A Study of Melphalan Flufenamide (Melflufen)-Dex or Pomalidomide-dex for RRMM Patients Refractory to Lenalidomide

NCT ID: NCT03151811

Last Updated: 2024-01-30

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 495 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-06-12
• Study Completion Date: 2023-02-03

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.

Conditions

Multiple Myeloma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Arm A: Melflufen+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.

Group Type: EXPERIMENTAL

Melflufen

Intervention Type: DRUG

Intravenous infusion

Dexamethasone

Intervention Type: DRUG

Oral tablets

Arm B: Pomalidomide+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.

Group Type: ACTIVE_COMPARATOR

Pomalidomide

Intervention Type: DRUG

Oral capsules

Dexamethasone

Intervention Type: DRUG

Oral tablets

Interventions

Melflufen

Intravenous infusion

Intervention Type: DRUG

Pomalidomide

Oral capsules

Intervention Type: DRUG

Dexamethasone

Oral tablets

Intervention Type: DRUG

Other Intervention Names

Melphalan Flufenamide; Pepaxti; Pomalyst; Imnovid; Dex; Fortecortin; Decadron

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Oncopeptides AB

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Pieter Sonneveld, Prof.

Role: PRINCIPAL_INVESTIGATOR

Erasmus Medical Center

Locations

US17

Tucson, Arizona, United States

US01

Fresno, California, United States

US11

Gainesville, Florida, United States

US12

Orange City, Florida, United States

US-19

Plantation, Florida, United States

US16

Boise, Idaho, United States

US-24

Louisville, Kentucky, United States

US13

Boston, Massachusetts, United States

US-27

Hattiesburg, Mississippi, United States

US-21

Salisbury, North Carolina, United States

US-30

Winston-Salem, North Carolina, United States

US06

Philadelphia, Pennsylvania, United States

US15

Fort Sam Houston, Texas, United States

US-18

Temple, Texas, United States

AT-02

Linz, , Austria

AT-01

Vienna, , Austria

BE-05

Edegem, , Belgium

BE-03

Liège, , Belgium

BE-02

Roeselare, , Belgium

CZ-05

Brno, , Czechia

CZ-03

Hradec Králové, , Czechia

CZ-04

Olomouc, , Czechia

CZ-01

Ostrava, , Czechia

Cz-02, Cz-06

Prague, , Czechia

DK01

Vejle, , Denmark

EE-01

Tallinn, , Estonia

EE-02

Tartu, , Estonia

FR04

Brest, , France

FR-11

Cholet, , France

FR01

Le Mans, , France

FR05

Limoges, , France

FR-07

Lyon, , France

FR06

Lyon, , France

FR03

Mulhouse, , France

FR-09

Nice, , France

FR-10

Périgueux, , France

FR-08

Poitiers, , France

Gr02, Gr03

Athens, , Greece

GR04

Pátrai, , Greece

GR01

Thessaloniki, , Greece

Hu02, Hu03, Hu04

Budapest, , Hungary

HU01

Debrecen, , Hungary

HU-06

Kaposvár, , Hungary

HU-05

Pécs, , Hungary

IL03

Jerusalem, , Israel

IL01

Nahariya, , Israel

IL05

Rehovot, , Israel

IL02

Safed, , Israel

IL04

Tel Aviv, , Israel

IL06

Tel Aviv, , Israel

IT07

Bergamo, , Italy

IT02

Bologna, , Italy

IT08

Brescia, , Italy

It03, It09

Milan, , Italy

IT06

Modena, , Italy

IT04

Piacenza, , Italy

IT05

Terni, , Italy

IT01

Torino, , Italy

LT-02

Kaunas, , Lithuania

LT-01

Vilnius, , Lithuania

NL01

Rotterdam, , Netherlands

NO-02

Ålesund, , Norway

NO01

Oslo, , Norway

PL03

Bialystok, , Poland

PL02

Chorzów, , Poland

PL06

Lodz, , Poland

PL05

Lublin, , Poland

PL-08

Olsztyn, , Poland

PL07

Poznan, , Poland

PL04

Rzeszów, , Poland

PL-09

Torun, , Poland

RO-02

Brasov, , Romania

RO-01

Bucharest, , Romania

RU-04

Izhevsk, , Russia

Ru-11, Ru-14

Krasnoyarsk, , Russia

RU-03

Moscow, , Russia

RU-09

Nizhny Novgorod, , Russia

RU-10

Novosibirsk, , Russia

RU-06

Petrozavodsk, , Russia

Ru-01, Ru-02, Ru-08, Ru-12, Ru-14

Saint Petersburg, , Russia

RU-07

Samara, , Russia

RU-13

Syktyvkar, , Russia

RU-05

Yekaterinburg, , Russia

KR-06

Busan, , South Korea

KR-05

Daegu, , South Korea

KR-04

Hwasun, , South Korea

Kr-01, Kr-02, Kr-03

Seoul, , South Korea

ES11

Badalona, , Spain

Es02, Es13, Es14

Barcelona, , Spain

Es01, Es04, Es09

Madrid, , Spain

ES-15

Málaga, , Spain

Es07, Es12

Pamplona, , Spain

ES10

Salamanca, , Spain

ES03

Santa Cruz de Tenerife, , Spain

ES08

Seville, , Spain

Es05, Es06

Valencia, , Spain

TW-02

Chiayi City, , Taiwan

Tw-04, Tw-07

Kaohsiung City, , Taiwan

TW-03

Taichung, , Taiwan

TW-05

Tainan City, , Taiwan

Tw-01, Tw-06

Taipei, , Taiwan

GB03

Liverpool, , United Kingdom

GB01

Manchester, , United Kingdom

GB02

Milton Keynes, , United Kingdom

GB04

Southampton, , United Kingdom

Countries

United States; Austria; Belgium; Czechia; Denmark; Estonia; France; Greece; Hungary; Israel; Italy; Lithuania; Netherlands; Norway; Poland; Romania; Russia; South Korea; Spain; Taiwan; United Kingdom

References

Schjesvold FH, Ludwig H, Delimpasi S, Robak P, Coriu D, Tomczak W, Pour L, Spicka I, Dimopoulos MA, Masszi T, Chernova NG, Sandberg A, Thuresson M, Norin S, Bakker NA, Mateos MV, Richardson PG, Sonneveld P. Health-related quality of life in relapsed/refractory multiple myeloma treated with melflufen and dexamethasone: analyses from the phase III OCEAN study. Haematologica. 2024 Jul 1;109(7):2331-2336. doi: 10.3324/haematol.2023.284635. No abstract available.

Reference Type: DERIVED

PMID: 38426292 (View on PubMed)

Sonneveld P, Richardson PG, Ludwig H, Dimopoulos MA, Schjesvold FH, Hajek R, Abdulhaq H, Thuresson M, Norin S, Bakker NA, Mateos MV. Benefit Versus Risk Assessment of Melflufen and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Analyses From Longer Follow-up of the OCEAN and HORIZON Studies. Clin Lymphoma Myeloma Leuk. 2023 Sep;23(9):687-696. doi: 10.1016/j.clml.2023.05.004. Epub 2023 May 6.

Reference Type: DERIVED

PMID: 37355418 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35032434 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

OP-103

Identifier Type: -

Identifier Source: org_study_id