Clinical Trials /

Study of SubQ Dara With Dose-Attenuated Bortezomib, Lenalidomide, Dexamethasone in Elderly NDMM

NCT04052880

Description:

This is a single center, open-label, phase 2 study in elderly (age > 70) subjects with newly diagnosed multiple myeloma who are transplant ineligible. Subjects will receive subcutaneous daratumumab, dose-attenuated bortezomib, revlimid, and dexamethasone until confirmed disease progression, discontinuation of study treatment due to unacceptable drug toxicity, or other reasons. Throughout the study, subjects will be monitored closely for adverse events, laboratory abnormalities, and clinical response.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of SubQ Dara With Dose-Attenuated Bortezomib, Lenalidomide, Dexamethasone in Elderly NDMM
  • Official Title: A Phase 2 Study of Subcutaneous Daratumumab in Combination With Dose-Attenuated Bortezomib, Lenalidomide, and Dexamethasone in Elderly Newly Diagnosed Multiple Myeloma Patients

Clinical Trial IDs

  • ORG STUDY ID: GCO 19-0944
  • NCT ID: NCT04052880

Conditions

  • Newly Diagnosed Multiple Myeloma

Interventions

DrugSynonymsArms
DaratumumabDaratumumab with dose-attenuated VRd
BortezomibDaratumumab with dose-attenuated VRd
LenalidomideDaratumumab with dose-attenuated VRd
DexamethasoneDaratumumab with dose-attenuated VRd
IxazomibDaratumumab with dose-attenuated VRd

Purpose

This is a single center, open-label, phase 2 study in elderly (age > 70) subjects with newly diagnosed multiple myeloma who are transplant ineligible. Subjects will receive subcutaneous daratumumab, dose-attenuated bortezomib, revlimid, and dexamethasone until confirmed disease progression, discontinuation of study treatment due to unacceptable drug toxicity, or other reasons. Throughout the study, subjects will be monitored closely for adverse events, laboratory abnormalities, and clinical response.

Detailed Description

      This is a single center, open-label, phase 2 study in elderly (age > 70) subjects with newly
      diagnosed multiple myeloma who are transplant ineligible. The main study consists of the
      following phases: a 28-day screening phase; followed by initial therapy with 12 cycles of
      daratumumab in combination with dose-attenuated VRd; and a maintenance phase that starts
      after Cycle 12 of therapy. Cycles are 28 days in length. Treatment can continue until disease
      progression or unacceptable toxicity. After 12 cycles of initial therapy, maintenance therapy
      will begin with 28 day cycles of daratumumab with either lenalidomide or ixazomib and the
      choice of maintenance therapy will be based on cytogenetic risk status at diagnosis. All
      subjects will continue maintenance treatment until disease progression, except maintenance
      daratumumab will be discontinued after 2 years if subjects remain on maintenance treatment at
      that time. All subjects will be followed in the longterm follow-up for at least 1 year after
      last dose of study treatment and will continue until death, withdrawal of consent for study
      participation, or the end of study definition is met. The end of study is defined as when all
      subjects have completed at least 1 year of long-term follow up and until death, withdrawal of
      consent for study participation, or 5 years after first patient begins daratumumab therapy,
      whichever occurs first.
    

Trial Arms

NameTypeDescriptionInterventions
Daratumumab with dose-attenuated VRdExperimentalSubQ Daratumumab with Dose-Attenuated VRd
  • Daratumumab
  • Bortezomib
  • Lenalidomide
  • Dexamethasone
  • Ixazomib

Eligibility Criteria

        Inclusion Criteria:

          -  Newly diagnosed, untreated, symptomatic MM as defined by standard criteria:Clonal bone
             marrow plasma cells >10% and presence of serum and/or urinary monoclonal protein and
             either evidence of end-organ damage that can be attributed to the underlying plasma
             cell proliferative disorder, specifically

               1. Hypercalcemia: serum calcium >11.5 mg/100 mL

               2. Renal insufficiency: serum creatinine >1.73 mmol/L

               3. Anemia: normochromic, normocytic with a hemoglobin value of >2 g/100 mL below the
                  lower limit of normal or a hemoglobin value <10 g/100 mL

               4. Bone lesions: lytic lesions, severe osteopenia or pathologic fractures

               5. Or Clonal bone marrow plasma cells greater than or equal to 60% or Serum free
                  light chain (FLC) ratio greater than or equal to 100 provided involved FLC level
                  is 100 mg/L or higher, or More than one focal lesion on MRI

          -  Age ≥ 70 and ineligible for autologous hematopoietic stem cell transplantation
             (defined as age, > 80 or age < 80 with cardiac/pulmonary/ or other comorbidities
             deemed by investigator likely to have a negative impact on tolerability of high dose
             chemotherapy with stem cell transplantation).

