A Study of Melphalan Flufenamide (Melflufen)-Dex or Pomalidomide-dex for RRMM Patients Refractory to Lenalidomide
- Conditions
- Multiple Myeloma
- Interventions
- Registration Number
- NCT03151811
- Lead Sponsor
- Oncopeptides AB
- Brief Summary
This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with RRMM following 2-4 lines of prior therapy and who were refractory to lenalidomide in the last line of therapy as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide. Patients received either melflufen+dex or pomalidomide+dex.
- Detailed Description
This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with RRMM following 2-4 lines of prior therapy and who were refractory to lenalidomide in the last line of therapy as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide.
Patients were randomized to either one of two arms:
Arm A: Melphalan flufenamide (Melflufen) 40 mg on Day 1 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle.
Arm B: Pomalidomide 4 mg daily on Days 1 to 21 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle.
Patients ≥ 75 years of age received a reduced dose of dexamethasone of 20 mg on Days 1, 8, 15 and 22 for both Arm A and Arm B.
Patients were to receive treatment until such time as there was documented disease progression, unacceptable toxicity, or the patient/treating physician determined it was not in the patient's best interest to continue.
Dose modifications and delays in therapy may have been implemented based on patient tolerability as detailed in the protocol. In the event of a cycle delay, unrelated to dexamethasone toxicity, it was recommended to continue dexamethasone weekly.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 495
-
Male or female, age 18 years or older
-
A prior diagnosis of multiple myeloma with documented disease progression requiring further treatment at time of screening
-
Measurable disease defined as any of the following:
- Serum monoclonal protein ≥ 0.5 g/dL by protein electrophoresis.
- ≥ 200 mg/24 hours of monoclonal protein in the urine on 24-hour electrophoresis
- Serum free light chain ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain ratio
-
Received 2-4 prior lines of therapy, including lenalidomide and a PI, either sequential or in the same line, and is refractory (relapsed and refractory or refractory) to both the last line of therapy and to lenalidomide (≥ 10 mg) administered within 18 months prior to randomization. Refractory to lenalidomide is defined as progression while on lenalidomide therapy or within 60 days of last dose, following at least 2 cycles of lenalidomide with at least 14 doses of lenalidomide per cycle.
-
Life expectancy of ≥ 6 months
-
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
-
Females of child bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to start of treatment. Participants must agree to ongoing pregnancy testing. All patients must be willing to comply with all requirements of the USA pomalidomide Risk Evaluation and Mitigation Strategy (REMS) program or the pomalidomide Pregnancy Prevention Plan (PPP).
-
Ability to understand the purpose and risks of the study and provide signed and dated informed consent.
-
12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec Fridericia Formula.
-
The following laboratory results must be met during screening and also immediately before study drug administration on Cycle 1 Day 1:
- Absolute neutrophil count (ANC) ≥ 1,000 cells/mm^3 (1.0 x 10^9/L)
- Platelet count ≥ 75,000 cells/mm^3 (75 x 10^9/L)
- Hemoglobin ≥ 8.0 g/dl
- Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), or patients diagnosed with Gilberts syndrome, that have been reviewed and approved by the medical monitor.
- Aspartate transaminase (AST /SGOT) and alanine transaminase (ALT/SGPT) ≤ 3.0 x ULN.
- Renal function: Estimated creatinine clearance by Cockcroft-Gault formula ≥ 45 mL/min.
-
Must be able to take antithrombotic prophylaxis.
-
Must have, or be willing to have an acceptable central catheter. (Port a cath, peripherally inserted central catheter [PICC-line], or central venous catheter) (Insertion only required if randomized to Arm A).
-
Primary refractory disease (i.e. never responded (≥ MR) to any prior therapy)
-
Evidence of mucosal or internal bleeding or platelet transfusion refractory
-
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.
-
Prior exposure to pomalidomide
-
Known intolerance to IMiDs.
-
Known active infection requiring parenteral or oral anti-infective treatment within 14 days of randomization.
-
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.
-
Pregnant or breast-feeding females
-
Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation
-
Known human immunodeficiency virus or active hepatitis C viral infection
-
Active hepatitis B viral infection (defined as HBsAg+).
- Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-HBs+, Anti-HBc-).
- Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) may be enrolled at the discretion of the investigator after consideration of risk of reactivation.
-
Concurrent symptomatic amyloidosis or plasma cell leukemia
-
POEMS syndrome
-
Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to randomization. IMiDs, PIs and or corticosteroids within 2 weeks prior to randomization. Other investigational therapies and monoclonal antibodies within 4 weeks of randomization. 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 randomization
-
Residual side effects to previous therapy > grade 1 prior to randomization (Alopecia any grade and/or neuropathy grade 2 without pain are permitted)
-
Prior peripheral stem cell transplant within 12 weeks of randomization
-
Prior allogeneic stem cell transplantation with active graft-versus-host-disease.
