Relapsed and/or Relapsed-refractory Multiple Myeloma
Conditions
Brief summary
The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.
Interventions
DRUGMelflufen
DRUGDexamethasone
Sponsors
Oncopeptides AB
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
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. Patient has a diagnosis of multiple myeloma with documented relapsed and/or relapsed-refractory disease 3. Patient has measurable disease defined as any of the following: 1. Serum monoclonal protein ≥ 0.5 g/dL by protein electrophoresis 2. ≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis 3. Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio 4. If no monoclonal protein is detected, then ≥ 30% monoclonal bone marrow plasma cells 4. Patient has had at least 2 or more prior lines of therapy including lenalidomide and bortezomib and has demonstrated disease progression on or within 60 days of completion of the last therapy 5. Life expectancy of ≥6 months 6. Patient has an ECOG performance status ≤ 2 (Patients with lower performance status based solely on bone pain secondary to multiple myeloma will be eligible) 7. Females of childbearing potential must have a negative serum or urine pregnancy test prior to patient registration 8. Female patients of child bearing potential and non-vasectomized male patients agree to practice appropriate methods of birth control 9. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information 10. The patient has, or accepts to have, an acceptable infusion device for infusion of melflufen 11. 12 lead ECG with QtcF interval ≤ 470 msec 12. The following laboratory results must be met within 21 days of patient registration: * Absolute neutrophil count ≥ 1,000 cells/dL (1.0 x 109/L) * Platelet count ≥ 75,000 cells/dL (75 x 109/L) * Hemoglobin ≥ 8.0 g/dL * Total Bilirubin ≤ 1.5 x upper limit of normal * Renal function: Estimated creatinine clearance ≥ 45 ml/min or serum creatinine ≤ 2.5 mg/dL * AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN
Exclusion criteria
1. Patient has evidence of mucosal or internal bleeding and/or is platelet transfusion refractory 2. Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participation in this study 3. Known active infection requiring parenteral or oral anti-infective treatment 4. Other malignancy within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix 5. Other ongoing anti-myeloma therapy. Patients may be receiving concomitant therapy with bisphosphonates and low dose corticosteroids for symptom management and comorbid conditions. Doses of corticosteroid should be stable for at least 7 days prior to patient registration. 6. Pregnant or breast-feeding females 7. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow-up evaluation 8. Known HIV or hepatitis B or C viral infection 9. Patient has concurrent symptomatic amyloidosis or plasma cell leukemia 10. POEMS syndrome 11. Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to start of study treatment. Biologic, novel therapy (including investigational agents in this class) or corticosteroids within 2 weeks prior to patient registration. Patient has side effects of the previous therapy \> grade 1 or previous baseline. 12. Prior peripheral stem cell transplant within 12 weeks of patient registration 13. Radiotherapy within 21 days prior to Cycle 1 Day 1. However, if the radiation portal covered ≤ 5% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy 14. Known intolerance to steroid therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Who Achieved Best Overall Disease Response | Baseline (Cycle 1 Day 1) and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | The best overall disease response on treatment including 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) were evaluated. Starting on completion of Cycle 2, response was assessed according to International Myeloma Working Group (IMWG) criteria based on Investigator's assessment for all patients at every cycle during treatment period. PD was defined as increase of ≥25% from lowest response value in any 1 of the following: serum M-component (absolute increase must be ≥0.5 gram/deciliter) and/or urine M-component (absolute increase must be ≥200 mg/24 hr); development of new bone lesions or soft tissue plasmacytomas or increase in size of existing bone lesions or soft tissue plasmacytomas or development of hypercalcemia that could be attributed solely to plasma cell proliferative disorder. SD was defined as not meeting criteria for CR, VGPR, PR or PD. |
| Overall Response Rate (ORR) | Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | ORR was defined as percentage of patients with an overall response (OR), defined as first occurrence of confirmed disease response including PR or better (i.e, PR, VGPR, CR or sCR). Starting on completion of Cycle 2, response was assessed according to IMWG criteria based on Investigator's assessment for all patients at every cycle during treatment period. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum plus urine M-protein level \<100 mg/24hr and \>90% decrease in difference between involved and uninvolved free light chain (FLC) levels (only in FLC diseased patients). CR was defined as negative immunofixation on serum and urine, loss of any soft tissue plasmacytomas, \<5% plasma cells in bone marrow and normal FLC ratio of 0.26 to 1.65 (only in FLC diseased patients). sCR was defined as CR plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or 2 to 4 color flow cytometry. |
