Clinical trial NCT03151811: A Study of Melphalan Flufenamide (Melflufen)-Dex or Pomalidomide-dex for RRMM Patients Refractory to Lenalidomide
Official title: A Randomized, Controlled, Open-label, Phase 3 Study of Melflufen/Dexamethasone Compared With Pomalidomide/Dexamethasone for Patients With Relapsed Refractory Multiple Myeloma Who Are Refractory to Lenalidomide
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Multiple Myeloma
Keywords: Refractory Multiple Myeloma
Relapsed Multiple Myeloma
Melphalan flufenamide (Melflufen)
Pomalidomide
Dexamethasone
Lead sponsor: Oncopeptides AB
Sponsor class: INDUSTRY
First posted: 2017-05-12
Enrollment: 495
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Male or female, age 18 years or older
2. A prior diagnosis of multiple myeloma with documented disease progression requiring further treatment at time of screening
3. 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
4. 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.
5. Life expectancy of ≥ 6 months
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
7. 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).
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 Fridericia Formula.
10. 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.
11. Must be able to take antithrombotic prophylaxis.
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) (Insertion only required if randomized to Arm A).

Exclusion Criteria:

1. Primary refractory disease (i.e. never responded (≥ MR) to any prior therapy)
2. Evidence of mucosal or internal bleeding or platelet transfusion refractory
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.
4. Prior exposure to pomalidomide
5. Known intolerance to IMiDs.
6. Known active infection requiring parenteral or oral anti-infective treatment within 14 days of randomization.
7. 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.
8. Pregnant or breast-feeding females
9. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation
10. Known human immunodeficiency virus or active hepatitis C viral infection
11. 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.
12. Concurrent symptomatic amyloidosis or plasma cell leukemia
13. POEMS syndrome
14. 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
15. Residual side effects to previous therapy \> grade 1 prior to randomization (Alopecia any grade and/or neuropathy grade 2 without pain are permitted)
16. Prior peripheral stem cell transplant within 12 weeks of randomization
17. Prior allogeneic stem cell transplantation with active graft-versus-host-disease.
18. Prior major surgical procedure or radiation therapy within 4 weeks of the randomization
19. Known intolerance to steroid therapy

