR, SD and PD |
| ORR | From initiation of therapy until disease progression. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. | To assess overall response rate (ORR), including CR/sCR, VGPR and PR, during the study with the criteria established by the IMWG-URC. |
| CBR | To be assessed at the end of study drug treatment. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. | To assess clinical benefit rate (CBR), i.e., proportion of patients that achieve a confirmed minimal response or better (sCR, CR, VGPR, PR and MR), during the study with the criteria established by the IMWG-URC. |
| DOR | From confirmed response until disease progression. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. | To assess duration of response (DOR): the time in months from the first evidence of confirmed assessment of sCR, CR, VGPR, or PR to first confirmed disease progression according to the criteria established by the IMWG-URC or to death due to any cause. DOR is defined only for patients with a confirmed PR or better. |
| DOCB | 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. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. | To assess duration of clinical benefit (DOCB) in patients with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), PR, or MR during the study with the criteria established by the IMWG-URC. |
| TTR | From initiation of therapy until documented disease response. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. | To assess time to response (TTR) in patients with PR or better during the study with the criteria established by the UMWG-URC. |
| TTP | From date of randomization until documented disease progression. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. | To assess time to progression (TTP) during the study with the criteria established by the IMWG-URC. |
| TTNT | From randomization to the date of next anti-myeloma treatment. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. | To assess time to next treatment (TTNT) |
| PFS | From initiation of therapy until documented disease progression or initiation of new therapy. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. | To assess progression free survival (PFS) |
| Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Median treatment durations for Arm A and Arm B were 29.14 and 12.14 weeks, respectively. The AE reporting period is estimated to be 30 days longer. | To assess safety and general tolerability of melflufen by collecting non-serious Adverse Events (AEs) from the start of study treatment until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first. Serious AEs (SAEs) were collected from the time the subject signed the ICF until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first. |
| Grade 5 Treatment-Emergent Adverse Events (TEAEs) | From signing of the ICF until 30 days after the last dose of any study drug or initiation of subsequent therapy, whichever comes first. Median treatment durations for Arms A and B were 29.14 weeks and 12.14 weeks. AE reporting period=30 days longer | To assess safety and general tolerability of melflufen by collecting serious adverse events (SAEs) from the signing of the ICF until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever comes first. |
Countries
Bulgaria, Czechia, Hungary, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC.
Melflufen: Peripheral versus central administration
Dexamethasone: Oral tablets | 14 |
| Arm B Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC.
Melflufen: Peripheral versus central administration
Dexamethasone: Oral tablets | 13 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Cycle 1 | Death | 0 | 3 |
| Cycle 1 | Disease progression | 1 | 2 |
| Cycle 2 | Death | 0 | 1 |
| Cycle 2 | Disease progression | 3 | 0 |
| Cycle 3 to End of Study (EOS) | Death | 1 | 3 |
| Cycle 3 to End of Study (EOS) | Disease progression | 4 | 2 |
| Cycle 3 to End of Study (EOS) | Study terminated by Sponsor | 4 | 2 |
| Cycle 3 to End of Study (EOS) | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Arm A | Arm B | Total |
|---|---|---|---|
| Age, Customized Age group >=65 - 75 years | 5 Participants | 5 Participants | 10 Participants |
| Age, Customized Age group <65 years | 8 Participants | 4 Participants | 12 Participants |
| Age, Customized Age group > 75 years | 1 Participants | 4 Participants | 5 Participants |
| Baseline fertility status Not able to bear children | 6 Participants | 7 Participants | 13 Participants |
| Baseline fertility status Potentially able to bear children | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 13 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 13 Participants | 27 Participants |
| Region of Enrollment Bulgaria | 6 participants | 1 participants | 7 participants |
| Region of Enrollment Czechia | 4 participants | 7 participants | 11 participants |
| Region of Enrollment Hungary | 1 participants | 3 participants | 4 participants |
| Region of Enrollment Ukraine | 3 participants | 2 participants | 5 participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 14 | 8 / 13 |
| other Total, other adverse events | 13 / 14 | 13 / 13 |
| serious Total, serious adverse events | 5 / 14 | 9 / 13 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melphalan
To evaluate and compare the pharmacokinetic (PK) variable AUC(0-inf) of melphalan after central and peripheral intravenous infusion of melflufen
Time frame: Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Population: Pharmacokinetic (PK) Set: All patients that received at least two melflufen doses of 40 mg and had sufficient PK samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series following peripheral administration and one PK sampling series following central administration. Patients with a dose reduction in cycle 2 were not evaluable for PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Peripheral Venous Catheter (PVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melphalan | Cycle 1 | 54216.70 min*ng/mL | Geometric Coefficient of Variation 23.794 |
| Peripheral Venous Catheter (PVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melphalan | Cycle 2 | 67403.07 min*ng/mL | Geometric Coefficient of Variation 30.149 |
| Central Venous Catheter (CVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melphalan | Cycle 1 | 66835.47 min*ng/mL | Geometric Coefficient of Variation 18.171 |
| Central Venous Catheter (CVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melphalan | Cycle 2 | 50835.59 min*ng/mL | Geometric Coefficient of Variation 44.728 |
Comparison: Based on a geometric mean ratio (GMR) peripheral vs. central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients.90% CI: [0.863, 1.058]
Primary
Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melphalan
To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of melphalan after central and peripheral intravenous infusion of melflufen.
