Clinical Trials /

KRDI in Transplant-Eligible MM

NCT04430894

Description:

This research study is testing the efficacy of an experimental drug combination for people with newly diagnosed multiple myeloma that are eligible for a stem cell transplant. The names of the study drugs involved in this study are: - Carfilzomib - Isatuximab - Lenalidomide - Dexamethasone

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: KRDI in Transplant-Eligible MM
  • Official Title: A Phase II Study of Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Isatuximab in Newly Diagnosed, Transplant-Eligible Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: 19-568
  • NCT ID: NCT04430894

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
CarfilzomibKyprolisInduction
IsatuximabSarclisaInduction
LenalidomideREVLIMIDInduction
DexamethasoneDecadronInduction

Purpose

This research study is testing the efficacy of an experimental drug combination for people with newly diagnosed multiple myeloma that are eligible for a stem cell transplant. The names of the study drugs involved in this study are: - Carfilzomib - Isatuximab - Lenalidomide - Dexamethasone

Detailed Description

      This is a phase II study to evaluate the efficacy of once weekly carfilzomib, lenalidomide,
      dexamethasone, and isatuximab (KRDI) in patients with newly diagnosed, transplant-eligible
      multiple myeloma. The research study procedures include screening for eligibility and study
      treatment including evaluations and follow up visits. The study treatment portion of this
      study is comprised of an induction phase and a maintenance phase.

        -  Induction Phase :

             -  All participants will receive the same study drugs (carfilzomib, isatuximab,
                lenalidomide, and dexamethasone) for up to 8 cycles. Each cycle is 28 days in
                length.

             -  All participants will perform stem cell collection after 4 cycles of therapy. Based
                on the recommendation participants may or may not proceed to an autologous stem
                cell transplant (SCT) as part of induction therapy.

        -  Maintenance Phase: During maintenance, participants will receive the study treatment for
           up to two years after induction until progressive disease or unacceptable toxicity

      It is expected that about 50 people will take part in this research study.

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational drug combination to learn whether the drug
      combination works in treating a specific disease.

      "Investigational" means that the drug combination is being studied.

      The U.S. Food and Drug Administration (FDA) has approved carfilzomib or isatuximab as a
      treatment for relapsed/refractory multiple myeloma.

      The FDA has also approved lenalidomide and dexamethasone as a treatment option for
      transplant-eligible multiple myeloma.

      However, the FDA has not approved the combination of isatuximab, carfilzomib, lenalidomide,
      and dexamethasone as an approved regimen. The combination is considered to be investigational
      for the treatment of individuals with newly diagnosed multiple myeloma.
    

Trial Arms

NameTypeDescriptionInterventions
InductionExperimentalAll participants will receive the same study drugs up to 8 cycles. Carfilzomib, Isatuximab, Lenalidomide, Dexamethasone: Each cycle is 28 days in length. Stem cell collection after 4 cycles of therapy. Based on the recommendation participants may or may not proceed to an autologous stem cell transplant (SCT) as part of induction therapy. Up Front Autologous Stem Cell Transplant: --- 4 cycles of treatment, followed by stem cell collection, high-dose chemotherapy, and autologous SCT followed by 2 additional cycles of therapy (called consolidation) and then maintenance. Deferring Stem Cell Transplant: Deferring SCT following collection: 4 cycles of treatment, followed by stem cell collection followed by 4 additional cycles of therapy and then maintenance
  • Carfilzomib
  • Isatuximab
  • Lenalidomide
  • Dexamethasone
Maintenance-High RiskExperimentalExperimental: Maintenance The treatment participants will receive for maintenance will be based on the biological features (or cytogenetics) of participants myeloma and categorized into two groups: Standard-risk and High Risk. High Risk: All participants will receive study treatment for up to two years after induction until progressive disease (PD) or unacceptable toxicity Lenalidomide Carfilzomib Isatuximab
  • Carfilzomib
  • Isatuximab
  • Lenalidomide
  • Dexamethasone
Maintenance- Standard RiskExperimentalThe treatment participants will receive for maintenance will be based on the biological features (or cytogenetics) of participants myeloma and categorized into two groups: Standard-risk and High Risk Lenalidomide - Standard of care All participants will receive study treatment for up to two years after induction until progressive disease (PD) or unacceptable toxicity
  • Lenalidomide

Eligibility Criteria

        Inclusion Criteria:

          -  Subject must be at least 18 years of age.

          -  Subject must have documented multiple myeloma satisfying the CRAB criteria and
             measurable disease defined as:

               -  Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy-proven
                  Plasmacytoma.

               -  Measurable disease as defined by any of the following:

               -  IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥.5 g/dL or urine
                  M-protein level ≥200 mg/24 hours; or

               -  IgA, IgM, or IgD multiple myeloma: serum M-protein level ≥0.25 g/dL or urine
                  M-protein level ≥200 mg/24 hours; or

               -  Light chain multiple myeloma: Serum immunoglobulin free light chain ≥10 mg/dL and
                  abnormal serum immunoglobulin kappa lambda free light chain ratio.

