Multiple Myeloma, Renal Impairment
Conditions
Brief summary
This was a multicenter study of the pharmacokinetics (PK) of melphalan during treatment with melflufen and dexamethasone in patients with relapsed refractory multiple myeloma (RRMM) and impaired renal function.
Detailed description
This was a multicenter study assessing the safety, tolerability, and efficacy of melflufen given on Day 1 of a 28-day cycle, together with weekly dexamethasone, in patients with relapsed multiple myeloma or RRMM and impaired renal function, as well as the relationship between renal function and PK parameters for the active metabolite melphalan.
Interventions
DRUGMelflufen
Melflufen was distributed in the European Union (EU) as a powder for concentrate for solution for infusion; in the US, it was distributed as a powder for injection. Melflufen was administered as a 30-minute intravenous infusion on Day 1 of every 28-day cycle via a central catheter.
DRUGDexamethasone
Tablets. Administered orally on Days 1, 8, 15, and 22 of each 28-day cycle. Dose of 40 mg for patients aged \<75 years. Dose of 20 mg for patients aged ≥75 years.
Sponsors
Oncopeptides AB
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Arms differed based on patients' level of renal function (moderate or severe impairment) and starting dose of melflufen.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female, age 18 years or older, at the time of signing the informed consent; 2. A prior diagnosis of multiple myeloma (MM) with documented disease progression in need of treatment at time of screening; 3. Received at least 2 prior lines of therapy; 4. Measurable disease defined as any of the following: * Serum monoclonal protein ≥0.5 g/dL by serum protein electrophoresis (SPEP). * ≥200 mg/24 hours of monoclonal protein in the urine on 24-hour urine electrophoresis (UPEP) * Serum free light chain (SFLC) ≥10 mg/dL AND abnormal serum kappa to lambda free light chain ratio 5. Life expectancy of ≥6 months; 6. Eastern Cooperative Oncology Group (ECOG) performance status ≤2. (Patients with lower performance status based solely on bone pain secondary to MM 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 the patient is 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; 10. Renal function: Estimated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula on 2 consecutive screening evaluations. Patients meeting criteria for Screening 1, must also meet criteria for Screening 2 following optimal hydration (as determined by the investigator). Screening 2 must be on or as close as possible to treatment start date (preferably \<24-48 hours) but cannot exceed 72 hours. • Cohort 1 (a and b): Screening 1: eGFR between ≥25 mL/min/1.73m² to \<45 mL/min/1.73m². Screening 2: eGFR between ≥30 mL/min/1.73m² to \<45 mL/min/1.73m². • Cohort 2 (a and b): Screening 1: eGFR between ≥10 mL/min/1.73m² to \<35 mL/min/1.73m². Screening 2: eGFR between ≥15 mL/min/1.73m² to \<30 mL/min/1.73m². Cohort 2b will only be enrolled following approval of Data Safety Monitoring Committee (DSMC) after evaluating data from Cohort 1a, 1b and 2a. Patients with fluctuating values of eGFR may be eligible following consideration of additional assessments in consultation with the medical monitor. 11. The following laboratory results must be met 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 (red blood cell \[RBC\] transfusions are permitted) * Total Bilirubin ≤1.5 x upper limit of normal (ULN), or higher in patients diagnosed with Gilbert's syndrome, that have been reviewed and approved by the medical monitor * Aspartate transaminase / serum glutamic oxaloacetic transaminase (AST / SGOT) and alanine transaminase / serum glutamic pyruvic transaminase (ALT / SGPT) ≤3.0 x ULN; 12. Must have, or be willing to have, an acceptable central catheter. (Port a cath, peripherally inserted central catheter \[PICC\] line, or central venous catheter). Footnote \*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.