Time frame: Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Population: Pharmacokinetic (PK) Set: All patients that received at least two melflufen doses of 40 mg and had sufficient PK samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series following peripheral administration and one PK sampling series following central administration. Patients with a dose reduction in cycle 2 were not evaluable for PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Peripheral Venous Catheter (PVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melphalan | Cycle 1 | 49518.36 min*ng/mL | Geometric Coefficient of Variation 23.71 |
| Peripheral Venous Catheter (PVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melphalan | Cycle 2 | 60273.95 min*ng/mL | Geometric Coefficient of Variation 30.037 |
| Central Venous Catheter (CVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melphalan | Cycle 1 | 59543.20 min*ng/mL | Geometric Coefficient of Variation 17.698 |
| Central Venous Catheter (CVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melphalan | Cycle 2 | 46173.13 min*ng/mL | Geometric Coefficient of Variation 43.336 |
Comparison: Based on a geometric mean ratio (GMR) peripheral vs. central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients.90% CI: [0.861, 1.053]
Primary
Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration
Assessment of the local tolerability of peripheral intravenous administration of melflufen using the Visual Infusion Phlebitis (VIP) scale. The VIP scale provides a score from 0 to 5, noting an ascending order of severity of inflammation. A score of 0 is the lowest possible score, meaning no inflammation detected, and 5 is the highest score, indicating the most severe reaction.
Time frame: 15 minutes and 4 hours after peripheral intravenous administration, pre- and post-infusion on Day 1 and Day 8
Population: Safety Analysis Set
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 1 Pre-Infusion | VIP score = 0 | 13 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 1 Pre-Infusion | VIP score = 1 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 1 Pre-Infusion | VIP score = 2 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 1 Pre-Infusion | VIP score = 3 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 1 Pre-Infusion | VIP score = 4 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 1 Pre-Infusion | VIP score = 5 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 1 Post-Infusion | VIP score = 0 | 13 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 1 Post-Infusion | VIP score = 1 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 1 Post-Infusion | VIP score = 2 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 1 Post-Infusion | VIP score = 3 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 1 Post-Infusion | VIP score = 4 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 1 Post-Infusion | VIP score = 5 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 8 | VIP score = 0 | 10 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 8 | VIP score = 1 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 8 | VIP score = 2 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 8 | VIP score = 3 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 8 | VIP score = 4 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 1 Day 8 | VIP score = 5 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 2 Day 1 Pre-Infusion | VIP score = 0 | 8 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 2 Day 1 Pre-Infusion | VIP score = 2 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 2 Day 1 Pre-Infusion | VIP score = 3 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 2 Day 1 Pre-Infusion | VIP score = 4 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 2 Day 1 Pre-Infusion | VIP score = 5 | 0 Participants |
| Peripheral Venous Catheter (PVC) | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Cycle 2 Day 1 Pre-Infusion | VIP score = 1 | 0 Participants |
Primary
Peak Plasma Concentration for Melphalan
To evaluate and compare the pharmacokinetic (PK) variable Cmax of melphalan after central and peripheral intravenous infusion of melflufen.