               -  Sixty percent or greater clonal plasma cells on bone marrow examination.

               -  Serum involved / uninvolved free light chain ratio of 100 or greater, provided
                  the absolute level of the involved free light chain is at least 100 mg/L (a
                  patient's "involved" free light chain - either kappa or lambda - is the one that
                  is above the normal reference range; the uninvolved light chain is the one that
                  typically is in, or below, the normal range).

               -  More than one focal lesion on magnetic resonance image (MRI) that is at least 5
                  mm or greater in size.

          -  Newly diagnosed and considered candidate for high-dose chemotherapy with stem cell
             transplant.

          -  Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status
             score of 0, 1, or 2.

          -  Subject must have pretreatment clinical laboratory values meeting the following
             criteria during the Screening Phase:

               -  hemoglobin ≥ 7.5 g/dL (≥ mmol/L; prior RBC transfusion or recombinant human
                  erythropoietin use is permitted);

               -  absolute neutrophil count ≥1.0 x 109/L (granulocyte colony stimulating factor
                  [GCSF] use is permitted);

               -  platelet count ≥70 x 109/L for subjects in whom <50% of bone marrow nucleated
                  cells are plasma cells; otherwise platelet count >50 × 109/L (transfusions are
                  not permitted to achieve this minimum platelet count)

               -  aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN);

               -  alanine aminotransferase (ALT) ≤2.5 x ULN;

               -  total bilirubin ≤2.0 x ULN, except in subjects with congenital bilirubinemia,
                  such as Gilbert syndrome (direct bilirubin ≤2.0 x ULN)

               -  creatinine clearance ≥30 mL/min

               -  corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L); or free ionized calcium <6.5
                  mg/dL (<1.6 mmol/L).

          -  Women of childbearing potential must commit to either abstain continuously from
             heterosexual sexual intercourse or to use 2 methods of reliable birth control
             simultaneously. This includes one highly effective form of contraception (tubal
             ligation, intrauterine device [IUD], hormonal [birth control pills, injections,
             hormonal patches, vaginal rings or implants] or partner's vasectomy) and one
             additional effective contraceptive method (male latex or synthetic condom, diaphragm,
             or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable
             contraception is indicated even where there has been a history of infertility, unless
             due to hysterectomy or bilateral oophorectomy.

          -  A man who is sexually active with a woman of childbearing potential must agree to use
             a latex or synthetic condom, even if they had a successful vasectomy. All men must
             also not donate sperm during the study, for 4 weeks after the last dose of
             lenalidomide, for 90 days after the last dose of carfilzomib, and for 4 months after
             the last dose of isatuximab.

          -  A woman of childbearing potential must have 2 negative serum or urine pregnancy tests
             at Screening, first within 10 to 14 days prior to dosing and the second within 24
             hours prior to dosing.

          -  Each subject (or their legally acceptable representative) must sign an informed
             consent form (ICF) indicating that he or she understands the purpose of and procedures
             required for the study and are willing to participate in the study. Subject must be
             willing and able to adhere to the prohibitions and restrictions specified in this
             protocol, as referenced in the ICF.

        Exclusion Criteria:

          -  Any potential subject who meets any of the following criteria will be excluded from
             participating in the study.

          -  Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined
             significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined
             significance is defined by presence of serum M-protein <3 g/dL; absence of lytic bone
             lesions, anemia, hypercalcemia, and renal insufficiency related to the M-protein; and
             (if determined) proportion of plasma cells in the bone marrow of 10% or less.
             Smoldering multiple myeloma is defined as asymptomatic MM with absence of related
             organ or tissue impairment end organ damage.

          -  Subject has a diagnosis of Waldenström's disease, or other conditions in which IgM
             M-protein is present in the absence of a clonal plasma cell infiltration with lytic
             bone lesions

          -  Subject has prior or current systemic therapy or SCT for MM, with the exception of an
             emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4
             days) of corticosteroids before treatment.

          -  Subject has a history of malignancy (other than MM) within 5 years before the date of
             enrollment (exceptions are squamous and basal cell carcinomas of the skin and
             carcinoma in situ of the cervix, or malignancy that in the opinion of the
             investigator, with concurrence with the sponsor's medical monitor, is considered cured
             with minimal risk of recurrence within 5 years).

          -  Subject has had radiation therapy within 14 days of enrollment.

          -  Subject has had plasmapheresis within 28 days of enrollment.

          -  Subject is exhibiting clinical signs of meningeal involvement of MM.

          -  Subject has known chronic obstructive pulmonary disease (COPD) (defined as a forced
             expiratory volume [FEV] in 1 second <60% of predicted normal), persistent asthma, or a
             history of asthma within the last 2 years (intermittent asthma is allowed). Subjects
             with known or suspected COPD or asthma must have a FEV1 test during screening.

          -  Subject is known to be seropositive for history of human immunodeficiency virus (HIV)
             or known to have active hepatitis B or hepatitis C.