Exclusion criteria
1. Primary refractory disease (i.e., never responded with ≥ minimal response \[MR\] to any prior therapy); 2. Evidence of mucosal or internal bleeding and/or platelet transfusion refractory (platelet count fails to increase by \>10,000 cells/mm³ \[10.0 x 10⁹/L\] 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 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; 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 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. Immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs) 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 2 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 study therapy (this does not include limited course of radiation used for management of bone pain to be completed within 7 days of initiation of study therapy). Plasmapheresis is not permitted within 14 days of initiation of therapy; 16. Known intolerance to steroid therapy; 17. Prior renal transplant; 18. Currently in need of renal dialysis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of Melphalan | Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion. | Maximum observed concentration (Cmax) |
| Tmax of Melphalan | Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion. | Time of maximum observed concentration (Tmax) |
| Area Under the Curve (0-t) of Melphalan | Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion. | Area under the concentration-time curve (AUC) from 0h to the last measurable concentration. |
| Area Under the Curve (Inf) of Melphalan | Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion. | Area under the concentration-time curve (AUC) from 0 hours to infinity |
| T1/2 of Melphalan | Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion. | Elimination half-life of melphalan |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Clinical Benefit | Patients were assessed from the first measure of a confirmed MR or better until confirmed progression, death, or initiation of subsequent therapy (maximum duration 127.1 weeks). | Duration of clinical benefit (DOCB) was calculated as time in months from the first evidence of confirmed assessment of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response (MR) to first confirmed disease progression, or to death due to any cause. DOCB was defined only for patients with a confirmed MR or better. DOCB was summarized using the Kaplan-Meier (K-M) method. The median DOCB was estimated from the 50th percentile of the corresponding K-M estimates. The 95% confidence interval for median DOCB was constructed using the method of Brookmeyer (Brookmeyer, 1982). |
| Time to Response | From initiation of therapy until documented disease response (maximum duration 127.1 weeks). | Time from first dose of therapy to first documented confirmed response of partial response (PR) or better. |
| Best Confirmed Response | Patients were assessed for response after each cycle. After discontinuation of therapy, patients continued to be assessed until documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy (max duration 127.1 weeks). | Best confirmed response required 2 consecutive assessments with the same response result made at any time. In case at the second consecutive assessment (made at any time) the response is higher than the previous one, then confirmed response (linked to the first assessment visit) will be the first one (e.g., PR - VGPR consecutive pair will lead to a PR confirmed response at the first visit). In case the second consecutive response is lower than the first one, then confirmed response (linked to the first assessment visit) will be the second one (e.g. CR-VGPR consecutive pair will lead to a VGPR confirmed response at the first visit). |
| Overall Survival | Patients were followed for overall survival until death or until the last patient in the study had documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy (maximum of 39.2 months). | Overall survival was defined as the time in months from initiation of therapy to death due to any cause. Patients still alive at the end of the study, or lost to follow up, were censored at last day known alive. |
| Time to Clinical Benefit | Patients were assessed for response after each cycle. After discontinuation of therapy, patients continued to be assessed until documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy (max duration 127.1 weeks). | Time to clinical benefit was defined as the time from first dose of therapy to first documented confirmed response of minimal response (MR) or better. |