| Clinical Benefit Response Rate (CBRR) | Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | The CBRR was defined as the percentage of patients with a clinical benefit response (CBR), defined as the first occurrence of confirmed disease response including MR or better (i.e, MR, PR, VGPR, CR, or sCR). Starting on completion of Cycle 2, response was assessed according to the IMWG criteria based on the Investigator's assessment for all patients at every cycle during the treatment period. MR was defined as ≥25% but \<49% reduction of serum M-protein and reduction in 24 hour urine M-protein by 50 to 89%, which still exceeds 200 mg/24 hours. In addition to above; if present at baseline, 25 to 49% reduction in the size of soft tissue plasmacytomas is also required. No increase in size or number of lytic bone lesions (development of compression fractures does not exclude response). PR was defined as 50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by ≥90% or to \<200 mg/24 hour. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-Free Survival (PFS) | Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | The PFS was defined as the time from the date of the first dose of melflufen (overall reference start date) to the date of the first occurrence of any disease response assessment available for PD or death. The PFS was estimated using Kaplan-Meier statistics. |
| Median Overall Survival (OS) | From baseline until death. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | The OS was defined as the time from the date of the first dose of melflufen (overall reference start date) to death. The OS was estimated using Kaplan-Meier statistics. |
| Duration of Disease Response (DOR) | Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | The DOR to treatment was defined as time from first response (PR or better) to disease progression or death, or date of last evaluable disease response assessment for those who had not progressed or died. DOR was estimated using Kaplan-Meier statistics. |
| Number of Patients With Treatment Emergent Adverse Events (TEAEs) | From the first dose of study drug up to and including the actual EOT date of 29 October 2019; up to a maximum of approximately 76 months. | An adverse event (AE) was any untoward medical occurrence in a study patient administered an investigational product and that does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was defined as any AE, occurring at any dose, that met any one or more of the following criteria: is fatal or immediately life-threatening; results in persistent or significant disability/incapacity; constitutes a congenital anomaly/birth defect; is medically significant; requires inpatient hospitalization or prolongation of existing hospitalization; or other important medical event. TEAEs were defined as AEs that started or worsened on or after the first dose of study drug (overall reference start date) up to and including the actual EOT date. TESAEs = Treatment emergent serious adverse events. |
| Time to First Subsequent Treatment | From baseline until start of first subsequent treatment. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | Time to first subsequent treatment start was defined as the time from the date of the actual end of treatment to the date of the first subsequent treatment. Time to first subsequent treatment was estimated using Kaplan-Meier statistics. |
| Time to Disease Response in Patients Who Achieved OR and CBR | Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | Time to first OR was defined as the time from the date of the first dose of study drug (overall reference start date) to the date of the first occurrence of PR or better (first of 2 consecutive assessments-confirmed response). Time to first CBR was defined as the time from the date of the first dose of study drug (overall reference start date) to the date of the first occurrence of MR or better (first of 2 consecutive assessments-confirmed response). Time to disease response was estimated using Kaplan-Meier statistics. |
| Time to Disease Progression | Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months. | Time to disease progression was defined as the time from the date of the first dose of study drug (overall reference start date) to the date of the first occurrence of evaluable PD. Time to disease progression was estimated using Kaplan-Meier statistics. |
Countries
Denmark, Italy, Netherlands, Sweden, United States
Participant flow
Recruitment details
This was an open-label, Phase I/IIa study conducted at 7 study centers in 5 countries in patients with relapsed and/or relapsed-refractory Multiple Myeloma (MM). Overall, 75 patients (23 during Phase I and 52 additional patients during Phase II) were enrolled. The study results are presented until the end of trial (EOT) date of 29 October 2019.
