Clinical Trials /

Phase II Study of the CD38 Antibody Daratumumab in Patients With High-Risk MGUS and Low-Risk Smoldering Multiple Myeloma

NCT03236428

Description:

This research study is studying a drug as a possible treatment for Monoclonal Gammopathy of Unknown Significance (MGUS) or Smoldering Multiple Myeloma (SMM). The drug involved in this study is: -Daratumumab

Related Conditions:
  • Monoclonal Gammopathy of Undetermined Significance
  • Smoldering Plasma Cell Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Study of the CD38 Antibody Daratumumab in Patients With High-Risk MGUS and Low-Risk Smoldering Multiple Myeloma
  • Official Title: A Phase II Study of the CD38 Antibody Daratumumab in Patients With High-Risk MGUS and Low-Risk Smoldering Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: 17-212
  • NCT ID: NCT03236428

Conditions

  • Monoclonal Gammopathy
  • Smoldering Multiple Myeloma

Interventions

DrugSynonymsArms
DaratumumabDarzalexDaratumumab

Purpose

This research study is studying a drug as a possible treatment for Monoclonal Gammopathy of Unknown Significance (MGUS) or Smoldering Multiple Myeloma (SMM). The drug involved in this study is: -Daratumumab

Detailed Description

      This research study is a Phase II clinical trial, which tests the effectiveness of an
      investigational drug. Preliminary experience suggests that daratumumab may prevent or
      postpone SMM from becoming active multiple myeloma. The purpose of this research study is to
      determine if the this drug may improve the rate of prevention of multiple myeloma.

      Multiple myeloma is a cancer of the plasma cell, which is an important part of the immune
      system. Patients with active multiple myeloma generally require treatment. There are
      currently no approved therapies for smoldering multiple myeloma or Monoclonal Gammopathy of
      Unknown Significance.

      Daratumumab is a drug that may kill or stop cancer cells from growing through a variety of
      mechanisms by attaching to the CD38 molecule, which is over-expressed in multiple myeloma
      cells. This type of drug is called a monoclonal antibody. The FDA (the U.S. Food and Drug
      Administration) has not approved Daratumumab for the participant specific disease but it has
      been approved for use in active Multiple Myeloma.
    

Trial Arms

NameTypeDescriptionInterventions
DaratumumabExperimentalDaratumumab will be administered by IV infusion weekly during cycles 1 and 2 Daratumumab will be administered by IV infusion every other week during cycles 3 through 6 Daratumumab will be administered by IV infusion monthly during cycles 7 through 20
  • Daratumumab

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥ 18 years

          -  Must meet criteria for high-risk MGUS or low-risk smoldering myeloma as described
             below:

        High-Risk MGUS

        Must have <10% plasma cells and <3.0g/dL M-spike and at least 2 of the following 3
        criteria:

          -  Abnormal free light-chain (FLC) ratio (<0.26 or >1.65)

          -  M-protein concentration (≥1.5 g/dL)

          -  Non-IgG M protein (including IgA)

        Low-Risk Smoldering Multiple Myeloma

        Must only present with 1 of the following criterion:

          -  Monoclonal Protein ≥ 3 g/dL

             ---≥ 10% Bone Marrow Plasma Cells

          -  FLC ratio < 0.125 or > 8

             -No evidence of CRAB criteria† or new criteria of active MM which including the
             following:

               -  Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the upper
                  limit of normal or >0.275 mmol/dL)

               -  Renal insufficiency (attributable to myeloma)

               -  Anemia (Hb 2 g/dL below the lower limit of normal or <10 g/dL)

               -  Bone lesions (lytic lesions or generalized osteoporosis with compression
                  fractures)

               -  No evidence of the following new criteria for active MM including the following:
                  Bone marrow plasma cells >60%, Serum involved/uninvolved FLC ratio ≥100, and MRI
                  with more than one focal lesion

                    -  Participants with CRAB criteria that are attributable to conditions other
                       than the disease under study may be eligible

                    -  ECOG Performance Status (PS) 0, 1, or 2 (Appendix A)

                    -  The following laboratory values obtained ≤ 21 days prior to registration:

               -  ANC ≥ 1000/uL

               -  PLT ≥ 50,000/uL

               -  Total bilirubin ≤ 2.0 mg/dL (If total is elevated check direct and if normal
                  patient is eligible.)

               -  AST ≤ 3 x institutional upper limit of normal (ULN)

               -  ALT ≤ 3 x institutional upper limit of normal (ULN)

               -  Creatinine ≤ 2 mg/dL or Creatinine Clearance ≥ 40 mL/min

                    -  Ability to understand and the willingness to sign an informed consent before
                       performance of any study-related procedure not part of normal medical care,
                       with the understanding that consent may be withdrawn by the subject at any
                       time without prejudice to future medical care.

                    -  Female patients who are postmenopausal for at least 1 year before the
                       screening visit or are surgically sterile are eligible. Females of
                       childbearing potential (as defined below) may also be eligible but must have
                       a negative serum or urine pregnancy test with a sensitivity of at least 25
                       mIU/mL within 21 days of registration.