| Overall Response Rate | Patients were assessed for response after each cycle. After discontinuation of therapy, patients continued to be assessed until disease progression (confirmed on 2 consecutive assessments) (maximum duration 127.1 weeks). | Overall response rate (ORR) is the percentage of patients who achieved a confirmed response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) as best response, as assessed by the Investigator. |
| Clinical Benefit Rate | Patients were assessed for response after each cycle (maximum duration 127.1 weeks). | Clinical benefit rate (CBR) is the proportion of patients who achieved a confirmed minimal response (MR) or better (stringent complete response \[sCR\], complete response \[CR\], very good partial response \[VGPR\], partial response \[PR\], and MR) as their best response, as assessed by the Investigator. |
| Progression-free Survival | Patients were assessed from the initiation of therapy until documented disease progression or initiation of new therapy (maximum duration 127.1 weeks). | Progression-free survival (PFS) was defined as the time from the date of first study drug (the earliest of melflufen and dexamethasone start date) initiation to the date of first documentation of confirmed PD or death due to any cause, whichever occurred first. Participants were deemed 'progressed' in case of i) unconfirmed progressive disease (PD) as the final response assessment, ii) death after at least one response assessment or PD based on at least two consecutive response assessments at any time, or iii) death before the first response assessment. The distribution of PFS was summarized using the Kaplan-Meier (K-M) method. The median PFS was estimated from the 50th percentile of the corresponding K-M estimates. The 95% confidence interval for median PFS was constructed using the method of Brookmeyer (Brookmeyer, 1982). |
| Duration of Response | Patients were assessed for response from the first measure of a confirmed response (PR or better) until confirmed progression, death, or initiation of subsequent therapy (maximum duration 127.1 weeks). | Duration of response (DOR) is defined as the time from the first evidence of confirmed assessment of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) to first confirmed disease progression, or to death due to any cause. The distribution of DOR was summarized using the Kaplan-Meier (K-M) method. The median DOR was estimated from the 50th percentile of the corresponding K-M estimates. The 95% confidence interval for median DOR was constructed using the method of Brookmeyer (Brookmeyer, 1982). |
Countries
Czechia, Greece, Poland
Participant flow
Recruitment details
The first patient (in Cohort 1a) received their first dose of study drug on 17 September 2018. The last patient (in Cohort 2a) received their first dose of study drug on 29 June 2021.
Pre-assignment details
All enrolled patients received study treatment and were included in the Safety Analysis Set.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1a, Melflufen 40 mg Patients with moderate renal impairment (eGFR ≥30 to \<45 mL/min/1.73m²) and a starting dose of melflufen of 40 mg. | 21 |
| Cohort 1b, Melflufen 30 mg Patients with moderate renal impairment (eGFR ≥30 to \<45 mL/min/1.73m²) and a starting dose of melflufen of 30 mg. | 10 |
| Cohort 2a, Melflufen 20 mg Patients with severe renal impairment (eGFR ≥15 to \<30 mL/min/1.73m²) and a starting dose of melflufen of 20 mg. | 4 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 1 | 0 |
| Overall Study | Disease progression | 8 | 5 | 3 |
| Overall Study | Patient request to stop treatment | 1 | 2 | 0 |
| Overall Study | Physician Decision | 3 | 1 | 0 |
| Overall Study | Study terminated by sponsor | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Cohort 1a, Melflufen 40 mg | Cohort 2a, Melflufen 20 mg | Cohort 1b, Melflufen 30 mg |
|---|---|---|---|---|
| Age, Continuous | 70.0 years | 70.0 years | 62.5 years | 72.0 years |
| Age, Customized ≥65 to ≤75 years | 14 Participants | 9 Participants | 0 Participants | 5 Participants |
| Age, Customized <65 years | 10 Participants | 4 Participants | 3 Participants | 3 Participants |
| Age, Customized >75 years | 11 Participants | 8 Participants | 1 Participants | 2 Participants |
| Baseline Eastern Cooperative Oncology Group (ECOG) score score = 0 | 17 Participants | 11 Participants | 3 Participants | 3 Participants |