Pre-assignment details
The study was conducted in 2 parts: Phase I (dose escalation) and Phase II (maximum tolerated dose \[MTD\]). During Phase I, the standard 3 + 3 design was followed with 3 to 6 patients tested at each dose level, depending on the dose limiting toxicity (DLT) observed. During Phase II, patients were treated at the MTD determined in Phase I.
Participants by arm
| Arm | Count |
|---|---|
| Phase I: Melflufen 15 mg + Dexamethasone Patients were treated with 15 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. | 4 |
| Phase I: Melflufen 25 mg + Dexamethasone Patients were treated with 25 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. | 7 |
| Phase I: Melflufen 40 mg + Dexamethasone Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. | 6 |
| Phase I: Melflufen 55 mg + Dexamethasone Patients were treated with 55 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. | 6 |
| Phase I + II: Melflufen 40 mg + Dexamethasone Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day or 28-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. In Protocol amendment 4, the cycle of melflufen was increased from 21 to 28 days. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each cycle. | 45 |
| Phase II: Melflufen 40 mg (Single Agent) Patients were treated with 40 mg melflufen as IV infusion on Day 1 of each 28-day treatment cycle. Dexamethasone was not administered as an antitumor compound. However, all patients were treated with 8 mg dexamethasone as an antiemetic on Days 1 and 2, and an optional 4 mg dexamethasone as an antiemetic on Days 3 and 4 of the same 28-day cycle, unless the Investigator decided to switch a patient to a combination regimen. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. | 13 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Phase I (Dose Escalation) | Adverse Event | 0 | 1 | 4 | 3 | 0 | 0 |
| Phase I (Dose Escalation) | Disease progression | 3 | 5 | 1 | 3 | 0 | 0 |
| Phase I (Dose Escalation) | Other | 0 | 1 | 0 | 0 | 0 | 0 |
| Phase II (MTD) | Death | 0 | 0 | 0 | 0 | 25 | 10 |
| Phase II (MTD) | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 |
| Phase II (MTD) | Other | 0 | 0 | 0 | 0 | 3 | 0 |
| Phase II (MTD) | Study terminated with patient alive | 0 | 0 | 0 | 0 | 1 | 0 |
| Phase II (MTD) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Phase I: Melflufen 15 mg + Dexamethasone | Phase I: Melflufen 25 mg + Dexamethasone | Phase I: Melflufen 40 mg + Dexamethasone | Phase I: Melflufen 55 mg + Dexamethasone | Total | Phase I + II: Melflufen 40 mg + Dexamethasone | Phase II: Melflufen 40 mg (Single Agent) |
|---|---|---|---|---|---|---|---|
| Age, Categorical Phase I <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | — | — |
| Age, Categorical Phase I >=65 years | 3 Participants | 4 Participants | 3 Participants | 4 Participants | 14 Participants | — | — |
| Age, Categorical Phase I Between 18 and 65 years | 1 Participants | 3 Participants | 3 Participants | 2 Participants | 9 Participants | — | — |
| Age, Categorical Phase II <=18 years | — | — | — | — | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Phase II >=65 years | — | — | — | — | 30 Participants | 25 Participants | 5 Participants |
| Age, Categorical Phase II Between 18 and 65 years | — | — | — | — | 28 Participants | 20 Participants | 8 Participants |
| Race/Ethnicity, Customized Phase I Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | — | — |
| Race/Ethnicity, Customized Phase I Caucasian | 3 Participants | 6 Participants | 6 Participants | 6 Participants | 21 Participants | — | — |
| Race/Ethnicity, Customized Phase I Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | — | — |
| Race/Ethnicity, Customized Phase I Not collected as per local laws | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | — | — |
| Race/Ethnicity, Customized Phase I Not Hispanic or Latino | 4 Participants | 6 Participants | 5 Participants | 5 Participants | 20 Participants | — | — |
