Clinical Trials /

Study of Selinexor Plus DRd for Newly Diagnosed Multiple Myeloma

NCT04782687

Description:

This is a single-arm, phase II, open-label trial to investigate the effects of selinexor (S) in combination with daratumumab, lenalidomide, and dexamethasone (DRd) for first-line treatment of multiple myeloma (MM). FDA has approved selinexor plus dexamethasone in multiple myeloma after four prior therapies, and DRd is also already approved by the FDA for multiple myeloma. This study will use all four (S-DRd) together to treat MM as an initial treatment.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Study of Selinexor Plus DRd for Newly Diagnosed Multiple Myeloma
  • Official Title: A Phase II Trial of Daratumumab, Lenalidomide and Dexamethasone (DRd) in Combination With Selinexor for Patients With Newly Diagnosed Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: 20285
  • SECONDARY ID: IST-337
  • NCT ID: NCT04782687

Conditions

  • Multiple Myeloma
  • Myeloma Multiple
  • Kahler Disease
  • Myeloma, Plasma Cell
  • Myeloma-Multiple
  • Myelomatosis
  • Plasma Cell Myeloma

Interventions

DrugSynonymsArms
SelinexorXpovioSelinexor plus DRd
Dexamethasone OralSelinexor plus DRd
DaratumumabDarzalexSelinexor plus DRd
LenalidomideRevlimidSelinexor plus DRd

Purpose

This is a single-arm, phase II, open-label trial to investigate the effects of selinexor (S) in combination with daratumumab, lenalidomide, and dexamethasone (DRd) for first-line treatment of multiple myeloma (MM). FDA has approved selinexor plus dexamethasone in multiple myeloma after four prior therapies, and DRd is also already approved by the FDA for multiple myeloma. This study will use all four (S-DRd) together to treat MM as an initial treatment.

Detailed Description

      Multiple myeloma (MM) is an incurable disease with high death rates as a result of developing
      resistance to treatments. Even with the advent of novel therapies, myeloma patients
      ultimately progress from frontline therapy. Common treatments include glucocorticoids,
      chemotherapy, proteasome inhibitors (PIs), Immunomodulatory imide drugs (IMiDs), stem cell
      transplants, and radiation therapy. Optimal frontline therapy with deeper remissions
      translates to improved overall survival and progression free survival. The purpose of this
      study is to investigate and improve upon reported outcomes in the frontline setting.

      Selinexor has shown potent anti-myeloma activity in preclinical models of MM and Phase 1,
      Phase 2 clinical studies as well as in a randomized phase 3 clinical trial called BOSTON.
      Selinexor was approved by the US FDA in July 2019 in combination with dexamethasone for the
      treatment of adult patients relapsed/refractory (RR) MM who have received at least four prior
      therapies and whose disease is refractory to at least two proteasome inhibitors, at least two
      immunomodulatory agents, and an anti-CD38 (anti-cluster of differentiation 38) monoclonal
      antibody. In June 2020, Selinexor was approved as a monotherapy by the FDA for adult patients
      with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 lines of
      systemic therapy.

      Treatment with combination therapies including daratumumab, lenalidomide, and dexamethasone
      has shown improvement in response rates, time to progression, and survival. Daratumumab is an
      approved CD38-directed cytolytic antibody used as a monotherapy for patients with heavily
      pre-treated MM, and in combination with lenalidomide and dexamethasone. The risk of death or
      disease progression was 44% lower and increased overall response rate (ORR) of 92.9% was
      observed in patients with newly diagnosed MM that received the triplet combination of
      daratumumab, lenalidomide, and dexamethasone (DRd) compared to lenalidomide and dexamethasone
      alone (Rd).

      Tolerability of the DRd combination in patients was consistent between DRd and Rd treatments.
      The safety profile of DRd was shown to be consistent with known safety profiles of
      daratumumab and Rd. Higher rates of infections (upper respiratory tract infection and
      pneumonia) and neutropenia in DRd treated patients than in Rd treated patients were observed.
      However, grade 3 or 4 infections were similar between DRd and Rd treatment groups and were
      managed by standard of care. After exposure to DRd for a median of 34 months, no new safety
      concerns were observed in the extended follow-up of the POLLUX phase III study.

      Preclinical data demonstrated that patient-derived MM cells were sensitized to the
      combination of Selinexor and daratumumab compared to the single agents. Clinical data
      demonstrate an ORR of 74% in patients with relapsed myeloma treated with Selinexor,
      daratumumab, and dexamethasone.

      The rationale for the combination of Selinexor, lenalidomide, daratumumab, and dexamethasone
      (S-DRd) in the current study is based on the following: preclinical synergistic activities
      observed with Selinexor and dexamethasone, the preclinical activity of Selinexor combined
      with both lenalidomide and daratumumab; as well as the clinical experience of the combination
      of Selinexor and lenalidomide/dexamethasone can be safely combined with 92% ORR in patients
      with relapsed myeloma; and the combination of Selinexor and daratumumab/dexamethasone can
      also be safely combined with an ORR of 74%. There is an urgent need to induce more efficient,
      deeper and durable responses in patients with newly diagnosed MM.
    