               -  A female of childbearing potential is a sexually mature female who:

          -  Has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral
             oophorectomy (the surgical removal of both ovaries)

        OR

        ---Has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule
        out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any
        time during the preceding 24 consecutive months)

        Exclusion Criteria:

          -  Any prior therapy for symptomatic Multiple Myeloma or smoldering Multiple Myeloma
             should also be excluded, including prior use of IMIDs, proteasome inhibitors, or CD138
             inhibitors. Prior therapy for smoldering Multiple Myeloma with agents that are not
             therapeutically active against MM is not an exclusion criterion.

          -  Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy
             considered investigational. Prior therapy with bisphosphonates is allowed. Prior
             radiation therapy to a solitary plasmacytoma is allowed.

          -  Concurrent exposure to any commercially available agents known to be active against
             SMM and MM.

          -  Serious medical or psychiatric illness likely to interfere with participation in this
             clinical study.

          -  Diagnosed or treated for another malignancy within 2 years of enrollment, with the
             exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
             the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

          -  Subject has known chronic obstructive pulmonary disease (COPD) with a Forced
             Expiratory Volume in 1 second (FEV1) < 50% of predicted normal.

          -  Note that FEV1 testing is required for patients suspected of having COPD and subjects
             must be excluded if FEV1 <50% of predicted normal.

               -  Subject has known moderate or severe persistent asthma within the past 2 years or
                  currently has uncontrolled asthma of any classification.

               -  Subjects who currently have controlled intermittent asthma or controlled mild
                  persistent asthma are allowed in the study

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris,
             uncontrollable cardiac arrhythmia, or psychiatric illness/social situations that would
             limit compliance with study requirements.

          -  Pregnant or nursing women will be excluded from the study.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to Daratumumab.

          -  Known seropositive for or active viral infection with human immunodeficiency virus
             (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are
             seropositive because of hepatitis B virus vaccine are eligible. Patients who are
             positive for hepatitis B core antibody or hepatitis B surface antigen must have a
             negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR
             positive will be excluded.

          -  Major surgery within 4 weeks before enrollment.

          -  Subject is known or suspected of not being able to comply with the study protocol (eg,
             because of alcoholism, drug dependency, or psychological disorder). Subject has any
             condition for which, in the opinion of the investigator, participation would not be in
             the best interest of the subject (eg, compromise the well-being) or that could
             prevent, limit, or confound the protocol-specified assessments.

          -  Vaccination with live attenuated vaccines within 4 weeks of first study agent
             administration

          -  Subject has clinically significant cardiac disease, including significant ischemic
             coronary disease, congestive heart failure (New York Heart Association [NYHA] Class
             III or IV), unstable arrhythmias, myocardial infarction or unstable angina within 6
             months before randomization, a history of additional risk factors for torsades de
             pointes (eg, electrolyte abnormalities, family history of Long QT Syndrome), or a
             family history of sudden cardiac death before age 40.

          -  Participation in other therapeutic clinical trials, including those with other
             investigational agents not included in this trial, within 30 days of the start of this
             trial and throughout the duration of this trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The Proportion Of Patients In Deep Response
Time Frame:2 years
Safety Issue:
Description:To determine the proportion of patients who are in VGPR or better after twenty cycles of therapy with Daratumumab. This will be determined at the time of best overall response. The estimate and the two-sided 90% binomial confidence interval will be provided in the analysis.

Secondary Outcome Measures

Measure:Objective Response Rate
Time Frame:2 years
Safety Issue:
Description:The objective response rate (partial response or better according to the modified IMWG criteria) and the proportion of patients with a MRD, CR, PR or MR will be reported with 90% exact binominal confidence interval (CI). The exact two-sided 90% CI around response rate will be no wider than 28% with 40 eligible patients.
Measure:Duration of Response
Time Frame:2 years
Safety Issue:
Description:To estimate the duration of response (time from objective response to disease progression or death, or date last known progression-free and alive for those who have not progressed or died) the Kaplan-Meier method will be used.
Measure:Complete Response Rate
Time Frame:2 years
Safety Issue:
Description:The duration of overall CR is progression or death. Patients who have not progressed or died are censored at the date last known progression-free.
Measure:Overall Response Rate
Time Frame:2 years
Safety Issue:
Description:The duration of overall response is measured as the time from initiation of first response to first documentation of disease progression or death. Patients who have not progressed or died are censored at the date last known progression-free.
Measure:Progression Free Survival
Time Frame:2 years
Safety Issue:
Description:PFS is defined as the time from first-dose to the disease progression or death from any cause. Patients who have not progressed or died are censored at the date last known progression-free.
Measure:Incidence of Treatment Emergent Adverse Events (Safety and Tolerability)
Time Frame:2 years
Safety Issue:
Description:Safety analysis will be conducted using the Safety Population defined as any patient receiving one dose of study treatment. For toxicity reporting, all adverse events and laboratory abnormalities will be graded and analyzed using CTCAE version 4 as appropriate.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Smoldering Multiple Myeloma
  • Monoclonal Gammopathy

Last Updated

January 27, 2020