Clinical Trials /

Daratumumab, Thalidomide and Dexamethasone in Relapse and/or Refractory Myeloma

NCT03143036

Description:

Myeloma patients who relapse after prior treatment with bortezomib and lenalidomide have survival of less than 1 year. A number of new drugs have been approved for the treatment of relapse myeloma in the last couple of years, including, Elotuzumab, Panobinostat, Ixazomib, carfilzomib and Pomalidomide. However, most of these drugs either do not have good single agent activity or still belongs to the category of immunomodulatory drugs or proteasome inhibitors. Daratumumab is a monoclonal antibody against CD38 that is highly expressed on myeloma plasma cells. In phase ½ studies, it has impressive single agent activity in relapse and refractory myeloma with a very acceptable toxicity profile. This set the stage for combinations with daratumumab to increase efficacy and improve outcome of patients with myeloma. The use of immunomodulatory drugs, such as thalidomide and lenalidomide, has been shown to augment NK cell activity. NK cells are important mediator of antibody dependent cellular cytotoxicity. We therefore hypothesize that the combination of Daratumumab with thalidomide may therefore improve the efficacy of the treatment. In this study, we will plan to perform a phase II trial using the Daratumumab, Thalidomide, Dexamethasone combination in 100 myeloma patients with relapse myeloma in Asia.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

URL:

https://clinicaltrials.gov/show/NCT03143036

Trial Eligibility

Document

Title

  • Brief Title: Daratumumab, Thalidomide and Dexamethasone in Relapse and/or Refractory Myeloma
  • Official Title: Phase 2 Study of Daratumumab in Combination With Thalidomide and Dexamethasone in Relapse and / or Refractory Myeloma

Clinical Trial IDs

  • ORG STUDY ID: AMN004
  • NCT ID: NCT03143036

Conditions

  • Relapse and / or Refractory Myeloma

Interventions

DrugSynonymsArms
Daratumumab, thalidomide and dexamethasoneDaratumumab, thalidomide and dexamethasone

Purpose

Myeloma patients who relapse after prior treatment with bortezomib and lenalidomide have survival of less than 1 year. A number of new drugs have been approved for the treatment of relapse myeloma in the last couple of years, including, Elotuzumab, Panobinostat, Ixazomib, carfilzomib and Pomalidomide. However, most of these drugs either do not have good single agent activity or still belongs to the category of immunomodulatory drugs or proteasome inhibitors. Daratumumab is a monoclonal antibody against CD38 that is highly expressed on myeloma plasma cells. In phase ½ studies, it has impressive single agent activity in relapse and refractory myeloma with a very acceptable toxicity profile. This set the stage for combinations with daratumumab to increase efficacy and improve outcome of patients with myeloma. The use of immunomodulatory drugs, such as thalidomide and lenalidomide, has been shown to augment NK cell activity. NK cells are important mediator of antibody dependent cellular cytotoxicity. We therefore hypothesize that the combination of Daratumumab with thalidomide may therefore improve the efficacy of the treatment. In this study, we will plan to perform a phase II trial using the Daratumumab, Thalidomide, Dexamethasone combination in 100 myeloma patients with relapse myeloma in Asia.

Detailed Description

      Daratumumab is a humanized antibody against CD38 which is expressed on myeloma cells.
      Daratumumab exhibited single agent activity in myeloma and is a promising new treatment.
      Recently, 2 phase 1 / 2 studies establishes the dosing regimen for Daratumumab and impressive
      single agent activity of about 30% response rates in patients who relapse after prior
      lenalidomide and bortezomib. Daratumumab also appear to be well tolerated. The most common
      toxicity is infusion-related and almost all confined to the first cycle. On the whole these
      are manageable with early intervention, concurrent corticosteroids and anti-histamines as
      well as slowing infusion rate. More recently, early results from 2 randomise study comparing
      Daratumumab plus lenalidomide and dexamethasone compared to lenalidomide and dexamethasone,
      and Daratumumab plus bortezomib and dexamethasone compared to bortezomib and dexamethasone,
      showed that the addition of Daratumumab significantly improved response and progression free
      survival, including a high minimal residual disease (MRD) negative rate of more than 20% in
      the relapse myeloma populations.

      In addition, the use of immunomodulatory drugs, such as thalidomide and lenalidomide, has
      been shown to augment NK cell activity. NK cells are important mediator of antibody dependent
      cellular cytotoxicity, which is an important mechanism of action for Daratumumab.
      Furthermore, in the studies using another antibody target SLAMF7, Elotuzumab, the addition of
      dexamethasone greatly improve efficacy. Furthermore, thalidomide plus dexamethasone
      combination have a long history in myeloma and is relatively well tolerated and
      cost-effective. We therefore propose to add Daratumumab to thalidomide and dexamethasone, as
      this combination will be relatively easy to deliver in the Asian population because of
      availability and there is good rationale that such a combination will be synergistic and
      well-tolerated

      Patients will be assessed every 28 days (+/-10 days). Patients shall receive the treatment
      until disease progression, unacceptable toxicity as determined by treating physician,
      withdrawal of consent or mortality (whichever occurs first). After disease progression, the
      treating physician should provide long-term follow-up data on disease status and survival.
      For patients who discontinued treatment before disease progression occurred, disease
      assessment measurements shall be performed once every 28 days (+/- 10 days) until disease
      progression. After patients have documented progression of disease, they will be followed for
      survival every 3 months (+/-10 days) until study closure or until patients withdraws consent,
      is lost to follow-up or until death, whichever comes first. For any patient who is lost to
      follow-up, the study site shall attempt to ascertain survival information via public database
      search.