Trial Arms

NameTypeDescriptionInterventions
Selinexor plus DRdExperimentalLenalidomide orally on Days 1-21 of each 28-day cycle Transplant ineligible patients will receive lenalidomide at 15mg dose level. Transplant eligible patients will receive lenalidomide at 20 mg dose level. Dexamethasone 40 mg on Days 1, 8, 15, 22 of each cycle Daratumumab 1800 mg subcutaneous injection once weekly in Cycles 1 and 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter. Selinexor 60 mg on Days 1, 8, 15, of cycles 1-3, with a planned dose-reduction to 40 mg on Days 1, 8, 15 for cycles beyond 3.
  • Selinexor
  • Dexamethasone Oral
  • Daratumumab
  • Lenalidomide

Eligibility Criteria

        Inclusion Criteria:

          1. At least 18 years of age.

          2. Have documented multiple myeloma as defined by the International Myeloma Working Group
             (IMWG) 2015 criteria below:

             Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary
             plasmacytoma. * In addition, the patient must meet one of the criteria in either 2a or
             2b.

               1. Evidence of end organ damage that can be attributed to the underlying plasma cell
                  proliferative disorder, specifically at least one of the following:

                    -  i. Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the
                       upper limit of normal (ULN) or >2.75 mmol/L (>11 mg/dL)

                    -  ii. Renal insufficiency: creatinine clearance 20-40 mL per min or serum
                       creatinine >177 μmol/L (>2 mg/dL)

                    -  iii. Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or
                       a hemoglobin value <100 g/L*

                    -  iv. * Using Calcium elevation, Renal dysfunction, Anemia, and Bone disease
                       (CRAB) criteria Bone lesions: one or more osteolytic lesions on skeletal
                       radiography, or CT (computed tomography) **.

               2. Any one or more of the following:

                    -  i. Clonal bone marrow plasma cell percentage* ≥60%

                    -  ii. Involved: uninvolved serum free light chains (FLC) ratio*** >100

                    -  iii. >1 focal lesions on MRI (magnetic resonance imaging) studies; Each
                       focal lesion must be 5 mm or more in size.

                    -  Clonality should be established by showing κ/λ-light-chain restriction on
                       flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow
                       plasma cell percentage should preferably be estimated from a core biopsy
                       specimen; in case of a disparity between the aspirate and core biopsy, the
                       highest value should be used.

                    -  If bone marrow has less than 10% clonal plasma cells, more than one bone
                       lesion is required to distinguish from solitary plasmacytoma with minimal
                       marrow involvement.

                    -  These values are based on the serum Freelite assay. The involved FLC must be
                       ≥100 mg/L.

          3. Have measurable disease as defined by any of the following:

               1. Serum M-protein level ≥1.0 g/dL or urine M protein level ≥200 mg/24 hours; or

               2. Immunoglobulins A, D, E or M multiple myeloma: serum M-protein level ≥0.5 g/dL or
                  urine M-protein level ≥200 mg/24 hours; or

               3. Light chain multiple myeloma without measurable disease in the urine: serum Ig
                  FLC ≥10 mg/dL and abnormal serum Ig kappa/lambda FLC ratio

          4. Have previously untreated myeloma. For previously untreated patients an emergency
             course of steroids (defined as no greater than 40 mg of dexamethasone, or equivalent
             per day for a maximum of 4 days) is permitted. In addition, radiation therapy is
             permitted prior to study entry, during screening, and during Cycles 1-2 of study
             treatment as needed for lytic bone disease.

          5. Have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or
             2.

          6. Female patients of childbearing potential must have a negative serum pregnancy test at
             screening and agree to use highly effective methods of contraception throughout the
             study and for 90 days following the last dose of study treatment. Childbearing
             potential excludes: Age >50 years and naturally amenorrhoeic for >1 year, or previous
             bilateral salpingo-oophorectomy, or hysterectomy.

          7. Male patients who are sexually active must use highly effective methods of
             contraception throughout the study and for 4 weeks after receiving the last dose of
             study drug. Male patients must agree not to donate sperm during the study treatment
             period and for 3 months after receiving the last dose of study drug.

          8. Patients must be willing and able to adhere to the prohibitions and restrictions
             specified in this protocol and referenced in the informed consent form (ICF).

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

        Exclusion Criteria:

          1. Exhibiting clinical signs of or has a known history of meningeal or central nervous
             system involvement by multiple myeloma.

          2. Is known to be seropositive for human immunodeficiency virus, known to have hepatitis
             B surface antigen positivity, or known to have a history of hepatitis C.

             Patients who completed treatment for hepatitis C and have no detectable circulating
             hepatitis C virus (HCV) by hepatitis C RNA polymerase chain reaction (PCR) for at
             least 6 months prior to screening and have no detectable, may participate in the
             study.