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Prior major surgical procedure or radiation therapy within 4 weeks of the randomization
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Known intolerance to steroid therapy
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm B: Pomalidomide+Dexamethasone Pomalidomide Pomalidomide 4 mg orally daily on Days 1 to 21 and dexamethasone 40 mg (20 mg for patients ≥ 75 years of age) on Days 1, 8, 15 and 22 of each 28-day cycle. Patients were to be treated until confirmed progression, unacceptable toxicity, or the patient or investigator decided it was not in the patient's best interest to continue. Arm A: Melflufen+Dexamethasone Dexamethasone Melflufen 40 mg i.v. on Day 1 and dexamethasone 40 mg (20 mg for patients ≥ 75 years of age) on Days 1, 8, 15 and 22 of each 28-day cycle. Patients were to be treated until confirmed progression, unacceptable toxicity, or the patient or investigator decided it was not in the patient's best interest to continue. Arm A: Melflufen+Dexamethasone Melflufen Melflufen 40 mg i.v. on Day 1 and dexamethasone 40 mg (20 mg for patients ≥ 75 years of age) on Days 1, 8, 15 and 22 of each 28-day cycle. Patients were to be treated until confirmed progression, unacceptable toxicity, or the patient or investigator decided it was not in the patient's best interest to continue. Arm B: Pomalidomide+Dexamethasone Dexamethasone Pomalidomide 4 mg orally daily on Days 1 to 21 and dexamethasone 40 mg (20 mg for patients ≥ 75 years of age) on Days 1, 8, 15 and 22 of each 28-day cycle. Patients were to be treated until confirmed progression, unacceptable toxicity, or the patient or investigator decided it was not in the patient's best interest to continue.
- Primary Outcome Measures
Name Time Method Progression Free Survival (PFS) From date of randomization until first evidence of confirmed disease progression or death due to any cause (whichever occurred first), up to the data cutoff date of 03 Feb 2021 (ie, assessed up to approximately 43 months). Progression Free Survival defined as the duration in months from randomization until first evidence of confirmed disease progression, as assessed by the Independent Review Committee (IRC) according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). Disease progression was defined according to the IMWG-URC as progressive disease or death due to any cause, whichever occurs first.
- Secondary Outcome Measures
Name Time Method Duration of Response (DOR) From first documentation of a confirmed response to first evidence of confirmed disease progression or death due to any cause, up to the data cutoff date of 03 Feb 2021 (ie, assessed up to approximately 43 months). DOR defined as the duration in months from first documentation of a confirmed response to first evidence of confirmed disease progression or death due to any cause.
Overall Response Rate (ORR) From randomization until best response achieved before confirmed disease progression or death due to any cause, up to data cutoff of 03 Feb 2021 (ie, assessed up to approx. 43 months). Median time to best response: Arm A=2.1 months and Arm B=2.0 months ORR defined as the proportion of patients for whom the best overall confirmed response is stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR), as assessed by IRC.
Overall Survival (OS) From date of randomization until up to 24 months following confirmed disease progression or initiation of subsequent therapy, up to the data cutoff date of 03 Feb 2023 (ie, assessed up to approximately 67 months). OS defined as the time in months from randomization to date of death due to any cause. Patients who were still alive at end of study, or lost to follow up, were censored at the last day the patient was known to be alive.
Safety and Tolerability: Number of Patients With Treatment-emergent Adverse Events (TEAEs), Including Clinical Laboratory and Vital Signs Abnormalities, as Assessed by CTCAE v4.0 From start of dosing until 30 days after the last dose of study treatment, up to the data cutoff date of 03 Feb 2023 (ie, assessed up to approximately 67 months). Median duration of study treatment was 25.2 and 22.1 weeks for Arm A and B, respectively. Number of patients with TEAEs, including clinical laboratory and vital signs abnormalities, as assessed by CTCAE v4.0 are presented. No formal statistical analysis was performed for safety endpoints.