Trial Arms

NameTypeDescriptionInterventions
Daratumumab, thalidomide and dexamethasoneExperimental
  • Daratumumab, thalidomide and dexamethasone

Eligibility Criteria

        Inclusion Criteria:

          1. Multiple myeloma, diagnosed according to standard criteria, with relapsing and
             refractory disease at study entry

          2. Patients must have evaluable multiple myeloma with at least one of the following
             (within 21 days of starting treatment)

               1. Serum M-protein ≥ 0.5g/dL, or

               2. In subjects without detectable serum M-protein, Urine M-protein ≥ 200mg/24 hour,
                  or serum free light chai (sFLC) > 100mg/L (involved light chain) and an abnormal
                  kappa/Lambda ratio

          3. Must receive at least 1 line of prior treatment. (Induction therapy followed by stem
             cell transplantation and consolidation/maintenance therapy will be considered as one
             line of treatment)

          4. Must have relapsed disease and/or be refractory to prior treatment except for
             thalidomide or lenalidomide. Refractoriness is defined as disease progression on
             treatment or progression within 6 months after the last dose of a given therapy.
             Relapse is defined according to the criteria of IMWG

          5. Males and females ≥ 18 years of age or > country's legal age for adult consent

          6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2

          7. Patients must meet the following clinical laboratory criteria with 21 days of starting
             treatment:

               1. Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet ≥ 50,000/mm3 (≥
                  30,000/mm3 if myeloma involvement in the bone marrow is >50%)

               2. Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN). Alanine
                  aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN.

               3. Calculated creatinine clearance ≥ 30mL/min.

          8. Written informed consent in accordance with federal, local and institutional
             guidelines

        Exclusion Criteria:

          1. Female patients who are lactating or pregnant

          2. Multiple Myeloma of IgM subtype

          3. Glucocorticoid therapy (prednisolone > 30mg/day or equivalent) within 14 days prior to
             informed consent obtained

          4. POEMS syndrome

          5. Plasma cell leukemia or circulating plasma cells ≥ 2 x 109/L

          6. Waldenstrom's Macroglobulinaemia

          7. Existing peripheral neuropathy of grade 2 or higher or presence of neuropathic pain

          8. Patients with known amyloidosis

          9. Chemotherapy with approved or investigation anticancer therapeutics within 21 days
             prior to starting Dara-TD treatment

         10. Focal radiation therapy within 7 days prior to start of Dara-TD. Radiation therapy to
             an extended field involving a significant volume of bone marrow within 21 days prior
             to start of pomalidomide

         11. Immunotherapy (excluding steroids) 21 days prior to start of Dara-TD

         12. Major surgery (excluding kyphoplasty) within 28 days prior to start of Dara-TD

         13. Active congestive heart failure (New York Heart Association [NYHA] Class III or IV),
             symptomatic ischaemia, or conduction abnormalities uncontrolled by conventional
             intervention. Myocardial infarction within 4 months prior to informed consent obtained

         14. Known HIV seropositive, hepatitis C infection, and/or hepatitis B (except for patients
             with hepatitis B surface antigen or core antibody receiving and responding to
             antiviral therapy directed at hepatitis B: these patients are allowed)

         15. Patients with known cirrhosis

         16. Patients with creatinine clearance <30m/min

         17. Second malignancy within the past 3 years except:

               1. Adequately treated basal cell or squamous cell skin cancer

               2. Carcinoma in situ of the cervix

               3. Breast carcinoma in situ with full surgical resection

         18. Patients with myelodysplastic syndrome

         19. Patients with steroid or thalidomide hypersensitivity

         20. Patients previously treated with daratumumab or other anti-CD38 antibodies.

         21. Ongoing graft-versus-host disease

         22. Patients with pleural effusions requiring thoracentesis or ascites requiring
             paracentesis within 14 days prior to starting Dara-TD treatment

         23. Disease refractory to thalidomide or lenalidomide

         24. Contraindication to any of the required concomitant drugs or supportive treatments

         25. Any clinically significant medical disease or psychiatric condition that, in the
             investigator's opinion, may interfere with protocol adherence or a patient's ability
             to give informed consent.
Maximum Eligible Age:99 Years
Minimum Eligible Age:21 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:Time from commencement of treatment to disease progression or death, whichever occurs first, assessed up to 100 months
Safety Issue:
Description:To assess the progression free survival (PFS) for daratumumab in combination with thalidomide and dexamethasone in Asian patients with relapsed myeloma.

Secondary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:anytime from commencement of treatment with daratumumab, thalidomide and dexamethasone to the end of studyaseline until disease progression, unmanageable adverse event or death, whichever occurs first, approximately up to 3 years
Safety Issue:
Description:percentage of patients enrolled that achieve a complete response (CR), or stringent complete response (sCR), or very good partial response (VGPR), or partial response (PR) based on the International Myeloma Working Group criteria
Measure:Overall survival (OS)
Time Frame:Up to approximately 5 years (anticipated) after the last participant is enrolled
Safety Issue:
Description:Time from commencement of treatment with daratumumab, thalidomide and dexamethasone to the date of death.
Measure:Duration of response (DOR)
Time Frame:the time from first evidence of PR or VGPR, or CR, or sCR to confirmation of disease progression or death due to any cause, assessed up to 100 months
Safety Issue:
Description:the time from first evidence of PR or VGPR, or CR, or sCR to confirmation of disease progression or death due to any cause.
Measure:Number of Participants affected by Adverse Events
Time Frame:from the time of enrolment into study till 3 years from the date of the last patient randomized
Safety Issue:
Description:assessed on the basis of the frequency and severity of adverse events

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National University Hospital, Singapore

Trial Keywords

  • daratumumab

Last Updated

June 7, 2018