Time frame: Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Population: Pharmacokinetic (PK) Set: All patients that received at least two melflufen doses of 40 mg and had sufficient PK samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series following peripheral administration and one PK sampling series following central administration. Patients with a dose reduction in cycle 2 were not evaluable for PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Peripheral Venous Catheter (PVC) | Peak Plasma Concentration for Melphalan | Cycle 1 | 486.1 ng/mL | Geometric Coefficient of Variation 21.34 |
| Peripheral Venous Catheter (PVC) | Peak Plasma Concentration for Melphalan | Cycle 2 | 546.3 ng/mL | Geometric Coefficient of Variation 31.83 |
| Central Venous Catheter (CVC) | Peak Plasma Concentration for Melphalan | Cycle 1 | 530.1 ng/mL | Geometric Coefficient of Variation 25.23 |
| Central Venous Catheter (CVC) | Peak Plasma Concentration for Melphalan | Cycle 2 | 449.2 ng/mL | Geometric Coefficient of Variation 40.66 |
Comparison: Based on a geometric mean ratio (GMR) peripheral vs. central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients.90% CI: [0.849, 1.053]
Secondary
Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melflufen and Desethyl-melflufen
To evaluate and compare the pharmacokinetic (PK) variable AUC(0-inf) of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen
Time frame: Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle)
Population: Pharmacokinetic (PK) Analysis set: All patients that received at least two melflufen doses of 40 mg and had sufficient PK samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series following peripheral administration and one PK sampling series following central administration. Patients with a dose reduction in Cycle 2 were not evaluable for PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Peripheral Venous Catheter (PVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melflufen and Desethyl-melflufen | Melflufen Cycle 1 (0-inf) | 3639.34 min x ng/mL | Geometric Coefficient of Variation 52.379 |
| Peripheral Venous Catheter (PVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melflufen and Desethyl-melflufen | Meflufen Cycle 2 (0-inf) | 3099.70 min x ng/mL | Geometric Coefficient of Variation 80.708 |
| Peripheral Venous Catheter (PVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melflufen and Desethyl-melflufen | Desethyl-melflufen Cycle 1 (0-inf) | 609.44 min x ng/mL | Geometric Coefficient of Variation 40.778 |
| Peripheral Venous Catheter (PVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melflufen and Desethyl-melflufen | Desethyl-melflufen Cycle 2 (0-inf) | 695.29 min x ng/mL | Geometric Coefficient of Variation 51.722 |
| Central Venous Catheter (CVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melflufen and Desethyl-melflufen | Desethyl-melflufen Cycle 2 (0-inf) | 440.65 min x ng/mL | Geometric Coefficient of Variation 43.547 |
| Central Venous Catheter (CVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melflufen and Desethyl-melflufen | Melflufen Cycle 1 (0-inf) | 2841.23 min x ng/mL | Geometric Coefficient of Variation 51.631 |
| Central Venous Catheter (CVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melflufen and Desethyl-melflufen | Desethyl-melflufen Cycle 1 (0-inf) | 759.25 min x ng/mL | Geometric Coefficient of Variation 34.619 |
| Central Venous Catheter (CVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melflufen and Desethyl-melflufen | Meflufen Cycle 2 (0-inf) | 3093.96 min x ng/mL | Geometric Coefficient of Variation 49.295 |
Comparison: Based on a geometric mean ratio (GMR) peripheral vs central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients.90% CI: [0.684, 1.124]
Comparison: Based on a geometric mean ratio (GMR) peripheral vs central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients.90% CI: [0.833, 0.989]
Secondary
Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melflufen and Desethyl-melflufen
To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen
Time frame: Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle)
Population: Pharmacokinetic (PK) analysis set: All patients that received at least two melflufen doses of 40 mg and had sufficient PK samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series following peripheral administration and one PK sampling series following central administration. Patients with a dose reduction in cycle 2 were not evaluable for PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Peripheral Venous Catheter (PVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melflufen and Desethyl-melflufen | Melflufen Cycle 1 (0-t) | 3617.03 min x ng/mL | Geometric Coefficient of Variation 52.244 |
| Peripheral Venous Catheter (PVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melflufen and Desethyl-melflufen | Melflufen Cycle 2 (0-t) | 3083.74 min x ng/mL | Geometric Coefficient of Variation 80.639 |
| Peripheral Venous Catheter (PVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melflufen and Desethyl-melflufen | Desethyl-melflufen Cycle 1 (0-t) | 563.34 min x ng/mL | Geometric Coefficient of Variation 42.086 |