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 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).
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: 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
measure: Duration of Response (DOR)
timeFrame: 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).
measure: Overall Survival (OS)
timeFrame: 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).
measure: 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
timeFrame: 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.
Other outcomes:
Locations:
city: Tucson
country: United States
facility: US17
state: Arizona
city: Fresno
country: United States
facility: US01
state: California
city: Gainesville
country: United States
facility: US11
state: Florida
city: Orange City
country: United States
facility: US12
state: Florida
city: Plantation
country: United States
facility: US-19
state: Florida
city: Boise
country: United States
facility: US16
state: Idaho
city: Louisville
country: United States
facility: US-24
state: Kentucky
city: Boston
country: United States
facility: US13
state: Massachusetts
city: Hattiesburg
country: United States
facility: US-27
state: Mississippi
city: Salisbury
country: United States
facility: US-21
state: North Carolina
city: Winston-Salem
country: United States
facility: US-30
state: North Carolina
city: Philadelphia
country: United States
facility: US06
state: Pennsylvania
city: Fort Sam Houston
country: United States
facility: US15
state: Texas
city: Temple
country: United States
facility: US-18
state: Texas
city: Linz
country: Austria
facility: AT-02
city: Vienna
country: Austria
facility: AT-01
city: Edegem
country: Belgium
facility: BE-05
city: Liège
country: Belgium
facility: BE-03
city: Roeselare
country: Belgium
facility: BE-02
city: Brno
country: Czechia
facility: CZ-05
city: Hradec Králové
country: Czechia
facility: CZ-03
city: Olomouc
country: Czechia
facility: CZ-04
city: Ostrava
country: Czechia
facility: CZ-01
city: Praha
country: Czechia
facility: Cz-02, Cz-06
city: Vejle
country: Denmark
facility: DK01
city: Tallinn
country: Estonia
facility: EE-01
city: Tartu
country: Estonia
facility: EE-02
city: Brest
country: France
facility: FR04
city: Cholet
country: France
facility: FR-11
city: Le Mans
country: France
facility: FR01
city: Limoges
country: France
facility: FR05
city: Lyon
country: France
facility: FR-07
city: Lyon
country: France
facility: FR06
city: Mulhouse
country: France
facility: FR03
city: Nice
country: France
facility: FR-09
city: Poitiers
country: France
facility: FR-08
city: Périgueux
country: France
facility: FR-10
city: Athens
country: Greece
facility: Gr02, Gr03
city: Pátra
country: Greece
facility: GR04
city: Thessaloníki
country: Greece
facility: GR01
city: Budapest
country: Hungary
facility: Hu02, Hu03, Hu04
city: Debrecen
country: Hungary
facility: HU01
city: Kaposvár
country: Hungary
facility: HU-06
city: Pécs
country: Hungary
facility: HU-05
city: Jerusalem
country: Israel
facility: IL03
city: Nahariya
country: Israel
facility: IL01
city: Rehovot
country: Israel
facility: IL05
city: Safed
country: Israel
facility: IL02
city: Tel Aviv
country: Israel
facility: IL04
city: Tel Aviv
country: Israel
facility: IL06
city: Bergamo
country: Italy
facility: IT07
city: Bologna
country: Italy
facility: IT02
city: Brescia
country: Italy
facility: IT08
city: Milano
country: Italy
facility: It03, It09
city: Modena
country: Italy
facility: IT06
city: Piacenza
country: Italy
facility: IT04
city: Terni
country: Italy
facility: IT05
city: Torino
country: Italy
facility: IT01
city: Busan
country: Korea, Republic of
facility: KR-06
city: Daegu
country: Korea, Republic of
facility: KR-05
city: Hwasun
country: Korea, Republic of
facility: KR-04
city: Seul
country: Korea, Republic of
facility: Kr-01, Kr-02, Kr-03
city: Kaunas
country: Lithuania
facility: LT-02
city: Vilnius
country: Lithuania
facility: LT-01
city: Rotterdam
country: Netherlands
facility: NL01
city: Oslo
country: Norway
facility: NO01
city: Ålesund
country: Norway
facility: NO-02
city: Białystok
country: Poland
facility: PL03
city: Chorzów
country: Poland
facility: PL02
city: Lublin
country: Poland
facility: PL05
city: Olsztyn
country: Poland
facility: PL-08
city: Poznań
country: Poland
facility: PL07
city: Rzeszów
country: Poland
facility: PL04
city: Toruń
country: Poland
facility: PL-09
city: Łódź
country: Poland
facility: PL06
city: Braşov
country: Romania
facility: RO-02
city: Bucharest
country: Romania
facility: RO-01
city: Ekaterinburg
country: Russian Federation
facility: RU-05
city: Izhevsk
country: Russian Federation
facility: RU-04
city: Krasnoyarsk
country: Russian Federation
facility: Ru-11, Ru-14
city: Moscow
country: Russian Federation
facility: RU-03
city: Nizhny Novgorod
country: Russian Federation
facility: RU-09
city: Novosibirsk
country: Russian Federation
facility: RU-10
city: Petrozavodsk
country: Russian Federation
facility: RU-06
city: Saint Petersburg
country: Russian Federation
facility: Ru-01, Ru-02, Ru-08, Ru-12, Ru-14
city: Samara
country: Russian Federation
facility: RU-07
city: Syktyvkar
country: Russian Federation
facility: RU-13
city: Badalona
country: Spain
facility: ES11
city: Barcelona
country: Spain
facility: Es02, Es13, Es14
city: Madrid
country: Spain
facility: Es01, Es04, Es09
city: Málaga
country: Spain
facility: ES-15
city: Pamplona
country: Spain
facility: Es07, Es12
city: Salamanca
country: Spain
facility: ES10
city: Santa Cruz de Tenerife
country: Spain
facility: ES03
city: Sevilla
country: Spain
facility: ES08
city: Valencia
country: Spain
facility: Es05, Es06
city: Chiayi City
country: Taiwan
facility: TW-02
city: Kaohsiung
country: Taiwan
facility: Tw-04, Tw-07
city: Taichung
country: Taiwan
facility: TW-03
city: Tainan
country: Taiwan
facility: TW-05
city: Taipei
country: Taiwan
facility: Tw-01, Tw-06
city: Liverpool
country: United Kingdom
facility: GB03
city: Manchester
country: United Kingdom
facility: GB01
city: Milton Keynes
country: United Kingdom
facility: GB02
city: Southampton
country: United Kingdom
facility: GB04
Study officials:
affiliation: Erasmus Medical Center
name: Pieter Sonneveld, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schjesvold FH, Dimopoulos MA, Delimpasi S, Robak P, Coriu D, Legiec W, Pour L, Spicka I, Masszi T, Doronin V, Minarik J, Salogub G, Alekseeva Y, Lazzaro A, Maisnar V, Mikala G, Rosinol L, Liberati AM, Symeonidis A, Moody V, Thuresson M, Byrne C, Harmenberg J, Bakker NA, Hajek R, Mateos MV, Richardson PG, Sonneveld P; OCEAN (OP-103) Investigators. Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study. Lancet Haematol. 2022 Feb;9(2):e98-e110. doi: 10.1016/S2352-3026(21)00381-1. Epub 2022 Jan 12.