Clinical Trials /

Monoclonal Antibody-Based Sequential Therapy for Deep Remission in Multiple Myeloma

NCT03224507

Description:

Multiple myeloma (MM), a plasma cell disorder, is the second most common hematologic malignancy in the U.S. No standard curative therapy has yet been found. A variety of therapeutic measures including high dose melphalan, induction therapy, and continuous therapy have been used but the goal of complete response without relapse has not been achieved. More active treatment regimens and better tools for response assessment are needed.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Monoclonal Antibody-Based Sequential Therapy for Deep Remission in Multiple Myeloma
  • Official Title: Monoclonal Antibody-Based Sequential Therapy for Deep Remission in Multiple Myeloma - MASTER Trial

Clinical Trial IDs

  • ORG STUDY ID: F170525008 (UAB 1735)
  • NCT ID: NCT03224507

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
KRdD followed by auto-HCTKRdD = Kyprolis (Carfilzomib), Revlimid (Lenalidomide), dexamethasone, Darzalex (Daratumumab)KRdD followed by auto-HCT
KRdD onlyKRdD = Kyprolis (Carfilzomib), Revlimid (Lenalidomide), dexamethasone, Darzalex (Daratumumab)KRdD only

Purpose

Multiple myeloma (MM), a plasma cell disorder, is the second most common hematologic malignancy in the U.S. No standard curative therapy has yet been found. A variety of therapeutic measures including high dose melphalan, induction therapy, and continuous therapy have been used but the goal of complete response without relapse has not been achieved. More active treatment regimens and better tools for response assessment are needed.

Detailed Description

      This trial will assess the safety and efficacy of an induction therapy using the combination
      of dexamethasone, lenalidomide (revlimid), daratumumab (Darzalex) and carfilzomib (Kyprolis)
      to treat patients with newly diagnosed multiple myeloma. The therapy with KRdD (Kyprolis,
      Revlimid, dexamethasone, Darzalex) will be followed by autologous hematopoietic cell
      transplantation (auto-HCT) and KRdD consolidation. Duration of therapy will be guided by
      eradication of minimal residual disease (MRD). The hypothesis is that the KRdD therapy
      particularly in combination with the auto-HCT will be safe and lead to deep remission.
      Patients who become MRD- will discontinue therapy (no maintenance therapy) and be actively
      monitored for resurgence of MRD or clinical relapse.
    

Trial Arms

NameTypeDescriptionInterventions
KRdD followed by auto-HCTExperimentalCycle 1-Dexamethasone 40mg orally days 1/8/15/22; Lenalidomide 25mg orally days 1-21; Carfilzomib 20mg/m2 days 8/9 then 36mg/m2 venous days 15/16; Daratumumab 16mg/kg venous days 1/8/15/22 (KRd-Dara). Cycle 2 the same except Carfilzomib 36mg/m2 venous days 1/2/8/9/15/16. Cycles 3,4 the same but no Daratumumab Days 8 and 22. Dosage adjusted for last tolerated dose (LTD). Following induction therapy, auto-HCT is done (consolidation 1), then up to two 4-cycle blocks of KRd-Dara consolidation (consolidations 2 and 3). Minimum residual disease (MRD) checked after each phase. Patients with confirmed MRD(-) at or after consolidation 1 will not undergo maintenance and will be actively monitored for resurgence of MRD or clinical relapse. After consolidation if MRD+ patients will undergo standard of care lenalidomide maintenance.
  • KRdD followed by auto-HCT
KRdD onlyExperimentalCycle 1-Dexamethasone 40mg orally days 1/8/15/22; Lenalidomide 25mg orally days 1-21; Carfilzomib 20mg/m2 days 8/9 then @ 36mg/m2 venous days 15/16; Daratumumab 16mg/kg venous days 1/8/15/22. Cycle 2 the same except Carfilzomib 36mg/m2 venous days 1/2/8/9/15/16. Cycles 3,4 the same but no Daratumumab Day 22. Dosage adjusted for last tolerated dose (LTD). Following induction therapy, Following induction therapy, patients will receive up to three 4-cycle blocks of KRd-Dara consolidation (consolidations 1, 2 and 3). Minimum residual disease (MRD) checked after each phase. Patients with confirmed MRD(-) at or after consolidation 1 will not undergo maintenance and will be actively monitored for resurgence of MRD or clinical relapse. After consolidation if MRD+ patients will undergo standard of care lenalidomide maintenance.
  • KRdD only

Eligibility Criteria

        Inclusion Criteria:

          -  Age >18 years with no upper age limit

          -  Diagnosis of newly diagnosed multiple myeloma with indication for initiation of
             therapy.