| Peripheral Venous Catheter (PVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melflufen and Desethyl-melflufen | Desethyl-melflufen Cycle 2 (0-t) | 636.06 min x ng/mL | Geometric Coefficient of Variation 51.627 |
| Central Venous Catheter (CVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melflufen and Desethyl-melflufen | Desethyl-melflufen Cycle 2 (0-t) | 391.11 min x ng/mL | Geometric Coefficient of Variation 49.458 |
| Central Venous Catheter (CVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melflufen and Desethyl-melflufen | Melflufen Cycle 1 (0-t) | 2828.69 min x ng/mL | Geometric Coefficient of Variation 51.646 |
| Central Venous Catheter (CVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melflufen and Desethyl-melflufen | Desethyl-melflufen Cycle 1 (0-t) | 639.39 min x ng/mL | Geometric Coefficient of Variation 34.053 |
| Central Venous Catheter (CVC) | Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melflufen and Desethyl-melflufen | Melflufen Cycle 2 (0-t) | 3078.21 min x ng/mL | Geometric Coefficient of Variation 49.443 |
Comparison: Based on a geometric mean ratio (GMR) peripheral vs central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients.90% CI: [0.684, 1.126]
Comparison: Based on a geometric mean ratio (GMR) peripheral vs central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients.90% CI: [0.819, 0.982]
Secondary
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)
To assess best response during the study with the criteria established by the International Myeloma Working Group Uniform Response Criteria (IMWG-URC) for sCR, CR, VGPR, PR, SD and PD
Time frame: From initiation of therapy until disease progression. Median treatment durations for Arm A and Arm B were 29.14 weeks and 12.14 weeks, respectively.
Population: Full Analysis Set: 14 participants randomized to Arm A and 13 participants randomized to Arm B.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Peripheral Venous Catheter (PVC) | 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) | Not available | 2 Participants |
| Peripheral Venous Catheter (PVC) | 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) | Minimal response | 4 Participants |
| Peripheral Venous Catheter (PVC) | 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) | Complete response | 1 Participants |
| Peripheral Venous Catheter (PVC) | 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) | Stringent complete response | 0 Participants |
| Peripheral Venous Catheter (PVC) | 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) | Partial response | 3 Participants |
| Peripheral Venous Catheter (PVC) | 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) | Progressive disease | 2 Participants |
| Peripheral Venous Catheter (PVC) | 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) | Stable disease | 2 Participants |
| Peripheral Venous Catheter (PVC) | 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) | Very good partial response | 0 Participants |
| Central Venous Catheter (CVC) | 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) | Stringent complete response | 0 Participants |
| Central Venous Catheter (CVC) | 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) | Stable disease | 6 Participants |
| Central Venous Catheter (CVC) | 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) | Progressive disease | 1 Participants |
| Central Venous Catheter (CVC) | 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) | Not available | 4 Participants |
| Central Venous Catheter (CVC) | 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) | Minimal response | 1 Participants |
| Central Venous Catheter (CVC) | 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) | Complete response | 0 Participants |
| Central Venous Catheter (CVC) | 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) | Very good partial response | 0 Participants |
| Central Venous Catheter (CVC) | 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) | Partial response | 1 Participants |
| Overall | 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) | Complete response | 1 Participants |
| Overall | 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) | Progressive disease | 3 Participants |
| Overall | 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) | Partial response | 4 Participants |
| Overall | 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) | Very good partial response | 0 Participants |
| Overall | 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) | Stable disease | 8 Participants |
| Overall | 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) | Stringent complete response | 0 Participants |
| Overall | 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) | Not available | 6 Participants |
| Overall | 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) | Minimal response | 5 Participants |
Secondary
CBR
To assess clinical benefit rate (CBR), i.e., proportion of patients that achieve a confirmed minimal response or better (sCR, CR, VGPR, PR and MR), during the study with the criteria established by the IMWG-URC.
