Study of Melphalan Flufenamide (Melflufen) + Dex With Bortezomib or Daratumumab in Patients With RRMM

NCT ID: NCT03481556

Last Updated: 2022-12-19

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 56 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-04-12
• Study Completion Date: 2022-02-02

Brief Summary

This is an open-label Phase 1/2a study which will enroll patients that have relapsed or relapsed-refractory multiple myeloma to combination regimens of melflufen with currently approved agents. Patients will receive either melflufen+dexamethasone+bortezomib or melflufen+dexamethasone+daratumumab.

Conditions

Multiple Myeloma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

A (melflufen+bortezomib+dex)

Melflufen 30 mg and 40 mg or 20 mg i.v. Day 1 of each 28-day cycle in combination with bortezomib at 1.3mg/m² S.Q. on Days 1, 4, 8, 11 and dexamethasone 20 mg (12 mg ≥ 75 years) Days 1, 4, 8, 11 and 40 mg (20 mg ≥ 75 years) on Day 15 and 22 of each 28-day cycle.

Group Type: EXPERIMENTAL

Melphalan flufenamide (Melflufen)

Intervention Type: DRUG

Intravenous infusion

Dexamethasone

Intervention Type: DRUG

Oral tablets

Bortezomib

Intervention Type: DRUG

Subcutaneous administration

B (melflufen+daratumumab+dex)

Melflufen 30 mg and 40 mg or 20 mg i.v. Day 1 of each 28-day cycle in combination with daratumumab 16 mg/kg weekly for 8 doses, every other week for 8 doses and then once every 4 weeks. Dexamethasone p.o. 40 mg weekly (20 mg weekly for patients age ≥ 75 years).

Group Type: EXPERIMENTAL

Melphalan flufenamide (Melflufen)

Intervention Type: DRUG

Intravenous infusion

Dexamethasone

Intervention Type: DRUG

Oral tablets

Daratumumab

Intervention Type: DRUG

Intravenous infusion

Interventions

Melphalan flufenamide (Melflufen)

Intravenous infusion

Intervention Type: DRUG

Dexamethasone

Oral tablets

Intervention Type: DRUG

Bortezomib

Subcutaneous administration

Intervention Type: DRUG

Daratumumab

Intravenous infusion

Intervention Type: DRUG

Other Intervention Names

Dex; Fortecortin; Decadron; Velcade; Dara; Darzalex

Eligibility Criteria

Inclusion Criteria

1. Male or female, age 18 years or older

2. A prior diagnosis of multiple myeloma with documented disease progression in need of treatment at time of screening

3. One to four prior lines of therapy

4. Measurable disease defined as any of the following:

• Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP)
• ≥ 200 mg/24 hours of monoclonal protein in the urine on 24-hour urine electrophoresis (UPEP)
• Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain ratio

5. Life expectancy of ≥ 6 months

6. ECOG performance status ≤ 2. (Patients with lower performance status based solely on bone pain secondary to multiple myeloma may be eligible following consultation and approval of the medical monitor)

7. Patient is a female of childbearing potential (FCBP)* with a negative serum or urine pregnancy test prior to initiation of therapy and agrees to practice appropriate methods of birth control, or the patient is male and agrees to practice appropriate methods of birth control

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

10. Adequate organ function with the following laboratory results during screening (within 21 days) and immediately before study drug administration on Cycle 1 Day 1:

• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) (Growth factors cannot be used within 10 days (14 days for pegfilgrastim) prior to initiation of therapy)
• Platelet count ≥ 75,000 cells/mm3 (75 x 109/L) (without required transfusions during the 10 days prior to initiation of therapy)
• Hemoglobin ≥ 8.0 g/dl (red blood cell (RBC) transfusions are permitted)
• Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), or patients diagnosed with Gilbert's syndrome, that have been reviewed and approved by the medical monitor
• AST/SGOT and ALT/SGPT ≤ 3.0 x ULN
• Renal function: Estimated creatinine clearance by Cockcroft-Gault formula ≥ 45 mL/min and serum creatinine ≤ 2 mg/dL

11. Must have, or be willing to have an acceptable central catheter. (Port a cath, peripherally inserted central catheter [PICC] line, or central venous catheter)

Regimen A

12. Must be intolerant or refractory to a prior IMiD; refractory defined as failure to respond (MR or better) or progression while on therapy or within 60 days of last dose.