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

          -  Patients must have measurable disease defined by at least 1 of the following 3
             measurements:

          -  Serum M-protein > 1 g/dL (10 g/L) or > 0.5 g/dL if IgA

          -  Urine M-protein > 200 mg/24 hours.

          -  Serum free light chain assay: involved free light chain level >10 mg/dL (> 100 mg/L)
             provided the serum free light chain ratio is abnormal

          -  Due to the teratogenicity of lenalidomide and the lack of adequate reproductive
             toxicity data for daratumumab, if a male subject is sexually active with a woman of
             child bearing potential, in addition to the user independent highly effective method
             of contraception, a male or female condom with or without spermicide, diaphragm, or
             cervical cap is required. Male condom and female condom should not be used together
             (due to risk of failure with friction).

          -  During the study (including during dose interruptions), and for 4 weeks following
             discontinuation of lenalidomide, and if receiving daratumumab, for 3 months after the
             last dose, in addition to the user independent highly effective method of
             contraception (even if he has undergone a successful vasectomy), a man:

               1. Who is sexually active with a woman of childbearing potential must agree to use a
                  barrier method of contraception (ie, latex or synthetic condom with spermicidal
                  foam/gel/film/cream/suppository)

               2. Who is sexually active with a woman who is pregnant must use a latex or synthetic
                  condom.

               3. Must agree not to donate sperm

          -  Willing and able to adhere to the prohibitions and restrictions specified in this
             protocol and referenced in the informed consent form (ICF)

          -  Must sign an ICF (or their legally acceptable representative must sign) indicating
             that he or she understands the purpose of, and procedures required for, the study and
             is willing to participate in the study.

        Exclusion Criteria:

          -  Peripheral neuropathy > Grade 2 or >Grade 1 with pain on clinical examination during
             the Screening period.

          -  Kidney failure with CrCl ≤ 15 mL/min by Cockfraft Gault

          -  Significant cardiac disease as determined by the investigator including:

               1. Known or suspected cardiac amyloidosis

               2. Congestive heart failure of Class III or IV of the NYHA classification

               3. Uncontrolled angina, hypertension or arrhythmia

               4. Myocardial infarction in the past 6 months

               5. Any uncontrolled or severe cardiovascular disease

               6. QTc > 470 milliseconds (msec) on a 12-lead ECG obtained during the Screening
                  period. If a machine reading is above this value, the ECG should be reviewed by a
                  qualified reader and confirmed on a subsequent ECG or by manual calculation.

          -  Prior cerebrovascular event with persistent neurologic deficit.

          -  Subject is:

               1. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
                  antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg
                  negative but positive for antibodies to hepatitis B core antigen [anti-HBc]
                  and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened
                  using realtime polymerase chain reaction (PCR) measurement of hepatitis B virus
                  (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION:
                  Subjects with serologic findings suggestive of HBV vaccination (anti-HBs
                  positivity as the only serologic marker) AND a known history of prior HBV
                  vaccination, do not need to be tested for HBV DNA by PCR.

               2. Seropositive for hepatitis C (except in the setting of a sustained virologic
                  response [SVR], defined as aviremia at least 12 weeks after completion of
                  antiviral therapy).

          -  Human immunodeficiency virus infection

          -  Any medical conditions that, in the investigator's opinion, would impose excessive
             risk to the subject.

          -  Prior or concurrent malignancy, except for the following:

               1. Adequately treated basal cell or squamous cell skin cancer

               2. Cervical carcinoma in situ

               3. Adequately treated Stage I or II cancer from which the subject is currently in
                  complete remission.

               4. Or any other cancer from which the subject has been disease-free for ≥ 3 years

          -  Known GI disease or GI procedure that could interfere with the oral absorption or
             tolerance of study drug, including difficulty swallowing.

          -  Males sexually active with females of childbearing potential who do not agree to
             practice 2 effective methods of contraception, at the same time, from the time of
             signing the informed consent form (ICF) through 90 days after the last dose of study
             drug, or do not agree to practice true abstinence.

          -  Central nervous system involvement.

          -  Diagnosis of primary amyloidosis (with the exception of patients whose amyloidosis has
             been documented as a complication of MM, who will be evaluated on a case-by-case basis
             for trial participation).