          -  Subject has any concurrent medical or psychiatric condition or disease (eg, active
             systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary
             disease) that is likely to interfere with the study procedures or results, or that in
             the opinion of the investigator, would constitute a hazard for participating in this
             study.

          -  Subject has clinically significant cardiac disease, including:

               -  myocardial infarction within 1 year before enrollment, or an unstable or
                  uncontrolled disease/condition related to or affecting cardiac function (eg,
                  unstable angina, congestive heart failure, New York Heart Association Class
                  III-IV;

               -  uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology
                  Criteria for Adverse Events [NCI CTCAE] Version 4 Grade ≥2) or clinically
                  significant ECG abnormalities;

               -  screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's
                  formula (QTcF) >470 msec.

               -  uncontrolled hypertension

          -  Subject has known allergies, hypersensitivity, or intolerance to corticosteroids,
             monoclonal antibodies or human proteins, or their excipients (refer to respective
             package inserts or IB) or known sensitivity to mammalian-derived products.

          -  Subject has plasma cell leukemia (according to World Health Organization [WHO]
             criterion: ≥20% of cells in the peripheral blood with an absolute plasma cell count of
             more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,
             monoclonal protein, and skin changes).

          -  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.

          -  Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant
             while enrolled in this study within 30 days after the last dose of lenalidomide or
             carfilzomib, or within 4 months after the last dose of isatuximab. Or, subject is a
             man who plans to father a child while enrolled in this study, within 4 weeks after the
             last dose of lenalidomide, within 90 days of the last dose of carfilzomib, or within 4
             months after the last dose of isatuximab.

          -  Subject has had major surgery within 2 weeks before enrollment or has not fully
             recovered from surgery, or has surgery planned during the time the subject is expected
             to participate in the study. Kyphoplasty or vertebroplasty is not considered major
             surgery.

          -  Subject has received an investigational drug (including investigational vaccines) or
             used an invasive investigational medical device within 4 weeks before enrollment or is
             currently enrolled in an interventional investigational study.

          -  Subject has contraindications to required prophylaxis for deep vein thrombosis and
             pulmonary embolism.

          -  Incidence of gastrointestinal disease that may significantly alter the absorption of
             oral drugs.

          -  Peripheral neuropathy ≥ Grade 2 on clinical examination during the screening period.

          -  Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong
             inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole,
             ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin,
             rifapentine, rifabutin, carbamazepine, phenytoin, phenobartital), or use of Ginkgo
             biloba, St. John's wort within 14 days before the first dose of study treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Response (CR + stringent CR) rate
Time Frame:112 Days
Safety Issue:
Description:International Myeloma Working Group (IMWG) Uniform Response criteria after 4 cycles of KRDI.

Secondary Outcome Measures

Measure:Overall Response Rate
Time Frame:24 Months
Safety Issue:
Description:Overall response rate will be percent of patients who achieve at least partial response (PR).
Measure:Minimal residual disease (MRD) Rate
Time Frame:112 Days (4 Cycles)
Safety Issue:
Description:Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)
Measure:Minimal residual disease (MRD) Rate
Time Frame:168 Days (6 cycles, upfront transplant)
Safety Issue:
Description:Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)
Measure:Minimal residual disease (MRD) Rate
Time Frame:224 Days (8 cycles transplant-deferred)
Safety Issue:
Description:Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)
Measure:Minimal residual disease (MRD) Rate
Time Frame:24 Months
Safety Issue:
Description:Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)
Measure:Progression Free Survival
Time Frame:time from first dose of study treatment to the first documentation of PD or death from any cause during study up to 3 years
Safety Issue:
Description:Kaplan-Meier curves will be used to characterize the time-to-event outcomes
Measure:Overall Survival
Time Frame:First dose of study treatment to death from any cause up to 3 years
Safety Issue:
Description:Kaplan-Meier curves will be used to characterize the time-to-event outcomes
Measure:Number of Participants with Treatment-Related Adverse Events as NCI CTCAE Version 5.0 severity grades.
Time Frame:From the time of first treatment to treatment discontinuation (30 [d ± 7] days after last dose) up to 3 years
Safety Issue:
Description:NCI CTCAE Version 5.0 severity grades.
Measure:Complete Response rate (Transplant)
Time Frame:168 Days
Safety Issue:
Description:IMWG Uniform Response Criteria Complete response (CR + stringent CR) rate after 6 cycles in patients who undergo transplant
Measure:Complete Response rate (Transplant Deferred)
Time Frame:224 Days
Safety Issue:
Description:IMWG Uniform Response Criteria Complete response (CR + stringent CR) rate after 8 cycles in patients who do not undergo transplant
Measure:Complete Response rate (All )
Time Frame:24 Months
Safety Issue:
Description:IMWG Uniform Response Criteria

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Massachusetts General Hospital

Trial Keywords

  • Multiple Myeloma

Last Updated

June 11, 2020