Regimen B

13. Must have had a prior IMiD and a proteasome inhibitor (PI); alone or in combination and must be refractory or intolerant to an IMiD, PI or both.

• (FCBP) is any sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (not having menstrual cycles due to cancer therapy does not rule out childbearing potential) for at least 24 consecutive months.

Exclusion Criteria

1. Primary refractory disease (i.e. never responded with ≥ MR to any prior therapy)

2. Evidence of mucosal or internal bleeding and/or are platelet transfusion refractory (i.e. platelet count fails to increase by > 10,000 cells/mm3 after transfusion of an appropriate dose of platelets)

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. Examples of such conditions are: a significant history of cardiovascular disease (e.g., myocardial infarction, significant conduction system abnormalities, uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the last 6 months)

4. Known active infection requiring parenteral or oral anti-infective treatment within 14 days of initiation of therapy

5. 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

6. Pregnant or breast-feeding females

7. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation

8. Known human immunodeficiency virus or active hepatitis B or C viral infection

9. Concurrent symptomatic amyloidosis or plasma cell leukemia

10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)

11. Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy. The use of live vaccines within 30 days before initiation of therapy. IMiDs, PIs and or corticosteroids within 2 weeks prior to initiation of therapy. Other investigational therapies and monoclonal antibodies (mAb) within 4 weeks of initiation of therapy Prednisone up to but no more than 10 mg orally once daily (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 initiation of therapy

12. Residual side effects to previous therapy > Grade 1 prior to initiation of therapy (Alopecia any grade and/or neuropathy Grade 1 without pain are permitted)

13. Prior peripheral stem cell transplant within 12 weeks of initiation of therapy

14. Prior allogeneic stem cell transplantation with active graft-versus-host- disease

15. Prior major surgical procedure or radiation therapy within 4 weeks of initiation of therapy (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of therapy)

16. Known intolerance to the required dose and schedule of steroid therapy as determined by the investigator

17. Prior treatment with melflufen

Regimen A

18. Refractory to a PI in the last line of therapy prior to enrollment in this trial; refractory defined as failure to respond (MR or better) or progression while on therapy or within 60 days of last dose

19. History of allergic reaction/hypersensitivity attributed to compounds containing boron, mannitol, polysorbate 80 or sodium citrate dihydrate

Regimen B

20. Prior exposure to an antiCD-38 mAb

21. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) less than 50% of predicted normal

22. Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification

23. ≥ Grade 3 conduction system abnormalities unless patient has a pacemaker

24. Active hepatitis B (defined as HBsAg+) or those at risk for reactivation (HBsAg-, Anti- HBs+, Anti-HBc+)

• 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 only be enrolled after approval of the sponsor and consideration of risk of reactivation (additional screening and monitoring for reactivation of Hepatitis B and consultation with a liver disease specialist may be required)

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

Sponsors

Oncopeptides AB

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Dana Farber Cancer Institute

Boston, Massachusetts, United States

The Ohio State University

Columbus, Ohio, United States

Fakultní nemocnice Brno

Brno, , Czechia

Fakultní nemocnice Hradec Králové

Hradec Králové, , Czechia

Fakultní nemocnice Ostrava

Ostrava, , Czechia

Všeobecná fakultní nemocnice

Prague, , Czechia

Hôpital Morvan

Brest, , France

Centre Jean Bernard - Clinique Victor Hugo

Le Mans, , France

Hôpital privé du Confluent

Nantes, , France

Centre Hospitalier Lyon Sud

Pierre-Bénite, , France

Centre Hospitalier Universitaire Institut Gustave Roussy

Villejuif, , France

Hospital Universitai Germans Trias i Pujol

Badalona, , Spain

Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Hospital Universitario 12 de Octubre

Madrid, , Spain

Complejo Hospitalario de Salamanca

Salamanca, , Spain

Hospital Universitario Marques de Valdecilla

Santander, , Spain

Countries

United States; Czechia; France; Spain

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

OP-104

Identifier Type: -

Identifier Source: org_study_id