Time frame: To be assessed at the end of study drug treatment. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively.
Population: Full Analysis set: 14 participants randomized to Arm A and 13 participants randomized to Arm B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Peripheral Venous Catheter (PVC) | CBR | 8 Participants |
| Central Venous Catheter (CVC) | CBR | 2 Participants |
| Overall | CBR | 10 Participants |
Secondary
DOCB
To assess duration of clinical benefit (DOCB) in patients with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), PR, or MR during the study with the criteria established by the IMWG-URC.
Time frame: 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. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively.
Population: Full Analysis set: 14 participants randomized to Arm A and 13 participants randomized to Arm B.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Venous Catheter (PVC) | DOCB | NA months |
| Central Venous Catheter (CVC) | DOCB | NA months |
| Overall | DOCB | NA months |
Secondary
DOR
To assess duration of response (DOR): the time in months from the first evidence of confirmed assessment of sCR, CR, VGPR, or PR to first confirmed disease progression according to the criteria established by the IMWG-URC or to death due to any cause. DOR is defined only for patients with a confirmed PR or better.
Time frame: From confirmed response until disease progression. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively.
Population: Full Analysis set: 14 participants randomized to Arm A and 13 participants randomized to Arm B.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Venous Catheter (PVC) | DOR | NA months |
| Central Venous Catheter (CVC) | DOR | NA months |
| Overall | DOR | NA months |
Secondary
Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen
To evaluate elimination half-life (t½) for melflufen, melphalan and desethyl-melflufen after central and peripheral intravenous infusion of melflufen.
Time frame: Cycle 1 Day 1 and Cycle 2 Day 1 - 13 measurements during and post infusion (28 days cycle)
Population: Pharmacokinetic (PK) Analysis set:All patients that received at least two melflufen doses of 40 mg and had sufficient PK samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series following peripheral administration and one PK sampling series following central administration. Patients with a dose reduction in cycle 2 were not evaluable for PK.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Peripheral Venous Catheter (PVC) | Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen | Desethyl-melflufen Cycle 2 | 25.04 minutes | Standard Deviation 83.298 |
| Peripheral Venous Catheter (PVC) | Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen | Melphalan Cycle 2 | 78.09 minutes | Standard Deviation 18.118 |
| Peripheral Venous Catheter (PVC) | Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen | Melflufen Cycle 1 | 7.42 minutes | Standard Deviation 106.832 |
| Peripheral Venous Catheter (PVC) | Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen | Melflufen Cycle 2 | 6.15 minutes | Standard Deviation 81.278 |
| Peripheral Venous Catheter (PVC) | Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen | Desethyl-melflufen Cycle 1 | 18.44 minutes | Standard Deviation 49.68 |
| Peripheral Venous Catheter (PVC) | Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen | Melphalan Cycle 1 | 72.51 minutes | Standard Deviation 14.993 |
| Central Venous Catheter (CVC) | Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen | Desethyl-melflufen Cycle 1 | 23.49 minutes | Standard Deviation 43.423 |
| Central Venous Catheter (CVC) | Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen | Melphalan Cycle 1 | 80.09 minutes | Standard Deviation 12.85 |
| Central Venous Catheter (CVC) | Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen | Melflufen Cycle 2 | 5.74 minutes | Standard Deviation 80.837 |
| Central Venous Catheter (CVC) | Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen | Melphalan Cycle 2 | 72.97 minutes | Standard Deviation 16.84 |
| Central Venous Catheter (CVC) | Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen | Desethyl-melflufen Cycle 2 | 17.43 minutes | Standard Deviation 37.708 |
| Central Venous Catheter (CVC) | Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen | Melflufen Cycle 1 | 4.45 minutes | Standard Deviation 90.634 |
Secondary
Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT
To assess safety and general tolerability of melflufen by collecting non-serious Adverse Events (AEs) from the start of study treatment until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first. Serious AEs (SAEs) were collected from the time the subject signed the ICF until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first.