Trial Locations
- Locations (105)
CZ-01
🇨🇿Ostrava, Czechia
US-19
🇺🇸Plantation, Florida, United States
US01
🇺🇸Fresno, California, United States
HU01
🇭🇺Debrecen, Hungary
RU-06
🇷🇺Petrozavodsk, Russian Federation
US16
🇺🇸Boise, Idaho, United States
GR04
🇬🇷Pátra, Greece
BE-03
🇧🇪Liège, Belgium
GR01
🇬🇷Thessaloníki, Greece
AT-02
🇦🇹Linz, Austria
AT-01
🇦🇹Vienna, Austria
BE-02
🇧🇪Roeselare, Belgium
RU-13
🇷🇺Syktyvkar, Russian Federation
BE-05
🇧🇪Edegem, Belgium
Hu02, Hu03, Hu04
🇭🇺Budapest, Hungary
IT02
🇮🇹Bologna, Italy
IT08
🇮🇹Brescia, Italy
It03, It09
🇮🇹Milano, Italy
IT06
🇮🇹Modena, Italy
IT04
🇮🇹Piacenza, Italy
IT05
🇮🇹Terni, Italy
IT01
🇮🇹Torino, Italy
PL04
🇵🇱Rzeszów, Poland
PL-09
🇵🇱Toruń, Poland
PL06
🇵🇱Łódź, Poland
RO-02
🇷🇴Braşov, Romania
US17
🇺🇸Tucson, Arizona, United States
US13
🇺🇸Boston, Massachusetts, United States
DK01
🇩🇰Vejle, Denmark
Cz-02, Cz-06
🇨🇿Praha, Czechia
FR05
🇫🇷Limoges, France
FR-07
🇫🇷Lyon, France
HU-06
🇭🇺Kaposvár, Hungary
HU-05
🇭🇺Pécs, Hungary
IL03
🇮🇱Jerusalem, Israel
IL01
🇮🇱Nahariya, Israel
IL05
🇮🇱Rehovot, Israel
IT07
🇮🇹Bergamo, Italy
IL02
🇮🇱Safed, Israel
KR-05
🇰🇷Daegu, Korea, Republic of
Kr-01, Kr-02, Kr-03
🇰🇷Seul, Korea, Republic of
IL04
🇮🇱Tel Aviv, Israel
IL06
🇮🇱Tel Aviv, Israel
KR-06
🇰🇷Busan, Korea, Republic of
PL02
🇵🇱Chorzów, Poland
LT-02
🇱🇹Kaunas, Lithuania
LT-01
🇱🇹Vilnius, Lithuania
NL01
🇳🇱Rotterdam, Netherlands
NO01
🇳🇴Oslo, Norway
NO-02
🇳🇴Ålesund, Norway
PL03
🇵🇱Białystok, Poland
RU-10
🇷🇺Novosibirsk, Russian Federation
Ru-01, Ru-02, Ru-08, Ru-12, Ru-14
🇷🇺Saint Petersburg, Russian Federation
RU-07
🇷🇺Samara, Russian Federation
PL05
🇵🇱Lublin, Poland
PL-08
🇵🇱Olsztyn, Poland
RU-05
🇷🇺Ekaterinburg, Russian Federation
RU-04
🇷🇺Izhevsk, Russian Federation
Ru-11, Ru-14
🇷🇺Krasnoyarsk, Russian Federation
RU-03
🇷🇺Moscow, Russian Federation
PL07
🇵🇱Poznań, Poland
RO-01
🇷🇴Bucharest, Romania
RU-09
🇷🇺Nizhny Novgorod, Russian Federation
Es02, Es13, Es14
🇪🇸Barcelona, Spain
Es01, Es04, Es09
🇪🇸Madrid, Spain
ES08
🇪🇸Sevilla, Spain
GB01
🇬🇧Manchester, United Kingdom
TW-02
🇨🇳Chiayi City, Taiwan
Es05, Es06
🇪🇸Valencia, Spain
Tw-04, Tw-07
🇨🇳Kaohsiung, Taiwan
TW-03
🇨🇳Taichung, Taiwan
TW-05
🇨🇳Tainan, Taiwan
Tw-01, Tw-06
🇨🇳Taipei, Taiwan
GB04
🇬🇧Southampton, United Kingdom
GB03
🇬🇧Liverpool, United Kingdom
GB02
🇬🇧Milton Keynes, United Kingdom
FR03
🇫🇷Mulhouse, France
FR04
🇫🇷Brest, France
FR06
🇫🇷Lyon, France
FR-11
🇫🇷Cholet, France
FR01
🇫🇷Le Mans, France
ES-15
🇪🇸Málaga, Spain
ES10
🇪🇸Salamanca, Spain
Es07, Es12
🇪🇸Pamplona, Spain
ES03
🇪🇸Santa Cruz de Tenerife, Spain
US-27
🇺🇸Hattiesburg, Mississippi, United States
US-30
🇺🇸Winston-Salem, North Carolina, United States
US06
🇺🇸Philadelphia, Pennsylvania, United States
US11
🇺🇸Gainesville, Florida, United States
US12
🇺🇸Orange City, Florida, United States
US-24
🇺🇸Louisville, Kentucky, United States
US-21
🇺🇸Salisbury, North Carolina, United States
US15
🇺🇸Fort Sam Houston, Texas, United States
CZ-05
🇨🇿Brno, Czechia
US-18
🇺🇸Temple, Texas, United States
CZ-03
🇨🇿Hradec Králové, Czechia
CZ-04
🇨🇿Olomouc, Czechia
EE-01
🇪🇪Tallinn, Estonia
EE-02
🇪🇪Tartu, Estonia
FR-10
🇫🇷Périgueux, France
Gr02, Gr03
🇬🇷Athens, Greece
FR-08
🇫🇷Poitiers, France
FR-09
🇫🇷Nice, France
KR-04
🇰🇷Hwasun, Korea, Republic of
ES11
🇪🇸Badalona, Spain