| Race/Ethnicity, Customized Phase II Black or African American | — | — | — | — | 6 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Phase II Caucasian | — | — | — | — | 51 Participants | 41 Participants | 10 Participants |
| Race/Ethnicity, Customized Phase II Hispanic or Latino | — | — | — | — | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Phase II Not collected as per local laws | — | — | — | — | 8 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Phase II Not Hispanic or Latino | — | — | — | — | 49 Participants | 37 Participants | 12 Participants |
| Sex: Female, Male Phase I Female | 2 Participants | 4 Participants | 2 Participants | 3 Participants | 11 Participants | — | — |
| Sex: Female, Male Phase I Male | 2 Participants | 3 Participants | 4 Participants | 3 Participants | 12 Participants | — | — |
| Sex: Female, Male Phase II Female | — | — | — | — | 20 Participants | 15 Participants | 5 Participants |
| Sex: Female, Male Phase II Male | — | — | — | — | 38 Participants | 30 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 4 | 5 / 7 | 2 / 6 | 5 / 6 | 30 / 45 | 10 / 13 |
| other Total, other adverse events | 4 / 4 | 7 / 7 | 6 / 6 | 6 / 6 | 45 / 45 | 12 / 13 |
| serious Total, serious adverse events | 3 / 4 | 4 / 7 | 2 / 6 | 4 / 6 | 17 / 45 | 9 / 13 |
Outcome results
Primary
Clinical Benefit Response Rate (CBRR)
The CBRR was defined as the percentage of patients with a clinical benefit response (CBR), defined as the first occurrence of confirmed disease response including MR or better (i.e, MR, PR, VGPR, CR, or sCR). Starting on completion of Cycle 2, response was assessed according to the IMWG criteria based on the Investigator's assessment for all patients at every cycle during the treatment period. MR was defined as ≥25% but \<49% reduction of serum M-protein and reduction in 24 hour urine M-protein by 50 to 89%, which still exceeds 200 mg/24 hours. In addition to above; if present at baseline, 25 to 49% reduction in the size of soft tissue plasmacytomas is also required. No increase in size or number of lytic bone lesions (development of compression fractures does not exclude response). PR was defined as 50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by ≥90% or to \<200 mg/24 hour.
Time frame: Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
Population: For Phase I arms: The Safety Analysis Set included all patients who received at least 1 dose, or part thereof, of study drug.~For Phase II arms: The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Melflufen 15 mg + Dexamethasone | Clinical Benefit Response Rate (CBRR) | 0.0 percentage of patients |
| Phase I: Melflufen 25 mg + Dexamethasone | Clinical Benefit Response Rate (CBRR) | 0.0 percentage of patients |
| Phase I: Melflufen 40 mg + Dexamethasone | Clinical Benefit Response Rate (CBRR) | 66.7 percentage of patients |
| Phase I: Melflufen 55 mg + Dexamethasone | Clinical Benefit Response Rate (CBRR) | 16.7 percentage of patients |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Clinical Benefit Response Rate (CBRR) | 48.9 percentage of patients |
| Phase II: Melflufen 40 mg (Single Agent) | Clinical Benefit Response Rate (CBRR) | 23.1 percentage of patients |
Primary
Overall Response Rate (ORR)
ORR was defined as percentage of patients with an overall response (OR), defined as first occurrence of confirmed disease response including PR or better (i.e, PR, VGPR, CR or sCR). Starting on completion of Cycle 2, response was assessed according to IMWG criteria based on Investigator's assessment for all patients at every cycle during treatment period. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum plus urine M-protein level \<100 mg/24hr and \>90% decrease in difference between involved and uninvolved free light chain (FLC) levels (only in FLC diseased patients). CR was defined as negative immunofixation on serum and urine, loss of any soft tissue plasmacytomas, \<5% plasma cells in bone marrow and normal FLC ratio of 0.26 to 1.65 (only in FLC diseased patients). sCR was defined as CR plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or 2 to 4 color flow cytometry.