| Baseline Eastern Cooperative Oncology Group (ECOG) score score = 1 | 15 Participants | 8 Participants | 1 Participants | 6 Participants |
| Baseline Eastern Cooperative Oncology Group (ECOG) score score = 2 | 3 Participants | 2 Participants | 0 Participants | 1 Participants |
| Baseline estimated glomerular filtration rate (eGFR) ≥15 to <30 mL/min/1.73m² | 6 Participants | 0 Participants | 4 Participants | 2 Participants |
| Baseline estimated glomerular filtration rate (eGFR) ≥30 to <45 mL/min/1.73m² | 27 Participants | 19 Participants | 0 Participants | 8 Participants |
| Baseline estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73m² | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Baseline height | 168.0 cm | 165.0 cm | 172.5 cm | 169.0 cm |
| Baseline weight | 74.00 kg | 73.00 kg | 85.50 kg | 75.25 kg |
| Cytogenetics abnormalities by interphase fluorescence in situ hybridization (iFISH) at study entry High-risk abnormalities | 10 Participants | 5 Participants | 0 Participants | 5 Participants |
| Cytogenetics abnormalities by interphase fluorescence in situ hybridization (iFISH) at study entry Missing | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Cytogenetics abnormalities by interphase fluorescence in situ hybridization (iFISH) at study entry Standard-risk abnormalities | 23 Participants | 16 Participants | 3 Participants | 4 Participants |
| Cytogenetics abnormalities by interphase fluorescence in situ hybridization (iFISH) at study entry Unknown | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Disease status at study entry Relapsed | 18 Participants | 13 Participants | 2 Participants | 3 Participants |
| Disease status at study entry Relapsed-refractory | 17 Participants | 8 Participants | 2 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 21 Participants | 4 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Evidence of extramedullary disease at study entry No | 32 Participants | 20 Participants | 3 Participants | 9 Participants |
| Evidence of extramedullary disease at study entry Yes | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Evidence of lytic bone disease at study entry No | 6 Participants | 5 Participants | 0 Participants | 1 Participants |
| Evidence of lytic bone disease at study entry Yes | 29 Participants | 16 Participants | 4 Participants | 9 Participants |
| International Staging System (ISS) stage at study entry stage I | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| International Staging System (ISS) stage at study entry stage II | 14 Participants | 9 Participants | 1 Participants | 4 Participants |
| International Staging System (ISS) stage at study entry stage III | 18 Participants | 9 Participants | 3 Participants | 6 Participants |
| International Staging System (ISS) stage at study entry unknown | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Number of prior systemic therapy lines 2 prior lines of therapy | 13 Participants | 5 Participants | 2 Participants | 6 Participants |
| Number of prior systemic therapy lines 3 prior lines of therapy | 10 Participants | 7 Participants | 1 Participants | 2 Participants |
| Number of prior systemic therapy lines 4 prior lines of therapy | 12 Participants | 9 Participants | 1 Participants | 2 Participants |
| Prior autologous transplant | 11 Participants | 9 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 35 Participants | 21 Participants | 4 Participants | 10 Participants |
| Region of Enrollment Czechia | 9 participants | 4 participants | 1 participants | 4 participants |
| Region of Enrollment Greece | 16 participants | 9 participants | 3 participants | 4 participants |
| Region of Enrollment Poland | 10 participants | 8 participants | 0 participants | 2 participants |
| Sex: Female, Male Female | 16 Participants | 9 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 19 Participants | 12 Participants | 3 Participants | 4 Participants |
| Time since diagnosis | 4.78 years | 6.47 years | 5.13 years | 3.82 years |
| Time since most recent relapse/progression | 1.25 months | 1.12 months | 3.29 months | 1.49 months |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 16 / 21 | 3 / 10 | 1 / 4 |
| other Total, other adverse events | 20 / 21 | 10 / 10 | 3 / 4 |
| serious Total, serious adverse events | 9 / 21 | 5 / 10 | 0 / 4 |
Outcome results
Primary
Area Under the Curve (0-t) of Melphalan
Area under the concentration-time curve (AUC) from 0h to the last measurable concentration.
Time frame: Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion.