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  No prior MM-directed therapy except for dexamethasone (up to 160 mg) and/or bortezomib
             (up to 5.2 mg/m2) and/or cyclophosphamide up to 1000 mg/m2 administered for management
             of acute manifestations of MM (hypercalcemia, renal impairment, pain) for no longer
             than 4 weeks prior to enrollment. If subject received any prior therapy, pretreatment
             parameters necessary for disease characterization and response assessment must be
             available.

          -  Measurable disease meeting at least one of the following criteria:

               1. Serum monoclonal (M) protein ≥1.0 g/dl

               2. ≥ 200 mg of M protein/24h in the urine

               3. Serum-free light chain ≥10 mg/dL and abnormal kappa to lambda ratio.

          -  Life expectancy ≥12 months.

          -  Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and
             serum direct bilirubin ≤ 2 mg/dL (34 μmol/L) within 21 days prior to initiation of
             therapy.

          -  Creatinine clearance (CrCl) ≥ 40 mL/minute within 21 days prior to start of therapy
             either measured or calculated using a standard formula (eg. Cockcroft and Gault).

          -  Written informed consent in accordance with federal, local, and institutional
             guidelines.

          -  Females of childbearing potential must agree to ongoing pregnancy testing and to
             practice contraception. Male subjects must agree to practice contraception.

          -  All subjects must agree to comply with and be enrolled in Revlimid REMS program.

        Exclusion Criteria:

          -  Diagnosis of amyloidosis, Crow-Fukase syndrome, Waldenstrom's macroglobulinemia,
             smoldering MM.

          -  Major surgery, radiotherapy or infection requiring therapy within 14 days of starting
             treatment.

          -  Known FEV1 or cDLCO < 50% of predicted.

          -  Pregnant or lactating females.

          -  Known human immunodeficiency virus infection.

          -  Active hepatitis B (Hepatitis B core antibody positive and subsequent Hepatitis B
             surface antigen positive or Hepatitis B DNA positive) or C infection (Hepatitis C
             antibody positive and subsequent detectable viral load).

          -  Unstable angina or myocardial infarction within 4 months prior to registration, New
             York Heart Association Class II, III or IV heart failure, uncontrolled angina, 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.

          -  Cerebrovascular disease manifested as prior stroke at any time or TIA in the 12 months
             prior to initiation of therapy

          -  Non-hematologic malignancy within the past 3 years with the exception of a) adequately
             treated basal cell carcinoma, squamous cell skin cancer, or localized 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 21 days prior to
             registration.

          -  Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize
             carfilzomib).

          -  Subjects with pleural effusions requiring thoracentesis or ascites requiring
             paracentesis within 21 days prior to registration.

          -  Contraindication or intolerance to required supportive care medications (Aspirin and
             Acyclovir).

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of patients with MRD(-) remissions at the completion of consolidation therapy
Time Frame:Baseline until MRD(-) is reached estimated to be up to 15 months.
Safety Issue:
Description:The primary endpoint of MRD(-) rate, or percentage of patients with MRD(-) remissions, will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences.

Secondary Outcome Measures

Measure:Serious adverse events (SAEs) from the KRdD treatment
Time Frame:Baseline until the progression of disease or MRD(-) status up to an estimated 15 months.
Safety Issue:
Description:The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be used for this assessment. SAEs include events that are Grade 3 and above; non-serious events are Grades 1-2.
Measure:Percentage of patients with MRD(-) status at the completion of induction therapy
Time Frame:Baseline until MRD(-) status estimated at 6 months or until disease progression
Safety Issue:
Description:The primary endpoint of MRD(-) rate will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences.
Measure:Percentage of patients with auto-HCT that convert from positive to negative MRD
Time Frame:From baseline up to an estimated 9 months
Safety Issue:
Description:The primary endpoint of MRD(-) rate will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences.
Measure:Percentage of patients achieving complete remission following complete therapy
Time Frame:Baseline up to 15 months
Safety Issue:
Description:The primary endpoint of MRD(-) rate will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences. Complete therapy incorporates induction and consolidation therapy.
Measure:Percentage of patients that convert from MRD(-) to MRD(+) following treatment discontinuation
Time Frame:Baseline to 2 years
Safety Issue:
Description:The primary endpoint of MRD(-) rate will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences.
Measure:Progression-free survival
Time Frame:From date of study entry until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months.
Safety Issue:
Description:Progression-free survival is defined as the interval from the start of therapy to the earliest occurrence of the following: disease progression, initiation of anti-myeloma therapy that is not an accepted maintenance therapy of lenalidomide or death from any cause. Kaplan-Meier methods will used.
Measure:Overall survival
Time Frame:From date of study entry until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months.
Safety Issue:
Description:Overall survival is defined as the time from date of study enrollment until death from any cause.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Alabama at Birmingham

Trial Keywords

  • multiple myeloma
  • induction therapy
  • autologous hematopoietic cell transplantation
  • KRdD
  • Daratumumab
  • Carfilzomib
  • Lenalidomide

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