Time frame: Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
Population: For Phase I arms: The Safety Analysis Set included all patients who received at least 1 dose, or part thereof, of study drug.~For Phase II arms: The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Melflufen 15 mg + Dexamethasone | Overall Response Rate (ORR) | 0.0 percentage of patients |
| Phase I: Melflufen 25 mg + Dexamethasone | Overall Response Rate (ORR) | 0.0 percentage of patients |
| Phase I: Melflufen 40 mg + Dexamethasone | Overall Response Rate (ORR) | 66.7 percentage of patients |
| Phase I: Melflufen 55 mg + Dexamethasone | Overall Response Rate (ORR) | 16.7 percentage of patients |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Overall Response Rate (ORR) | 31.1 percentage of patients |
| Phase II: Melflufen 40 mg (Single Agent) | Overall Response Rate (ORR) | 7.7 percentage of patients |
Primary
Percentage of Patients Who Achieved Best Overall Disease Response
The best overall disease response on treatment including 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) were evaluated. Starting on completion of Cycle 2, response was assessed according to International Myeloma Working Group (IMWG) criteria based on Investigator's assessment for all patients at every cycle during treatment period. PD was defined as increase of ≥25% from lowest response value in any 1 of the following: serum M-component (absolute increase must be ≥0.5 gram/deciliter) and/or urine M-component (absolute increase must be ≥200 mg/24 hr); development of new bone lesions or soft tissue plasmacytomas or increase in size of existing bone lesions or soft tissue plasmacytomas or development of hypercalcemia that could be attributed solely to plasma cell proliferative disorder. SD was defined as not meeting criteria for CR, VGPR, PR or PD.
Time frame: Baseline (Cycle 1 Day 1) and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
Population: For Phase I arms: The Safety Analysis Set included all patients who received at least 1 dose, or part thereof, of study drug.~For Phase II arms: Modified Intent-to-Treat (mITT) Analysis Set included all patients considered to be valid for Safety Analysis Set and who received at least 1 dose of study drug at the MTD as initial dose.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I: Melflufen 15 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | PR | 0.0 percentage of patients |
| Phase I: Melflufen 15 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | VGPR | 0.0 percentage of patients |
| Phase I: Melflufen 15 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | sCR + CR + VGPR | 0.0 percentage of patients |
| Phase I: Melflufen 15 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | sCR + CR | 0.0 percentage of patients |
| Phase I: Melflufen 15 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | Missing | 0.0 percentage of patients |
| Phase I: Melflufen 15 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | PD | 25.0 percentage of patients |
| Phase I: Melflufen 15 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | CR | 0.0 percentage of patients |
| Phase I: Melflufen 15 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | sCR | 0.0 percentage of patients |
| Phase I: Melflufen 15 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | SD | 75.0 percentage of patients |
| Phase I: Melflufen 15 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | MR | 0.0 percentage of patients |
| Phase I: Melflufen 25 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | CR | 0.0 percentage of patients |
| Phase I: Melflufen 25 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | sCR | 0.0 percentage of patients |
| Phase I: Melflufen 25 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | VGPR | 0.0 percentage of patients |
| Phase I: Melflufen 25 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | PR | 0.0 percentage of patients |
| Phase I: Melflufen 25 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | MR | 0.0 percentage of patients |
| Phase I: Melflufen 25 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | SD | 42.9 percentage of patients |
| Phase I: Melflufen 25 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | PD | 57.1 percentage of patients |
| Phase I: Melflufen 25 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | Missing | 0.0 percentage of patients |
| Phase I: Melflufen 25 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | sCR + CR | 0.0 percentage of patients |
| Phase I: Melflufen 25 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | sCR + CR + VGPR | 0.0 percentage of patients |
| Phase I: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | PR | 50.0 percentage of patients |
| Phase I: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | Missing | 0.0 percentage of patients |