Population: Some patients were not evaluable for PK and were excluded from Cycle 1 and/or Cycle 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1a, Melflufen 40 mg | Area Under the Curve (0-t) of Melphalan | Cycle 1 | 78250.3462 minutes*ng/mL | Standard Deviation 21391.384 |
| Cohort 1a, Melflufen 40 mg | Area Under the Curve (0-t) of Melphalan | Cycle 2 | 74415.5556 minutes*ng/mL | Standard Deviation 21354.648 |
| Cohort 1b, Melflufen 30 mg | Area Under the Curve (0-t) of Melphalan | Cycle 1 | 70303.4400 minutes*ng/mL | Standard Deviation 16874.787 |
| Cohort 1b, Melflufen 30 mg | Area Under the Curve (0-t) of Melphalan | Cycle 2 | 67458.0000 minutes*ng/mL | Standard Deviation 19241.04 |
| Cohort 2a, Melflufen 20 mg | Area Under the Curve (0-t) of Melphalan | Cycle 1 | 27912.7125 minutes*ng/mL | Standard Deviation 10385.219 |
| Cohort 2a, Melflufen 20 mg | Area Under the Curve (0-t) of Melphalan | Cycle 2 | 32146.0000 minutes*ng/mL | Standard Deviation 5804.816 |
Primary
Area Under the Curve (Inf) of Melphalan
Area under the concentration-time curve (AUC) from 0 hours to infinity
Time frame: Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion.
Population: Some patients were not evaluable for PK and were excluded from Cycle 1 and/or Cycle 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1a, Melflufen 40 mg | Area Under the Curve (Inf) of Melphalan | Cycle 1 | 85123.3635 minutes*ng/mL | Standard Deviation 22765.646 |
| Cohort 1a, Melflufen 40 mg | Area Under the Curve (Inf) of Melphalan | Cycle 2 | 80365.5468 minutes*ng/mL | Standard Deviation 22334.049 |
| Cohort 1b, Melflufen 30 mg | Area Under the Curve (Inf) of Melphalan | Cycle 1 | 77173.0689 minutes*ng/mL | Standard Deviation 15347.431 |
| Cohort 1b, Melflufen 30 mg | Area Under the Curve (Inf) of Melphalan | Cycle 2 | 72830.2410 minutes*ng/mL | Standard Deviation 20632.358 |
| Cohort 2a, Melflufen 20 mg | Area Under the Curve (Inf) of Melphalan | Cycle 1 | 31712.9042 minutes*ng/mL | Standard Deviation 11597.404 |
| Cohort 2a, Melflufen 20 mg | Area Under the Curve (Inf) of Melphalan | Cycle 2 | 39685.8277 minutes*ng/mL | Standard Deviation 6405.267 |
Primary
Cmax of Melphalan
Maximum observed concentration (Cmax)
Time frame: Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion.
Population: Some patients were not evaluable for pharmacokinetics (PK) and were excluded from Cycle 1 and/or Cycle 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1a, Melflufen 40 mg | Cmax of Melphalan | Cycle 1 | 550.1538 ng/mL | Standard Deviation 170.024 |
| Cohort 1a, Melflufen 40 mg | Cmax of Melphalan | Cycle 2 | 539.4444 ng/mL | Standard Deviation 178.246 |
| Cohort 1b, Melflufen 30 mg | Cmax of Melphalan | Cycle 1 | 472.2000 ng/mL | Standard Deviation 141.505 |
| Cohort 1b, Melflufen 30 mg | Cmax of Melphalan | Cycle 2 | 469.5000 ng/mL | Standard Deviation 177.34 |
| Cohort 2a, Melflufen 20 mg | Cmax of Melphalan | Cycle 1 | 181.2500 ng/mL | Standard Deviation 76.098 |
| Cohort 2a, Melflufen 20 mg | Cmax of Melphalan | Cycle 2 | 194.0000 ng/mL | Standard Deviation 57.663 |
Primary
T1/2 of Melphalan
Elimination half-life of melphalan
Time frame: Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion.
