Clinical Trials /

Study of Melflufen + Dex With Bortezomib or Daratumumab in Patients With RRMM

NCT03481556

Description:

This is an open-label Phase 1/2a study which will enroll patients that have relapsed or relapsed-refractory multiple myeloma following 1-4 lines of prior therapy. Patients will receive either melflufen+dexamethasone+bortezomib or melflufen+dexamethasone+daratumumab and are required to be IMiD refractory to be enrolled to the bortezomib regimen, and to not have any prior exposure to daratumumab or other antiCD-38 mAb to be enrolled to the daratumumab regimen.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Melflufen + Dex With Bortezomib or Daratumumab in Patients With RRMM
  • Official Title: An Open-Label Phase 1/2a Study of the Safety and Efficacy of Melflufen and Dexamethasone in Combination With Either Bortezomib or Daratumumab in Patients With Relapsed or Relapsed-Refractory Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: OP-104
  • NCT ID: NCT03481556

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
MelflufenA (melflufen+bortezomib+dex)
DexamethasoneDex, Fortecortin, DecadronA (melflufen+bortezomib+dex)
BortezomibVelcadeA (melflufen+bortezomib+dex)
DaratumumabDara, DarzalexB (melflufen+daratumumab+dex)

Purpose

This is an open-label Phase 1/2a study which will enroll patients that have relapsed or relapsed-refractory multiple myeloma following 1-4 lines of prior therapy. Patients will receive either melflufen+dexamethasone+bortezomib or melflufen+dexamethasone+daratumumab and are required to be IMiD refractory to be enrolled to the bortezomib regimen, and to not have any prior exposure to daratumumab or other antiCD-38 mAb to be enrolled to the daratumumab regimen.

Trial Arms

NameTypeDescriptionInterventions
A (melflufen+bortezomib+dex)ExperimentalMelflufen 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.
  • Melflufen
  • Dexamethasone
  • Bortezomib
B (melflufen+daratumumab+dex)ExperimentalMelflufen 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 until PD. Dexamethasone will be given day of and after daratumumab infusions, 20 mg i.v. pre daratumumab and 20 mg p.o. day after daratumumab (20 mg total for ≥ 75 years).
  • Melflufen
  • Dexamethasone
  • Daratumumab

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)

               -  (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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: The primary endpoint of Phase 1 is to monitor and analyze the frequency and grade of AEs occurring during Cycle 1 at each dose level to be tested. Each Regimen to be evaluated separately.
Time Frame:During first cycle (28 days) of each cohort
Safety Issue:
Description:Dose-limiting toxicity to determine the optimal dose of melflufen, up to a maximum of 40 mg, given every 28 days in triple drug combination therapy

Secondary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:From start of treatment until best response achieved before confirmed progression. For an average patient this is achieved within 6 months.
Safety Issue:
Description:To evaluate overall response rate according to IMWG, including CR, VGPR and PR.
Measure:Duration of Response (DOR)
Time Frame:From first evidence of response until confirmed progression, to be assessed up to 24 months
Safety Issue:
Description:To assess the DOR
Measure:Time to Response (TTR)
Time Frame:From start of dosing until time of response. For an average patient this is achieved within 6 months.
Safety Issue:
Description:To assess the TTR
Measure:Progression-Free Survival (PFS)
Time Frame:From start of dosing until confirmed progression, to be assessed up to 24 months
Safety Issue:
Description:To assess the PFS
Measure:Overall Survival (OS)
Time Frame:From start of dosing until end of study (2 years after confirmed progression)
Safety Issue:
Description:To assess the OS data
Measure:Incidence of Treatment-Emergent Adverse Events
Time Frame:From start of dosing until 30 days after last dose, to be assessed up to 24 months
Safety Issue:
Description:To assess the safety and tolerability through AE reporting following CTCAE v4

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Oncopeptides AB

Last Updated

December 4, 2019