| Phase I: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | sCR | 0.0 percentage of patients |
| Phase I: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | MR | 0.0 percentage of patients |
| Phase I: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | VGPR | 16.7 percentage of patients |
| Phase I: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | CR | 0.0 percentage of patients |
| Phase I: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | SD | 16.7 percentage of patients |
| Phase I: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | sCR + CR | 0.0 percentage of patients |
| Phase I: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | sCR + CR + VGPR | 16.7 percentage of patients |
| Phase I: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | PD | 16.7 percentage of patients |
| Phase I: Melflufen 55 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | PD | 16.7 percentage of patients |
| Phase I: Melflufen 55 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | Missing | 0.0 percentage of patients |
| Phase I: Melflufen 55 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | CR | 0.0 percentage of patients |
| Phase I: Melflufen 55 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | sCR + CR + VGPR | 16.7 percentage of patients |
| Phase I: Melflufen 55 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | sCR + CR | 0.0 percentage of patients |
| Phase I: Melflufen 55 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | sCR | 0.0 percentage of patients |
| Phase I: Melflufen 55 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | SD | 66.7 percentage of patients |
| Phase I: Melflufen 55 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | MR | 0.0 percentage of patients |
| Phase I: Melflufen 55 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | PR | 0.0 percentage of patients |
| Phase I: Melflufen 55 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | VGPR | 16.7 percentage of patients |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | PD | 15.6 percentage of patients |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | PR | 20.0 percentage of patients |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | MR | 17.8 percentage of patients |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | SD | 26.7 percentage of patients |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | sCR | 0.0 percentage of patients |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | Missing | 8.9 percentage of patients |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | sCR + CR + VGPR | 11.1 percentage of patients |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | sCR + CR | 0.0 percentage of patients |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | VGPR | 11.1 percentage of patients |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Percentage of Patients Who Achieved Best Overall Disease Response | CR | 0.0 percentage of patients |
| Phase II: Melflufen 40 mg (Single Agent) | Percentage of Patients Who Achieved Best Overall Disease Response | SD | 69.2 percentage of patients |
| Phase II: Melflufen 40 mg (Single Agent) | Percentage of Patients Who Achieved Best Overall Disease Response | sCR + CR + VGPR | 0.0 percentage of patients |
| Phase II: Melflufen 40 mg (Single Agent) | Percentage of Patients Who Achieved Best Overall Disease Response | CR | 0.0 percentage of patients |
| Phase II: Melflufen 40 mg (Single Agent) | Percentage of Patients Who Achieved Best Overall Disease Response | VGPR | 0.0 percentage of patients |
| Phase II: Melflufen 40 mg (Single Agent) | Percentage of Patients Who Achieved Best Overall Disease Response | MR | 15.4 percentage of patients |
| Phase II: Melflufen 40 mg (Single Agent) | Percentage of Patients Who Achieved Best Overall Disease Response | PD | 7.7 percentage of patients |
| Phase II: Melflufen 40 mg (Single Agent) | Percentage of Patients Who Achieved Best Overall Disease Response | PR | 7.7 percentage of patients |
| Phase II: Melflufen 40 mg (Single Agent) | Percentage of Patients Who Achieved Best Overall Disease Response | Missing | 0.0 percentage of patients |
| Phase II: Melflufen 40 mg (Single Agent) | Percentage of Patients Who Achieved Best Overall Disease Response | sCR | 0.0 percentage of patients |
| Phase II: Melflufen 40 mg (Single Agent) | Percentage of Patients Who Achieved Best Overall Disease Response | sCR + CR | 0.0 percentage of patients |
Secondary
Duration of Disease Response (DOR)
The DOR to treatment was defined as time from first response (PR or better) to disease progression or death, or date of last evaluable disease response assessment for those who had not progressed or died. DOR was estimated using Kaplan-Meier statistics.