Population: Some patients were not evaluable for PK and were excluded from Cycle 1 and/or Cycle 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1a, Melflufen 40 mg | T1/2 of Melphalan | Cycle 1 | 89.1390 minutes | Standard Deviation 15.575 |
| Cohort 1a, Melflufen 40 mg | T1/2 of Melphalan | Cycle 2 | 87.5544 minutes | Standard Deviation 15.86 |
| Cohort 1b, Melflufen 30 mg | T1/2 of Melphalan | Cycle 1 | 98.3568 minutes | Standard Deviation 27.249 |
| Cohort 1b, Melflufen 30 mg | T1/2 of Melphalan | Cycle 2 | 90.7844 minutes | Standard Deviation 14.411 |
| Cohort 2a, Melflufen 20 mg | T1/2 of Melphalan | Cycle 1 | 109.5502 minutes | Standard Deviation 22.221 |
| Cohort 2a, Melflufen 20 mg | T1/2 of Melphalan | Cycle 2 | 136.2193 minutes | Standard Deviation 13.679 |
Primary
Tmax of Melphalan
Time of maximum observed concentration (Tmax)
Time frame: Samples were drawn 5-10 minutes after the end of infusion, 2-3 hours after the end of infusion, and 5-7 hours after the end of infusion.
Population: Some patients were not evaluable for PK and were excluded from Cycle 1 and/or Cycle 2.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1a, Melflufen 40 mg | Tmax of Melphalan | Cycle 1 | 38.0000 minutes |
| Cohort 1a, Melflufen 40 mg | Tmax of Melphalan | Cycle 2 | 37.0000 minutes |
| Cohort 1b, Melflufen 30 mg | Tmax of Melphalan | Cycle 2 | 40.0000 minutes |
| Cohort 1b, Melflufen 30 mg | Tmax of Melphalan | Cycle 1 | 40.0000 minutes |
| Cohort 2a, Melflufen 20 mg | Tmax of Melphalan | Cycle 2 | 36.0000 minutes |
| Cohort 2a, Melflufen 20 mg | Tmax of Melphalan | Cycle 1 | 37.0000 minutes |
Secondary
Best Confirmed Response
Best confirmed response required 2 consecutive assessments with the same response result made at any time. In case at the second consecutive assessment (made at any time) the response is higher than the previous one, then confirmed response (linked to the first assessment visit) will be the first one (e.g., PR - VGPR consecutive pair will lead to a PR confirmed response at the first visit). In case the second consecutive response is lower than the first one, then confirmed response (linked to the first assessment visit) will be the second one (e.g. CR-VGPR consecutive pair will lead to a VGPR confirmed response at the first visit).
Time frame: Patients were assessed for response after each cycle. After discontinuation of therapy, patients continued to be assessed until documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy (max duration 127.1 weeks).
Population: This analysis was performed in the Safety Analysis Set, which is defined as all patients who received at least 1 or partial dose of melflufen or dexamethasone.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1a, Melflufen 40 mg | Best Confirmed Response | Stringent complete response (sCR) | 0 Participants |
| Cohort 1a, Melflufen 40 mg | Best Confirmed Response | Complete response (CR) | 0 Participants |
| Cohort 1a, Melflufen 40 mg | Best Confirmed Response | Very good partial response (VGPR) | 3 Participants |
| Cohort 1a, Melflufen 40 mg | Best Confirmed Response | Partial response (PR) | 7 Participants |
| Cohort 1a, Melflufen 40 mg | Best Confirmed Response | Minimal response (MR) | 1 Participants |
| Cohort 1a, Melflufen 40 mg | Best Confirmed Response | Stable disease (SD) | 5 Participants |
| Cohort 1a, Melflufen 40 mg | Best Confirmed Response | Progressive disease (PD) | 2 Participants |
| Cohort 1a, Melflufen 40 mg | Best Confirmed Response | Non-evaluable | 3 Participants |
| Cohort 1b, Melflufen 30 mg | Best Confirmed Response | Very good partial response (VGPR) | 1 Participants |
| Cohort 1b, Melflufen 30 mg | Best Confirmed Response | Progressive disease (PD) | 0 Participants |
| Cohort 1b, Melflufen 30 mg | Best Confirmed Response | Partial response (PR) | 4 Participants |
| Cohort 1b, Melflufen 30 mg | Best Confirmed Response | Minimal response (MR) | 1 Participants |
