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Isa-KRd vs KRd in Newly Diagnosed Multiple Myeloma Patients Eligible for Autologous Stem Cell Transplantation (IsKia TRIAL) (IsKia)

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ClinicalTrials.gov Identifier: NCT04483739
Recruitment Status : Recruiting
First Posted : July 23, 2020
Last Update Posted : January 5, 2021
Sponsor:
Collaborators:
EMN Research Italy
Sanofi
Amgen
Information provided by (Responsible Party):
European Myeloma Network

Tracking Information
First Submitted Date  ICMJE June 23, 2020
First Posted Date  ICMJE July 23, 2020
Last Update Posted Date January 5, 2021
Actual Study Start Date  ICMJE September 25, 2020
Estimated Primary Completion Date July 31, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 20, 2020)
Rate of MRD negativity after ASCT consolidation treatment by NGS [ Time Frame: The end of consolidation, average of 12 months ]
The rate of MRD negativity is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level) after ASCT consolidation treatment using ITT principle. For patients who withdraw from the study or are lost to follow up before four post ASCT consolidation cycles, the best MRD assessment will be considered. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 20, 2020)
  • Post induction MRD negativity rate by NGS [ Time Frame: The end of induction, average of 4 months ]
    The rate of MRD negativity after induction is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level, NGS) after the induction phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment/sample not adequate.
  • Progression-free survival (PFS) in the 2 arms [ Time Frame: approximately up to 5 years ]
    PFS will be measured from the date of randomization to the date of first observation of PD, or death from any cause as an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. All subjects who were lost to FU will also be censored at the time of last complete disease assessment
  • Post light-consolidation MRD negativity rate by NGS [ Time Frame: At the end of light-consolidation, average of 24 months ]
    The rate of MRD negativity after light consolidation is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level, NGS) after light consolidation phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment/sample not adequate. Patients who withdraw from the study or are lost to follow up before MRD evaluation, the best MRD assessment will be considered
  • Overall Response Rate (ORR) post-induction [ Time Frame: Approx 4 months ]
    Response rate (sCR, CR, VGPR, PR, ORR) will be evaluated according to IMWG Response criteria after induction.
  • Overall Response Rate (ORR) post-transplant [ Time Frame: Approximately 8 months ]
    Response rate (sCR, CR, VGPR, PR, ORR) will be evaluated according to IMWG Response criteria after ASCT.
  • Overall Response Rate (ORR) post-consolidation [ Time Frame: Approximately 12 months ]
    Response rate (sCR, CR, VGPR, PR, ORR) will be evaluated according to IMWG Response criteria after consolidation.
  • Overall Response Rate (ORR) post light-consolidation [ Time Frame: Approximately 24 months ]
    Response rate (sCR, CR, VGPR, PR, ORR) will be evaluated according to IMWG Response criteria after light consolidation.
  • Post ASCT MRD negativity rate by NGS [ Time Frame: After ASCT, approximately 8 months. ]
    The rate of MRD negativity after ASCT is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level), NGS using ITT principle. For patients who withdraw from the study or are lost to follow up before ASCT, the best MRD assessment will be considered. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.
  • MRD negativity rate by NGF post induction [ Time Frame: Approximately 4 months ]
    The rate of MRD negativity (by NGF) after induction is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level) after the specific phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment. Patients who withdraw from the study or are lost to follow up before MRD evaluation phase, the best MRD assessment will be considered.
  • MRD negativity rate by NGF post induction [ Time Frame: Approximately 8 months ]
    The rate of MRD negativity (by NGF) after ASCT is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level) after the specific phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment. Patients who withdraw from the study or are lost to follow up before MRD evaluation phase, the best MRD assessment will be considered.
  • MRD negativity rate by NGF post consolidation [ Time Frame: Approximately 8 months ]
    The rate of MRD negativity (by NGF) after consolidation is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level) after the specific phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment. Patients who withdraw from the study or are lost to follow up before MRD evaluation phase, the best MRD assessment will be considered.
  • MRD negativity rate by NGF post light consolidation [ Time Frame: Approximately 24 months ]
    The rate of MRD negativity (by NGF) after light consolidation are determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level) after the specific phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment. Patients who withdraw from the study or are lost to follow up before MRD evaluation phase, the best MRD assessment will be considered.
  • Duration of response [ Time Frame: approximately up to 9 years ]