Time frame: Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
Population: The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Only patients who had achieved at least PR were evaluated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: Melflufen 15 mg + Dexamethasone | Duration of Disease Response (DOR) | 8.4 months |
| Phase I: Melflufen 25 mg + Dexamethasone | Duration of Disease Response (DOR) | 7.2 months |
Secondary
Median Overall Survival (OS)
The OS was defined as the time from the date of the first dose of melflufen (overall reference start date) to death. The OS was estimated using Kaplan-Meier statistics.
Time frame: From baseline until death. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
Population: The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Only patients who had information about OS at the time of EOT(29 October 2019) were reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: Melflufen 15 mg + Dexamethasone | Median Overall Survival (OS) | 20.7 months |
| Phase I: Melflufen 25 mg + Dexamethasone | Median Overall Survival (OS) | 15.5 months |
Secondary
Median Progression-Free Survival (PFS)
The PFS was defined as the time from the date of the first dose of melflufen (overall reference start date) to the date of the first occurrence of any disease response assessment available for PD or death. The PFS was estimated using Kaplan-Meier statistics.
Time frame: Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
Population: The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Only patients who had information about PFS at the time of EOT (29 October 2019) were reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: Melflufen 15 mg + Dexamethasone | Median Progression-Free Survival (PFS) | 5.7 months |
| Phase I: Melflufen 25 mg + Dexamethasone | Median Progression-Free Survival (PFS) | 4.4 months |
Secondary
Number of Patients With Treatment Emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a study patient administered an investigational product and that does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was defined as any AE, occurring at any dose, that met any one or more of the following criteria: is fatal or immediately life-threatening; results in persistent or significant disability/incapacity; constitutes a congenital anomaly/birth defect; is medically significant; requires inpatient hospitalization or prolongation of existing hospitalization; or other important medical event. TEAEs were defined as AEs that started or worsened on or after the first dose of study drug (overall reference start date) up to and including the actual EOT date. TESAEs = Treatment emergent serious adverse events.
Time frame: From the first dose of study drug up to and including the actual EOT date of 29 October 2019; up to a maximum of approximately 76 months.
Population: The Safety Analysis Set included all patients who received at least 1 dose, or part thereof, of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I: Melflufen 15 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs related to melflufen and/or dexamethasone | 4 Participants |
| Phase I: Melflufen 15 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs (including both serious and non-serious AEs) | 4 Participants |
| Phase I: Melflufen 15 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TESAEs | 3 Participants |
| Phase I: Melflufen 15 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | DLT TEAEs | 0 Participants |
| Phase I: Melflufen 15 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TESAEs related to melflufen and/or dexamethasone | 3 Participants |
| Phase I: Melflufen 15 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| Phase I: Melflufen 25 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 1 Participants |
| Phase I: Melflufen 25 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs related to melflufen and/or dexamethasone | 7 Participants |
| Phase I: Melflufen 25 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs (including both serious and non-serious AEs) | 7 Participants |
| Phase I: Melflufen 25 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TESAEs | 4 Participants |
| Phase I: Melflufen 25 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TESAEs related to melflufen and/or dexamethasone | 4 Participants |
| Phase I: Melflufen 25 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | DLT TEAEs | 0 Participants |
| Phase I: Melflufen 40 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TESAEs related to melflufen and/or dexamethasone | 2 Participants |
| Phase I: Melflufen 40 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | DLT TEAEs | 0 Participants |
| Phase I: Melflufen 40 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| Phase I: Melflufen 40 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs related to melflufen and/or dexamethasone | 6 Participants |
| Phase I: Melflufen 40 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TESAEs | 2 Participants |