          -  Infection requiring systemic antibiotic therapy or other serious infection within 14
             days before study drug administration.

          -  Known chronic obstructive pulmonary disease with a forced expiratory volume in 1
             second (FEV1) <50% of predicted normal (for subjects > 65 years old FEV1 <50% or DLCO
             <50%). Note: FEV1 testing is required for subjects suspected of having chronic
             obstructive pulmonary disease and subjects must be excluded if FEV1 <50% of predicted
             normal.

          -  Known moderate or severe persistent asthma within the past 2 years or currently has
             uncontrolled asthma of any classification. Note: Subjects who currently have
             controlled intermittent asthma or controlled mild persistent asthma are allowed in the
             study.

          -  Persistent corrected serum calcium ≥ 14 mg/dL within 2 weeks of enrollment (despite
             appropriate measure such a short course of steroids, bisphosphonates, hydration,
             calcitonin).

          -  Absolute neutrophil count < 1000 cells/mm3. No growth factors allowed within 1 week of
             enrollment.

          -  Platelets < 75,000 cell/mm3 (75 x 109/L). Qualifying laboratory value must occur at
             most recent measurement before enrollment and must be no more than 14 days before
             enrollment. No transfusions are allowed within 72 hours prior to study drug
             administration.

          -  Hemoglobin < 8 g/dL. Qualifying laboratory value must occur at most recent measurement
             before enrollment and must be no more than 14 days before enrollment. No transfusions
             are allowed within 72 hours before qualifying laboratory value.

          -  Total bilirubin > 1.5 x ULN, unless known have Gilbert's syndrome in which case 3 x
             ULN).

          -  AST or ALT ≥ 3 x ULN.

          -  Major surgery or radiation therapy within 14 days before study drug administration.

          -  Kyphoplasty or vertebroplasty within 1 week of enrollment.

          -  Administration of chemotherapy, biological, immunotherapy, or investigational agent
             (therapeutic or diagnostic) within 3 weeks before enrollment; however, a cumulative
             dose of ≤ 160 mg dexamethasone or equivalent during screening is permitted.

          -  NSAIDs, IV contrast, aminoglycosides, or other potentially nephrotoxic drugs within 2
             weeks of enrollment.

          -  Known hypersensitivity to bortezomib, lenalidomide, dexamethasone, or daratumumab
      
Maximum Eligible Age:N/A
Minimum Eligible Age:70 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Responses: VGPR or better
Time Frame:At the end of cycle 8, each cycle is 28 days
Safety Issue:
Description:≥ VGPR rate after 8 cycles of therapy, defined as the proportion of subjects who have achieved VGPR or better, according to the IMWG criteria.

Secondary Outcome Measures

Measure:Overall Response Rates
Time Frame:Within a year
Safety Issue:
Description:ORR (≥PR), CBR (≥SD), ≥CR, and sCR rates defined as the proportion of subjects who achieve each of these response categories (or better response category) according to the IMWG criteria
Measure:Duration of ORR (≥PR), ≥VGPR, ≥CR, and sCR
Time Frame:Within two years
Safety Issue:
Description:Defined as the duration from the date of initial attainment of a response category (or better response category), according to the IMWG criteria, to the date of first documented evidence of relapse from CR (or sCR) or progressive disease (PD)
Measure:Time to Overall Response Rate
Time Frame:Within a year
Safety Issue:
Description:Defined as the duration from the date of initial therapy to the date of attainment of a response category and was subsequently confirmed by a repeated measurement as required by the IMWG criteria
Measure:Time to Progression
Time Frame:Within 2 years
Safety Issue:
Description:Defined as the duration from the date of initial therapy to the date of first documented evidence of progressive disease according to the IMWG criteria
Measure:Progression Free Survival
Time Frame:Within 5 years
Safety Issue:
Description:Defined as the duration from the date of initial therapy to the date of first documented evidence of PD or death, whichever comes first
Measure:Overall Survival
Time Frame:Within 5 years
Safety Issue:
Description:Defined as the duration from the date of initial therapy to the date of the subject's death.
Measure:Number of Adverse Events
Time Frame:Within 5 years
Safety Issue:
Description:To assess safety and tolerability using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE Version 4.03)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Ajai Chari

Trial Keywords

  • Multiple myeloma
  • Newly diagnosed multiple myeloma
  • Myeloma
  • Elderly
  • Daratumumab

Last Updated

October 28, 2019