    Duration of response is defined as the time between first documentation of response (achievement of at least a PR) and PD with deaths owning to causes other than progression not counted, but censored. Responders without disease progression at the cut-off date of final analysis will be censored either at the time of lost to FU, at the time of death due to other cause than PD, or at the at the time of last contact
  • Duration of MRD negativity (by NGS and NGF) [ Time Frame: approximately up to 9 years ]
    The duration of MRD Negativity (by NGS and NGF) is defined as time between first MRD Negativity and first MRD positivity. Patients without MRD positivity will be censored at last complete assessment
  • Determine the rate of sustained for 1-year MRD negativity (by NGF and NGS) from post ASCT consolidation to post light consolidation [ Time Frame: approximately up to 9 years ]
    Rate of 1 year sustained MRD negativity by NGS (from post ASCT consolidation to post light consolidation) will be also evaluated.
  • Determine the time to progression (TTP) [ Time Frame: approximately up to 9 years ]
    From the date of randomization to the date of first disease progression or death per PD, whichever occurs first
  • Overall Survival (OS) [ Time Frame: approximately up to 9 years ]
    Overall Survival (OS), measured from the date of from randomization to the date the subject's death
  • Time to next therapy (TNT) [ Time Frame: approximately up to 9 years ]
    TNT will be measured from the date of randomization to the date of next anti-myeloma therapy. Death due to any cause before starting therapy will be considered an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. Subjects lost to FU will also be censored at the time of last contact.
  • Progression-free survival on the next line of therapy (PFS2) [ Time Frame: approximately up to 9 years ]
    Progression-free survival on the next line of therapy (PFS2) is defined as the time from randomization to progression on the next line of treatment or death, whichever comes first.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Isa-KRd vs KRd in Newly Diagnosed Multiple Myeloma Patients Eligible for Autologous Stem Cell Transplantation (IsKia TRIAL)
Official Title  ICMJE Phase III Study of Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone (Isa-KRd) Versus Carfilzomib-Lenalidomide-Dexamethasone (KRd) in Newly Diagnosed Multiple Myeloma Patients Eligible for Autologous Stem Cell Transplantation (IsKia TRIAL
Brief Summary This protocol is a phase III study designed to compare the efficacy and the safety of Isa-KRd induction, transplant, Isa-KRd post ASCT consolidation and Isa-KRd light consolidation vs KRd induction, transplant, KRd post ASCT consolidation and KRd light consolidation After confirmation of eligibility criteria patients will be randomized to one of the 2 treatment groups in a 1:1 randomization ratio.
Detailed Description This is a open-label randomized phase III study that enrolls newly diagnosed MM patient eligible for high-dose chemotherapy and ASCT. Patients will be randomized at enrolment (1:1, stratification according to ISS Stage [3 levels: I vs II vs III] and cytogenetic risk FISH [2 levels: high-risk vs standard risk/missing] based on presence of t(4;14), t(14;16), and/or del 17p)) into 2 treatment arms: -ARM A: induction with 4 cycles of Isatuximab-Carfilzomib-Lenalidomide-dexamethasone (Isa-KRd) followed by cyclophophamide and stem cell collections, chemotherapy with Melphalan 200 mg/m2 followed by ASCT (Mel200-ASCT), 4 cycles of Isa-KRd post ASCT consolidation and 12 cycles of Isatuximab-Lenalidomide-Carfilzomib-dexamethasone (IsaKRd) light consolidation; ARM B: induction with 4 cycles of Carfilzomib-Lenalidomide-dexamethasone (KRd) followed by cyclophophamide and stem cell collections, chemotherapy with Melphalan 200 mg/m2 followed by ASCT (Mel200-ASCT), 4 cycles of KRd post ASCT consolidation and 12 cycles of Carfilzomib-Lenalidomide-dexamethasone (KRd) light consolidation. Details of all treatments (dose and schedule) are given in paragraph 8. After light consolidation patients are allowed to receive Lenalidomide maintenance as per standard of care.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Multiple Myeloma
Intervention  ICMJE
  • Drug: Carfilzomib Lenalidomide Dexamethasone
    Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone (Isa-KRd) versus Carfilzomib-Lenalidomide-Dexamethasone (KRd) in newly diagnosed multiple myeloma patients eligible for autologous stem cell transplantation
    Other Name: KRd
  • Drug: Isatuximab Carfilzomib Lenalidomide Dexamethasone
    Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone (Isa-KRd) versus Carfilzomib-Lenalidomide-Dexamethasone (KRd) in newly diagnosed multiple myeloma patients eligible for autologous stem cell transplantation
    Other Name: Isa-KRD
Study Arms  ICMJE
  • Experimental: Krd Induction
    4 28 day cycles of Carfilzomib = 20 mg/m2 IV on day 1 cycle 1 only, followed by 56 mg/m2 IV on days 8, 15 cycle 1 and on days 1, 8, 15 for cycles 2-4 Lenalidomide= 25 mg orally daily on days 1-21 Dexamethasone = 40 mg orally/IV on days 1, 8, 15, 22
    Intervention: Drug: Carfilzomib Lenalidomide Dexamethasone
  • Experimental: Isa-KRd induction

    Isatuximab= 10 mg/kg IV on day 1, 8, 15, and 22 during Cycle 1, followed by 10 mg/kg IV on days 1 and 15 during Cycles 2 to 4.