| Phase I: Melflufen 40 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs (including both serious and non-serious AEs) | 6 Participants |
| Phase I: Melflufen 55 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs (including both serious and non-serious AEs) | 6 Participants |
| Phase I: Melflufen 55 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| Phase I: Melflufen 55 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TESAEs | 4 Participants |
| Phase I: Melflufen 55 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | DLT TEAEs | 4 Participants |
| Phase I: Melflufen 55 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs related to melflufen and/or dexamethasone | 6 Participants |
| Phase I: Melflufen 55 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TESAEs related to melflufen and/or dexamethasone | 4 Participants |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TESAEs | 17 Participants |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs (including both serious and non-serious AEs) | 45 Participants |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 3 Participants |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TESAEs related to melflufen and/or dexamethasone | 17 Participants |
| Phase I + II: Melflufen 40 mg + Dexamethasone | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs related to melflufen and/or dexamethasone | 45 Participants |
| Phase II: Melflufen 40 mg (Single Agent) | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs related to melflufen and/or dexamethasone | 13 Participants |
| Phase II: Melflufen 40 mg (Single Agent) | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TESAEs | 9 Participants |
| Phase II: Melflufen 40 mg (Single Agent) | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TESAEs related to melflufen and/or dexamethasone | 9 Participants |
| Phase II: Melflufen 40 mg (Single Agent) | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| Phase II: Melflufen 40 mg (Single Agent) | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs (including both serious and non-serious AEs) | 13 Participants |
Secondary
Time to Disease Progression
Time to disease progression was defined as the time from the date of the first dose of study drug (overall reference start date) to the date of the first occurrence of evaluable PD. Time to disease progression was estimated using Kaplan-Meier statistics.
Time frame: Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
Population: The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: Melflufen 15 mg + Dexamethasone | Time to Disease Progression | 6.5 months |
| Phase I: Melflufen 25 mg + Dexamethasone | Time to Disease Progression | 4.4 months |
Secondary
Time to Disease Response in Patients Who Achieved OR and CBR
Time to first OR was defined as the time from the date of the first dose of study drug (overall reference start date) to the date of the first occurrence of PR or better (first of 2 consecutive assessments-confirmed response). Time to first CBR was defined as the time from the date of the first dose of study drug (overall reference start date) to the date of the first occurrence of MR or better (first of 2 consecutive assessments-confirmed response). Time to disease response was estimated using Kaplan-Meier statistics.
Time frame: Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
Population: The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Only patients who had achieved OR and CBR were evaluated, for each respective time to response parameter.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase I: Melflufen 15 mg + Dexamethasone | Time to Disease Response in Patients Who Achieved OR and CBR | OR | 2.8 months |
| Phase I: Melflufen 15 mg + Dexamethasone | Time to Disease Response in Patients Who Achieved OR and CBR | CBR | 2.4 months |
| Phase I: Melflufen 25 mg + Dexamethasone | Time to Disease Response in Patients Who Achieved OR and CBR | OR | 6.7 months |
| Phase I: Melflufen 25 mg + Dexamethasone | Time to Disease Response in Patients Who Achieved OR and CBR | CBR | 2.8 months |
Secondary
Time to First Subsequent Treatment
Time to first subsequent treatment start was defined as the time from the date of the actual end of treatment to the date of the first subsequent treatment. Time to first subsequent treatment was estimated using Kaplan-Meier statistics.
Time frame: From baseline until start of first subsequent treatment. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
Population: The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Only patients who had information about first subsequent treatment at the time of EOT (29 October 2019) were reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: Melflufen 15 mg + Dexamethasone | Time to First Subsequent Treatment | 10.5 months |
| Phase I: Melflufen 25 mg + Dexamethasone | Time to First Subsequent Treatment | 10.7 months |