| Cohort 1b, Melflufen 30 mg | Best Confirmed Response | Stable disease (SD) | 2 Participants |
| Cohort 1b, Melflufen 30 mg | Best Confirmed Response | Stringent complete response (sCR) | 0 Participants |
| Cohort 1b, Melflufen 30 mg | Best Confirmed Response | Complete response (CR) | 2 Participants |
| Cohort 1b, Melflufen 30 mg | Best Confirmed Response | Non-evaluable | 0 Participants |
| Cohort 2a, Melflufen 20 mg | Best Confirmed Response | Very good partial response (VGPR) | 0 Participants |
| Cohort 2a, Melflufen 20 mg | Best Confirmed Response | Complete response (CR) | 0 Participants |
| Cohort 2a, Melflufen 20 mg | Best Confirmed Response | Stringent complete response (sCR) | 0 Participants |
| Cohort 2a, Melflufen 20 mg | Best Confirmed Response | Partial response (PR) | 1 Participants |
| Cohort 2a, Melflufen 20 mg | Best Confirmed Response | Progressive disease (PD) | 3 Participants |
| Cohort 2a, Melflufen 20 mg | Best Confirmed Response | Stable disease (SD) | 0 Participants |
| Cohort 2a, Melflufen 20 mg | Best Confirmed Response | Minimal response (MR) | 0 Participants |
| Cohort 2a, Melflufen 20 mg | Best Confirmed Response | Non-evaluable | 0 Participants |
Secondary
Clinical Benefit Rate
Clinical benefit rate (CBR) is the proportion of patients who achieved a confirmed minimal response (MR) or better (stringent complete response \[sCR\], complete response \[CR\], very good partial response \[VGPR\], partial response \[PR\], and MR) as their best response, as assessed by the Investigator.
Time frame: Patients were assessed for response after each cycle (maximum duration 127.1 weeks).
Population: This analysis was performed in the Safety Analysis Set, which is defined as all patients who received at least 1 or partial dose of melflufen or dexamethasone.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1a, Melflufen 40 mg | Clinical Benefit Rate | 11 Participants |
| Cohort 1b, Melflufen 30 mg | Clinical Benefit Rate | 8 Participants |
| Cohort 2a, Melflufen 20 mg | Clinical Benefit Rate | 1 Participants |
Secondary
Duration of Clinical Benefit
Duration of clinical benefit (DOCB) was calculated as time in months from the first evidence of confirmed assessment of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response (MR) to first confirmed disease progression, or to death due to any cause. DOCB was defined only for patients with a confirmed MR or better. DOCB was summarized using the Kaplan-Meier (K-M) method. The median DOCB was estimated from the 50th percentile of the corresponding K-M estimates. The 95% confidence interval for median DOCB was constructed using the method of Brookmeyer (Brookmeyer, 1982).
Time frame: Patients were assessed from the first measure of a confirmed MR or better until confirmed progression, death, or initiation of subsequent therapy (maximum duration 127.1 weeks).
Population: This analysis included patients who achieved a best response of MR or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1a, Melflufen 40 mg | Duration of Clinical Benefit | 9.26 months |
| Cohort 1b, Melflufen 30 mg | Duration of Clinical Benefit | 10.58 months |
| Cohort 2a, Melflufen 20 mg | Duration of Clinical Benefit | NA months |
Secondary
Duration of Response
Duration of response (DOR) is defined as the time from the first evidence of confirmed assessment of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) to first confirmed disease progression, or to death due to any cause. The distribution of DOR was summarized using the Kaplan-Meier (K-M) method. The median DOR was estimated from the 50th percentile of the corresponding K-M estimates. The 95% confidence interval for median DOR was constructed using the method of Brookmeyer (Brookmeyer, 1982).
Time frame: Patients were assessed for response from the first measure of a confirmed response (PR or better) until confirmed progression, death, or initiation of subsequent therapy (maximum duration 127.1 weeks).