    Carfilzomib = 20 mg/m2 IV on day 1 cycle 1 only, followed by 56 mg/m2 IV on days 8, 15 cycle 1 and on days 1, 8, 15 for cycles 2-4 Lenalidomide= 25 mg orally daily on days 1-21 Dexamethasone = 40 mg orally/IV on days 1, 8, 15, 22

    Intervention: Drug: Isatuximab Carfilzomib Lenalidomide Dexamethasone
  • Experimental: KRd post ASCT consolidation
    4 28 day cycles of Carfilzomib = 56 mg/m2 IV on days 1, 8, 15 cycle 5-8 Lenalidomide= 25 mg orally daily on days 1-21 Dexamethasone = 40 mg orally/IV on days 1, 8, 15, 22
    Intervention: Drug: Carfilzomib Lenalidomide Dexamethasone
  • Experimental: Isa-KRd post ASCT consolidation:
    4 28 day cycles of Isatuximab= 10 mg/kg IV on days 1 and 15 on cycles 5-8 Carfilzomib = 56 mg/m2 IV on days 1, 8, 15 cycle 5-8 Lenalidomide= 25 mg orally daily on days 1-21 Dexamethasone = 40 mg orally/IV on days 1, 8, 15, 22
    Intervention: Drug: Isatuximab Carfilzomib Lenalidomide Dexamethasone
  • Experimental: KRd light consolidation
    12 28 day cycles of Carfilzomib = 56 mg/m2 IV on days 1, 15 Lenalidomide = 10 mg orally on days 1-21 Dexamethasone = 20 mg orally/IV on days 1, 15
    Intervention: Drug: Carfilzomib Lenalidomide Dexamethasone
  • Experimental: Isa-KRd light consolidation
    Isatuximab= 10 mg/kg IV on day 1 Carfilzomib = 56 mg/m2 IV on days 1, 15 Lenalidomide = 10 mg orally on days 1-21 Dexamethasone = 20 mg orally/IV on days 1, 15
    Intervention: Drug: Isatuximab Carfilzomib Lenalidomide Dexamethasone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 20, 2020)
300
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2032
Estimated Primary Completion Date July 31, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patient with newly diagnosed multiple myeloma and eligible to ASCT.
  • Patient is, in the investigator's opinion, willing and able to comply with the study visits and procedures required per protocol.
  • Patient has provided written informed consent in accordance with federal, local, and institutional guidelines prior to initiation of any study-specific activities or procedures. Subject does not have kind of condition that, in the opinion of the Investigator, may compromise the ability of the subject to give written informed consent and patient is, in the investigator(s) opinion, willing and able to comply with the protocol requirements.
  • Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma and documented multiple myeloma satisfying at least one of the calcium, renal, anemia, bone (CRAB) criteria or biomarkers of malignancy criteria:
  • CRAB criteria:

    • Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than upper limit of normal (ULN) or >2.75 mmol/L (>11 mg/dL)
    • Renal insufficiency: creatinine clearance <40mL/min or serum creatinine >177 μmol/L (>2 mg/dL)
    • Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10 g/dL
    • Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT
  • Biomarkers of Malignancy:

    • Clonal bone marrow plasma cell percentage ≥60%
    • Involved: uninvolved serum FLC ratio ≥100
    • >1 focal lesion on magnetic resonance imaging (MRI) studies
  • Patient is 18 - 70 years old and is eligible for autologous stem cell transplantation
  • Patient has measurable disease as defined by any one of the following:

    • Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or
    • Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin FLC ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio.
  • Life expectancy ≥ 3 months
  • ECOG status ≤2
  • Clinical laboratory values meeting the following criteria during the Screening Phase:

    • Adequate hepatic function, with serum (alanine aminotransferase) ALT ≤ 2.5 times the upper limit of normal (ULN), AST (aspartate transaminase) ≤ 2.5 x the ULN
    • Serum direct bilirubin ≤ 1.5 ULN) (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubinemia ≤ 1.5 ULN)
    • Absolute neutrophil count (ANC) ≥ 1.0 × 109/L
    • Platelet count ≥ 75× 109/L (≥ 50× 109/L if myeloma involvement in the bone marrow is > 50%) and no platelet infusion in the 1 week prior to screening platelet count
    • Creatinine clearance (CrCl) ≥ 30 mL/minute. Creatinine clearance should be calculated using eGFR (Modified Diet in Renal Disese [MDRD])
    • Corrected serum calcium ≤ 13.5 mg/dL (3.4 mmol/L)
    • LVEF ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available.
  • Females of childbearing potential (FCBP)* complies with the conditions of the Pregnancy Prevention Plan, including confirmation that she has an adequate level of understanding and must agree to ongoing pregnancy testing and to practice contraception or true abstinence. FCBP must use a highly effective and an additional barrier contraception method simultaneously for 4 weeks before starting therapy, during treatment and dose interruptions and for 5 months after the last dose of study drugs.
  • Male subjects must agree to practice contraception if sexually active with FCBP during the treatment and for 5 months after the last dose of study drugs. Males must agree to refrain from donating sperm for at least 90 days after the last dose of carfilzomib and for at least 5 months after the last dose of isatuximab.
  • *Note 1: a FCBP is a woman who:
  • has achieved menarche at some time point,
  • has not undergone a hysterectomy or bilateral oophorectomy or,
  • has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).
  • Note 2: true abstinence is acceptable when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

  • Previous treatment with anti-myeloma therapy (does not include radiotherapy, biphosphonates, or a single short course of steroid ≤ to the equivalent of dexamethasone 40 mg/day for 4 days).
  • Patients with non-secretory MM unless serum free light chains are present and the ratio is abnormal or a plasmacytoma with minimum largest diameters of > 2 cm.
  • Patients with plasma cell leukemia, amyloidosis, Waldenstrom Disease, POEMS syndrome
  • Meningeal involvement of multiple myeloma
  • Patient ineligible for autologous transplantation
  • Pregnant or lactating females
  • Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomization
  • Known human immunodeficiency virus infection (HIV)
  • Active hepatitis A, B or C infection. Hepatitis C infection (subjects with hepatitis C that achieve a sustained virologic response after antiviral therapy are allowed), or hepatitis B infection (subjects with hepatitis B surface antigen or core antibody that achieve sustained virologic response with antiviral therapy are allowed). Tests to be performed if required per local country regulations. In fact it is not possible to avoid the risk of virological reactivation with the study treatments.
  • Unstable angina or myocardial infarction within 4 months prior to randomization, NYHA Class III or IV heart failure, uncontrolled angina, uncontrolled hypertension, (Uncontrolled hypertension, defined as an average systolic blood pressure ≥ 160 mmHg or diastolic ≥ 100 mmHg despite optimal treatment (measured following European Society of Hypertension/European Society of Cardiology 2013 guidelines), pulmonary embolia, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker
  • Non-hematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas
  • Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to randomization as defined by National Cancer Institute Common Toxicity Criteria (NCI CTCAE) 5.0
  • Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib) and to PS80; prior hypersensitivity to sucrose, histidine (as base and hydrochloride salt), or any of the components (active substance or excipients) of study treatments that are not amenable to premedication with steroids, or H2 blockers, that would prohibit further treatment with these agents.
  • Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
  • Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent
  • Pregnant or breastfeeding woman or woman who intends to become pregnant during the participation in the study. FCBP unwilling to prevent pregnancy by the use of 2 reliable methods of contraception for ≥4 weeks before the start of study treatment, during treatment (including dose interruptions), and for at least 28 days following discontinuation of study lenalidomide, or 30 days following discontinuation of carfilzomib or for 5 months after discontinuation of isatuximab treatment, whichever occurs last,
  • Male participants who disagree to practice true abstinence or disagree to use a condom during sexual contact with a pregnant woman or a FCBP while participating in the study, during dose interruptions, and for at least 28 days following discontinuation of study lenalidomide, or 30 days following discontinuation of carfilzomib, or for 5 months after discontinuation of isatuximab treatment, whichever occurs last, even if he has undergone a successful vasectomy.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Andrea Novali +393924398409 amministrazione@emnresearch.it
Listed Location Countries  ICMJE Czechia,   Germany,   Greece,   Italy,   Netherlands,   Norway,   Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04483739
Other Study ID Numbers  ICMJE EMN24
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party European Myeloma Network
Study Sponsor  ICMJE European Myeloma Network
Collaborators  ICMJE
  • EMN Research Italy
  • Sanofi
  • Amgen
Investigators  ICMJE Not Provided
PRS Account European Myeloma Network
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP