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

Multiple Myeloma Clinical Trial

— OCEAN  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03151811
• Other study ID #: OP-103
• Status: Terminated
• Phase: Phase 3
• Start date: June 12, 2017
• Est. completion date: February 3, 2023

Study information

• Verified date: December 2023
• Source: Oncopeptides AB
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 495
• Est. completion date: February 3, 2023
• Est. primary completion date: February 3, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Melflufen
Intravenous infusion
• Pomalidomide
Oral capsules
• Dexamethasone
Oral tablets

Locations

Country	Name	City	State
Austria	AT-02	Linz
Austria	AT-01	Vienna
Belgium	BE-05	Edegem
Belgium	BE-03	Liège
Belgium	BE-02	Roeselare
Czechia	CZ-05	Brno
Czechia	CZ-03	Hradec Králové
Czechia	CZ-04	Olomouc
Czechia	CZ-01	Ostrava
Czechia	Cz-02, Cz-06	Praha
Denmark	DK01	Vejle
Estonia	EE-01	Tallinn
Estonia	EE-02	Tartu
France	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
Greece	Gr02, Gr03	Athens
Greece	GR04	Pátra
Greece	GR01	Thessaloníki
Hungary	Hu02, Hu03, Hu04	Budapest
Hungary	HU01	Debrecen
Hungary	HU-06	Kaposvár
Hungary	HU-05	Pécs
Israel	IL03	Jerusalem
Israel	IL01	Nahariya
Israel	IL05	Rehovot
Israel	IL02	Safed
Israel	IL04	Tel Aviv
Israel	IL06	Tel Aviv
Italy	IT07	Bergamo
Italy	IT02	Bologna
Italy	IT08	Brescia
Italy	It03, It09	Milano
Italy	IT06	Modena
Italy	IT04	Piacenza
Italy	IT05	Terni
Italy	IT01	Torino
Korea, Republic of	KR-06	Busan
Korea, Republic of	KR-05	Daegu
Korea, Republic of	KR-04	Hwasun
Korea, Republic of	Kr-01, Kr-02, Kr-03	Seul
Lithuania	LT-02	Kaunas
Lithuania	LT-01	Vilnius
Netherlands	NL01	Rotterdam
Norway	NO-02	Ålesund
Norway	NO01	Oslo
Poland	PL03	Bialystok
Poland	PL02	Chorzów
Poland	PL06	Lódz
Poland	PL05	Lublin
Poland	PL-08	Olsztyn
Poland	PL07	Poznan
Poland	PL04	Rzeszów
Poland	PL-09	Torun
Romania	RO-02	Brasov
Romania	RO-01	Bucharest
Russian Federation	RU-05	Ekaterinburg
Russian Federation	RU-04	Izhevsk
Russian Federation	Ru-11, Ru-14	Krasnoyarsk
Russian Federation	RU-03	Moscow
Russian Federation	RU-09	Nizhny Novgorod
Russian Federation	RU-10	Novosibirsk
Russian Federation	RU-06	Petrozavodsk
Russian Federation	Ru-01, Ru-02, Ru-08, Ru-12, Ru-14	Saint Petersburg
Russian Federation	RU-07	Samara
Russian Federation	RU-13	Syktyvkar
Spain	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	Sevilla
Spain	Es05, Es06	Valencia
Taiwan	TW-02	Chiayi City
Taiwan	Tw-04, Tw-07	Kaohsiung
Taiwan	TW-03	Taichung
Taiwan	TW-05	Tainan
Taiwan	Tw-01, Tw-06	Taipei
United Kingdom	GB03	Liverpool
United Kingdom	GB01	Manchester
United Kingdom	GB02	Milton Keynes
United Kingdom	GB04	Southampton
United States	US16	Boise	Idaho
United States	US13	Boston	Massachusetts
United States	US15	Fort Sam Houston	Texas
United States	US01	Fresno	California
United States	US11	Gainesville	Florida
United States	US-27	Hattiesburg	Mississippi
United States	US-24	Louisville	Kentucky
United States	US12	Orange City	Florida
United States	US06	Philadelphia	Pennsylvania
United States	US-19	Plantation	Florida
United States	US-21	Salisbury	North Carolina
United States	US-18	Temple	Texas
United States	US17	Tucson	Arizona
United States	US-30	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Oncopeptides AB

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Czechia,  Denmark,  Estonia,  France,  Greece,  Hungary,  Israel,  Italy,  Korea, Republic of,  Lithuania,  Netherlands,  Norway,  Poland,  Romania,  Russian Federation,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS)	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.	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	Overall Response Rate (ORR)	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.	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
Secondary	Duration of Response (DOR)	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.	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).
Secondary	Overall Survival (OS)	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.	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).
Secondary	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	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.	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.