Population: This analysis included patients who achieved a best confirmed response of PR or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1a, Melflufen 40 mg | Duration of Response | 8.31 months |
| Cohort 1b, Melflufen 30 mg | Duration of Response | 13.83 months |
| Cohort 2a, Melflufen 20 mg | Duration of Response | NA months |
Secondary
Overall Response Rate
Overall response rate (ORR) is the percentage of patients who achieved a confirmed response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) as best response, as assessed by the Investigator.
Time frame: Patients were assessed for response after each cycle. After discontinuation of therapy, patients continued to be assessed until disease progression (confirmed on 2 consecutive assessments) (maximum duration 127.1 weeks).
Population: This analysis was performed in the Safety Analysis Set, which is defined as all patients who received at least 1 or partial dose of melflufen or dexamethasone.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1a, Melflufen 40 mg | Overall Response Rate | 10 Participants |
| Cohort 1b, Melflufen 30 mg | Overall Response Rate | 7 Participants |
| Cohort 2a, Melflufen 20 mg | Overall Response Rate | 1 Participants |
Secondary
Overall Survival
Overall survival was defined as the time in months from initiation of therapy to death due to any cause. Patients still alive at the end of the study, or lost to follow up, were censored at last day known alive.
Time frame: Patients were followed for overall survival until death or until the last patient in the study had documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy (maximum of 39.2 months).
Population: This analysis was performed in the Safety Analysis Set, which is defined as all patients who received at least 1 or partial dose of melflufen or dexamethasone.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1a, Melflufen 40 mg | Overall Survival | 9.76 months |
| Cohort 1b, Melflufen 30 mg | Overall Survival | NA months |
| Cohort 2a, Melflufen 20 mg | Overall Survival | NA months |
Secondary
Progression-free Survival
Progression-free survival (PFS) was defined as the time from the date of first study drug (the earliest of melflufen and dexamethasone start date) initiation to the date of first documentation of confirmed PD or death due to any cause, whichever occurred first. Participants were deemed 'progressed' in case of i) unconfirmed progressive disease (PD) as the final response assessment, ii) death after at least one response assessment or PD based on at least two consecutive response assessments at any time, or iii) death before the first response assessment. The distribution of PFS was summarized using the Kaplan-Meier (K-M) method. The median PFS was estimated from the 50th percentile of the corresponding K-M estimates. The 95% confidence interval for median PFS was constructed using the method of Brookmeyer (Brookmeyer, 1982).
Time frame: Patients were assessed from the initiation of therapy until documented disease progression or initiation of new therapy (maximum duration 127.1 weeks).
Population: This analysis was performed in the Safety Analysis Set, which is defined as all patients who received at least 1 or partial dose of melflufen or dexamethasone.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1a, Melflufen 40 mg | Progression-free Survival | 8.61 months |
| Cohort 1b, Melflufen 30 mg | Progression-free Survival | 7.66 months |
| Cohort 2a, Melflufen 20 mg | Progression-free Survival | 3.43 months |
Secondary
Time to Clinical Benefit
Time to clinical benefit was defined as the time from first dose of therapy to first documented confirmed response of minimal response (MR) or better.
Time frame: Patients were assessed for response after each cycle. After discontinuation of therapy, patients continued to be assessed until documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy (max duration 127.1 weeks).
Population: This analysis included patients who achieved a best response of MR or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1a, Melflufen 40 mg | Time to Clinical Benefit | 1.12 months |
| Cohort 1b, Melflufen 30 mg | Time to Clinical Benefit | 1.12 months |
| Cohort 2a, Melflufen 20 mg | Time to Clinical Benefit | 2.83 months |
Secondary
Time to Response
Time from first dose of therapy to first documented confirmed response of partial response (PR) or better.
Time frame: From initiation of therapy until documented disease response (maximum duration 127.1 weeks).
Population: This analysis included patients who achieved a best confirmed response of PR or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1a, Melflufen 40 mg | Time to Response | 2.45 months |
| Cohort 1b, Melflufen 30 mg | Time to Response | 1.18 months |
| Cohort 2a, Melflufen 20 mg | Time to Response | 2.83 months |