Time frame: Median treatment durations for Arm A and Arm B were 29.14 weeks and 12.14 weeks, respectively. The AE reporting period is estimated to be 30 days longer.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Pneumonia | 3 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Patients with at least 1 TEAE | 13 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Respiratory tract infection | 2 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | femur fracture | 0 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Neutropenia | 9 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | General disorders and administration site conditions | 5 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Infections and Infestations | 6 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | C-reactive protein increased | 2 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Skin and subcutaneous tissue disorders | 2 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | SARS-CoV-2 test positive | 2 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Fatigue | 1 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Thrombocytopenia | 10 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Anaemia | 9 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | General health deterioration | 0 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Rash | 2 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Injury, poisoning and procedural complications | 0 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Musculoskeletal and connective tissue disorders | 4 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Investigations | 4 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | COVID-19 pneumonia | 0 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Arthralgia | 1 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Blood and lymphatic system disorders | 13 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Leukopenia | 2 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Back pain | 2 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Pyrexia | 2 Participants |
| Peripheral Venous Catheter (PVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Bone pain | 2 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Leukopenia | 1 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Investigations | 4 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | SARS-CoV-2 test positive | 4 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Infections and Infestations | 7 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | C-reactive protein increased | 0 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Injury, poisoning and procedural complications | 3 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | femur fracture | 2 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Patients with at least 1 TEAE | 13 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Skin and subcutaneous tissue disorders | 0 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Pneumonia | 2 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Rash | 0 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Thrombocytopenia | 10 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | COVID-19 pneumonia | 3 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Respiratory tract infection | 0 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | General disorders and administration site conditions | 6 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Neutropenia | 9 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Pyrexia | 3 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Bone pain | 0 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Fatigue | 2 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | General health deterioration | 2 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Anaemia | 7 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Musculoskeletal and connective tissue disorders | 5 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Blood and lymphatic system disorders | 12 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Arthralgia | 2 Participants |
| Central Venous Catheter (CVC) | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Back pain | 1 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | femur fracture | 2 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Blood and lymphatic system disorders | 25 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Thrombocytopenia | 20 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Neutropenia | 18 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Anaemia | 16 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Leukopenia | 3 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Infections and Infestations | 13 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Pneumonia | 5 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | COVID-19 pneumonia | 3 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Respiratory tract infection | 2 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | General disorders and administration site conditions | 11 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Pyrexia | 5 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Fatigue | 3 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | General health deterioration | 2 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Musculoskeletal and connective tissue disorders | 9 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Arthralgia | 3 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Back pain | 3 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Bone pain | 2 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Investigations | 8 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | SARS-CoV-2 test positive | 6 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | C-reactive protein increased | 2 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Injury, poisoning and procedural complications | 3 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Skin and subcutaneous tissue disorders | 2 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Rash | 2 Participants |
| Overall | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | Patients with at least 1 TEAE | 26 Participants |
Secondary
Grade 3/4 Treatment-Emergent Adverse Events (TEAEs)
To assess safety and general tolerability of melflufen by collecting non-serious Adverse Events (AEs) from the start of study treatment until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first. Serious AEs (SAEs) were collected from the time the subject signed the ICF until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first.
Time frame: Median treatment durations for Arm A and Arm B were 29.14 and 12.14 weeks, respectively. The AE reporting period is estimated to be 30 days longer.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Ischaemic stroke | 1 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Pneumonia | 2 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Lymphopenia | 1 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Stomatitis | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | COVID-19 pneumonia | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Gastrointestinal disorders | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Femoral neck fracture | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Anaemia | 5 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Infections and infestations | 2 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Injury, poisoning and procedural complications | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | General disorders and administration site conditions | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Sepsis | 1 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Femur fracture | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | General physical health deterioration | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Neutropenia | 8 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Febrile neutropenia | 1 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Thrombocytopenia | 8 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Musculoskeletal and connective tissue disorders | 1 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Leukopenia | 2 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Blood and lymphatic system disorders | 12 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Back pain | 1 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Death | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Hypertension | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Musculoskeletal chest pain | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Asthenia | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Vascular disorders | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Nervous system disorders | 1 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Lymphopenia | 1 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Infections and infestations | 2 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | COVID-19 pneumonia | 1 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | General disorders and administration site conditions | 0 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Asthenia | 1 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Injury, poisoning and procedural complications | 3 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Stomatitis | 1 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Musculoskeletal and connective tissue disorders | 1 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Back pain | 0 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Musculoskeletal chest pain | 1 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Pneumonia | 1 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Febrile neutropenia | 1 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Sepsis | 0 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Death | 0 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | General physical health deterioration | 0 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Femur fracture | 2 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Femoral neck fracture | 1 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Gastrointestinal disorders | 1 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Nervous system disorders | 0 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Ischaemic stroke | 0 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Vascular disorders | 1 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Hypertension | 1 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Blood and lymphatic system disorders | 10 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Thrombocytopenia | 10 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Neutropenia | 7 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Anaemia | 3 Participants |
| Central Venous Catheter (CVC) | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Leukopenia | 1 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Nervous system disorders | 1 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Infections and infestations | 4 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Asthenia | 1 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Ischaemic stroke | 1 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Musculoskeletal chest pain | 1 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Febrile neutropenia | 2 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Vascular disorders | 1 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Back pain | 1 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Anaemia | 8 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Hypertension | 1 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Musculoskeletal and connective tissue disorders | 2 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | General disorders and administration site conditions | 0 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Blood and lymphatic system disorders | 22 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Stomatitis | 1 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Lymphopenia | 2 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | General physical health deterioration | 0 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Death | 0 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Thrombocytopenia | 18 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Femur fracture | 2 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | COVID-19 pneumonia | 1 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Injury, poisoning and procedural complications | 3 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Femoral neck fracture | 1 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Sepsis | 1 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Leukopenia | 3 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Gastrointestinal disorders | 1 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Pneumonia | 3 Participants |
| Overall | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | Neutropenia | 15 Participants |
Secondary
Grade 5 Treatment-Emergent Adverse Events (TEAEs)
To assess safety and general tolerability of melflufen by collecting serious adverse events (SAEs) from the signing of the ICF until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever comes first.
Time frame: From signing of the ICF until 30 days after the last dose of any study drug or initiation of subsequent therapy, whichever comes first. Median treatment durations for Arms A and B were 29.14 weeks and 12.14 weeks. AE reporting period=30 days longer
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Peripheral Venous Catheter (PVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | Death | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | Gastrointestinal disorders | 1 Participants |
| Peripheral Venous Catheter (PVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | COVID-19 pneumonia | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | Ileus | 1 Participants |
| Peripheral Venous Catheter (PVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | General disorders and administration site conditions | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | Infections and infestations | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | General physical health deterioration | 0 Participants |
| Peripheral Venous Catheter (PVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | Pneumonia | 0 Participants |
| Central Venous Catheter (CVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | Death | 1 Participants |
| Central Venous Catheter (CVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | Pneumonia | 1 Participants |
| Central Venous Catheter (CVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | General physical health deterioration | 2 Participants |
| Central Venous Catheter (CVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | Gastrointestinal disorders | 0 Participants |
| Central Venous Catheter (CVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | COVID-19 pneumonia | 2 Participants |
| Central Venous Catheter (CVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | General disorders and administration site conditions | 3 Participants |
| Central Venous Catheter (CVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | Ileus | 0 Participants |
| Central Venous Catheter (CVC) | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | Infections and infestations | 3 Participants |
| Overall | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | Ileus | 1 Participants |
| Overall | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | Infections and infestations | 3 Participants |
| Overall | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | Pneumonia | 1 Participants |
| Overall | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | COVID-19 pneumonia | 2 Participants |
| Overall | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | General disorders and administration site conditions | 3 Participants |
| Overall | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | General physical health deterioration | 2 Participants |
| Overall | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | Death | 1 Participants |
| Overall | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | Gastrointestinal disorders | 1 Participants |
Secondary
ORR
To assess overall response rate (ORR), including CR/sCR, VGPR and PR, during the study with the criteria established by the IMWG-URC.
Time frame: From initiation of therapy until disease progression. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively.
Population: Full Analysis set: 14 participants randomized to Arm A and 13 participants randomized to Arm B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Peripheral Venous Catheter (PVC) | ORR | 4 Participants |
| Central Venous Catheter (CVC) | ORR | 1 Participants |
| Overall | ORR | 5 Participants |
Secondary
Peak Plasma Concentration for Melflufen and Desethyl-melflufen
To evaluate and compare the pharmacokinetic (PK) variable Cmax of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen.