             Such patients will be required to undergo regular assessment for HCV reactivation
             during their participation in the study. Patients who test positive for HCV at any
             time during these assessments will be withdrawn from the study.

          3. Has any concurrent medical condition or disease (e.g., active systemic infection) that
             is likely to interfere with study procedures or results, or that in the opinion of the
             investigator would constitute a hazard for participating in this study.

          4. Has clinically significant cardiac disease, including:

               -  Myocardial infarction (MI) within 6 months before first day of first cycle
                  (C1D1), or unstable or uncontrolled disease/condition related to or affecting
                  cardiac function (e.g., unstable angina, congestive heart failure, New York Heart
                  Association Class III-IV)

               -  Uncontrolled cardiac arrhythmia (NCI-CTCAE Version 5.0 Grade 2 or higher) or
                  clinically significant electrocardiogram (ECG) abnormalities

          5. Screening 12-lead ECG shows a baseline QT interval (QTc) >470 msec

          6. Has any of the following laboratory test results during the screening phase:

               -  Absolute neutrophil count ≤1.0 × 109 /L; (granulocyte colony stimulating factor
                  use is permitted)

               -  Hemoglobin level ≤7.5 g/dL (≤5 mmol/L); blood transfusions to maintain hemoglobin
                  >7.5 are acceptable

               -  Platelet count <75 × 109 /L for patients in whom <50% of bone marrow nucleated
                  cells are plasma cells; otherwise platelet count <50 × 109 /L; no platelet
                  transfusions in the past 7 days are allowed

               -  Alanine aminotransferase (ALT) level ≥2.5 × upper limit of normal (ULN)

               -  Aspartate aminotransferase (AST) level ≥2.5 × ULN

               -  Total bilirubin level ≥1.5 × ULN, (except for Gilbert Syndrome: direct bilirubin
                  2 × ULN)

               -  Creatinine clearance ≤20 mL/min estimated using Cockcroft-Gault;

          7. Has known allergies, hypersensitivity, or intolerance to monoclonal antibodies or
             human proteins, daratumumab or its excipients (refer to Investigator's Brochure), or
             known sensitivity to mammalian-derived products

          8. Has plasma cell leukemia (>2.0 × 109 /L circulating plasma cells by standard
             differential), Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy,
             organomegaly, endocrinopathy, monoclonal protein, and/or skin changes), or amyloid
             light-chain amyloidosis

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

         10. Is considering becoming pregnant Has any condition for which, in the opinion of the
             investigator, participation would not be in the best interest of the patient (e.g.,
             compromise the well-being) or that could prevent, limit, or confound the protocol-
             specified assessments

         11. Has had major surgery within 2 weeks before C1D1, or will not have fully recovered
             from surgery, or has surgery planned during the time the patient is expected to
             participate in the study or within 2 weeks after the last dose of study drug
             administration. (Note: patients with planned surgical procedures to be conducted under
             local anesthesia may participate. Kyphoplasty is not considered a major surgery.)

        NOTE: Investigators should ensure that all study enrollment criteria have been met at
        screening. If a patient's status changes (including laboratory results or receipt of
        additional medical records) after screening but before C1D1 such that he or she no longer
        meets all eligibility criteria, then the patient should be excluded from participation in
        the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Response Rate (CR)
Time Frame:6 months
Safety Issue:
Description:percentage of patients who had complete response. Complete response is when patients achieve a negative immunofixation on the serum and urine and who also have an appearance of a soft tissue plasmacytomas and achieve less than or equal to 5% plasma cells in the bone marrow.

Secondary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:3 years
Safety Issue:
Description:percentage of patients who had either CR or sCR or very good partial response (VGPR) or partial response (PR).
Measure:Time to Next Treatment (TTNT)
Time Frame:3 years
Safety Issue:
Description:the median interval between the date of study treatment initiation and the date of start of a new treatment
Measure:Duration of Response
Time Frame:3 years
Safety Issue:
Description:the median time from first documented evidence of PR, CR,or sCR to date of progression or death or last date of contact for patients who did not progress or die
Measure:Progression-Free Survival (PFS)
Time Frame:3 years
Safety Issue:
Description:the median time from randomization until the date of disease progression or death (by any cause in the absence of progression), regardless of whether the subject withdraws from the assigned study treatment
Measure:Overall Survival (OS)
Time Frame:3 years
Safety Issue:
Description:the median time from randomization until death due to any cause or date of last contact for alive patients
Measure:Minimal Residual Disease (MRD)
Time Frame:3 years
Safety Issue:
Description:number of patients who had CR or sCR and had: absence of phenotypically abnormal clonal plasma cells from bone marrow aspirates using either a validated next-generation flow method (e.g. EuroFlow) or next-generation DNA sequencing method (e.g. LymphoSIGHT) that can detect 1 in 10 thousand nucleated cells or better

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:US Oncology Research

Trial Keywords

  • myeloma
  • cancer
  • newly diagnosed multiple myeloma

Last Updated

March 4, 2021