Time frame: Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle)
Population: Pharmacokinetic (PK) Analysis set: All patients that received at least two melflufen doses of 40 mg and had sufficient PK samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series following peripheral administration and one PK sampling series following central administration. Patients with a dose reduction in cycle 2 were not evaluable for PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Peripheral Venous Catheter (PVC) | Peak Plasma Concentration for Melflufen and Desethyl-melflufen | Melflufen Cycle 2 | 127.27 ng/mL | Geometric Coefficient of Variation 75.872 |
| Peripheral Venous Catheter (PVC) | Peak Plasma Concentration for Melflufen and Desethyl-melflufen | Desethyl-melflufen Cycle 2 | 16.801 ng/mL | Geometric Coefficient of Variation 43.8965 |
| Peripheral Venous Catheter (PVC) | Peak Plasma Concentration for Melflufen and Desethyl-melflufen | Desethyl-melflufen Cycle 1 | 16.721 ng/mL | Geometric Coefficient of Variation 33.2618 |
| Peripheral Venous Catheter (PVC) | Peak Plasma Concentration for Melflufen and Desethyl-melflufen | Melflufen Cycle 1 | 151.11 ng/mL | Geometric Coefficient of Variation 59.74 |
| Central Venous Catheter (CVC) | Peak Plasma Concentration for Melflufen and Desethyl-melflufen | Desethyl-melflufen Cycle 1 | 11.851 ng/mL | Geometric Coefficient of Variation 41.3587 |
| Central Venous Catheter (CVC) | Peak Plasma Concentration for Melflufen and Desethyl-melflufen | Melflufen Cycle 2 | 141.75 ng/mL | Geometric Coefficient of Variation 47.921 |
| Central Venous Catheter (CVC) | Peak Plasma Concentration for Melflufen and Desethyl-melflufen | Melflufen Cycle 1 | 123.0 ng/mL | Geometric Coefficient of Variation 47.498 |
| Central Venous Catheter (CVC) | Peak Plasma Concentration for Melflufen and Desethyl-melflufen | Desethyl-melflufen Cycle 2 | 11.851 ng/mL | Geometric Coefficient of Variation 41.3587 |
Comparison: For melflufen: Based on a geometric mean ratio (GMR) peripheral vs central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients.90% CI: [0.736, 1.222]
Comparison: For desmethyl-melflufen: Based on a geometric mean ratio (GMR) peripheral vs central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients.90% CI: [0.748, 0.957]
Secondary
PFS
To assess progression free survival (PFS)
Time frame: From initiation of therapy until documented disease progression or initiation of new therapy. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively.
Population: Full Analysis set: 14 participants randomized to Arm A and 13 participants randomized to Arm B.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Venous Catheter (PVC) | PFS | 5.21 months |
| Central Venous Catheter (CVC) | PFS | 2.89 months |
| Overall | PFS | 3.73 months |
Secondary
TTNT
To assess time to next treatment (TTNT)
Time frame: From randomization to the date of next anti-myeloma treatment. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively.
Population: Full Analysis set: 14 participants randomized to Arm A and 13 participants randomized to Arm B.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Venous Catheter (PVC) | TTNT | NA months |
| Central Venous Catheter (CVC) | TTNT | NA months |
| Overall | TTNT | NA months |
Secondary
TTP
To assess time to progression (TTP) during the study with the criteria established by the IMWG-URC.
Time frame: From date of randomization until documented disease progression. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively.
Population: Full Analysis set: 14 participants randomized to Arm A and 13 participants randomized to Arm B.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Venous Catheter (PVC) | TTP | 5.78 months |
| Central Venous Catheter (CVC) | TTP | 4.80 months |
| Overall | TTP | 5.78 months |
Secondary
TTR
To assess time to response (TTR) in patients with PR or better during the study with the criteria established by the UMWG-URC.
Time frame: From initiation of therapy until documented disease response. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively.
Population: Full Analysis set:14 participants randomized to Arm A and 13 participants randomized to Arm B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Peripheral Venous Catheter (PVC) | TTR | 4 Participants |
| Central Venous Catheter (CVC) | TTR | 1 Participants |
| Overall | TTR | 5 Participants |