Clinical Trials /

Isatuximab, Bendamustine, and Prednisone in Penta-Refractory Multiple Myeloma

NCT04083898

Description:

Isatuximab targets and kills CD38-positive myeloma cells in manner similar to rituximab's mechanism of action on CD20-positive lymphoma cells. Based on the synergy between rituximab and bendamustine, as well as the established clinical efficacy of bendamustine and isatuximab as single agents for multiple myeloma, the logical next step is to combine isatuximab with bendamustine and prednisone. Due to lack of effective therapies in penta-refractory multiple myeloma, herein the investigators propose studying this novel combination in this population, in order to address a significant unmet need. The aim of the investigators is to first determine the maximal tolerated dose of the combination in participants with relapsed/refractory myeloma and then to establish the efficacy of this novel combination.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Isatuximab, Bendamustine, and Prednisone in Penta-Refractory Multiple Myeloma
  • Official Title: A Phase I/II Trial of Isatuximab, Bendamustine, and Prednisone in Penta-Refractory Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: 19-x314
  • NCT ID: NCT04083898

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
IsatuximabPhase I Dose Level 1: Isatuximab + Bendamustine + Prednisone
BendamustineBendeka, TreandaPhase I Dose Level 1: Isatuximab + Bendamustine + Prednisone
PrednisoneDeltasone, Rayos, Prednisone IntensolPhase I Dose Level 1: Isatuximab + Bendamustine + Prednisone

Purpose

Isatuximab targets and kills CD38-positive myeloma cells in manner similar to rituximab's mechanism of action on CD20-positive lymphoma cells. Based on the synergy between rituximab and bendamustine, as well as the established clinical efficacy of bendamustine and isatuximab as single agents for multiple myeloma, the logical next step is to combine isatuximab with bendamustine and prednisone. Due to lack of effective therapies in penta-refractory multiple myeloma, herein the investigators propose studying this novel combination in this population, in order to address a significant unmet need. The aim of the investigators is to first determine the maximal tolerated dose of the combination in participants with relapsed/refractory myeloma and then to establish the efficacy of this novel combination.

Trial Arms

NameTypeDescriptionInterventions
Phase I Dose Level 1: Isatuximab + Bendamustine + PrednisoneExperimental-Isatuximab (10 mg/kg) on Days 1, 8, 15, and 22 during Cycle 1 and on Days 1 and 15 of subsequent cycles. Bendamustine (50 mg/m^2) will be administered on Days 1 and 2 and prednisone (60 mg) will be administered on Days 1 through 4 of each cycle.
  • Isatuximab
  • Bendamustine
  • Prednisone
Phase I Dose Level 2: Isatuximab + Bendamustine + PrednisoneExperimental-Isatuximab (10 mg/kg) on Days 1, 8, 15, and 22 during Cycle 1 and on Days 1 and 15 of subsequent cycles. Bendamustine (75 mg/m^2) will be administered on Days 1 and 2 and prednisone (60 mg) will be administered on Days 1 through 4 of each cycle.
  • Isatuximab
  • Bendamustine
  • Prednisone
Phase I Dose Level 3: Isatuximab + Bendamustine + PrednisoneExperimental-Isatuximab (10 mg/kg) on Days 1, 8, 15, and 22 during Cycle 1 and on Days 1 and 15 of subsequent cycles. Bendamustine (100 mg/m^2) will be administered on Days 1 and 2 and prednisone (60 mg) will be administered on Days 1 through 4 of each cycle.
  • Isatuximab
  • Bendamustine
  • Prednisone
Phase II: Isatuximab + Bendamustine + PrednisoneExperimental-Isatuximab (10 mg/kg) on Days 1, 8, 15, and 22 during Cycle 1 and on Days 1 and 15 of subsequent cycles. Bendamustine (dose determined in Phase I portion of study) will be administered on Days 1 and 2 and prednisone (60 mg) will be administered on Days 1 through 4 of each cycle.
  • Isatuximab
  • Bendamustine
  • Prednisone

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed diagnosis of multiple myeloma with a measurable disease
             parameter at time of screening. A measurable disease parameter is defined as one or
             more of the following:

               -  Serum monoclonal protein ≥ 0.5 g/dL

               -  24 hour urine monoclonal protein ≥ 0.2 g/24 hour

               -  Serum free light chain ratio > 5x normal ratio with an absolute difference of
                  10mg/dL between the involved and uninvolved free light chain

               -  Soft tissue plasmacytoma ≥ 2 cm measurable by either physical examination and/or
                  applicable radiographs (e.g. MRI, CT, etc.)

               -  Bone marrow plasma cells ≥ 30%

          -  Penta-refractory disease defined as both of the following:

               -  Previously received treatment with an alkylating agent, bortezomib, carfilzomib,
                  lenalidomide, pomalidomide, and daratumumab, in combination or as single-agents.

               -  Refractory (defined per IMWG Consensus Criteria as disease that is nonresponsive
                  while on therapy, or progresses within 60 days of last dose) to a proteasome
                  inhibitor, an IMID, and their most recent therapy.

          -  Patients must have had at least 3 cycles of daratumumab treatment with at least 6
             weeks from the last treatment with daratumumab to the first study treatment OR at
             least 2 cycles of daratumumab treatment in case another therapy is given between
             daratumumab and isatuximab with at least 12 weeks from the last treatment with
             daratumumab to the first study treatment.

          -  At least 18 years of age.

          -  Performance status of ECOG ≤ 2 Note: Participants with lower performance status based
             solely on bone pain secondary to multiple myeloma will be eligible.

          -  Normal bone marrow and organ function as defined as ALL of the following:

               -  Absolute neutrophil count ≥ 1500/mm3

               -  Platelets ≥ 75,000 (transfusions not permitted within 7 days of screening)

               -  ALT (SGPT) and AST (SGOT) < 3.5 x the upper limit of the institutional normal
                  value (ULN).

               -  Total bilirubin ≤ 2.0 x mg/dL.

               -  Creatinine clearance > 30 ml/min using Cockcroft-Gault formula

          -  Females of childbearing potential (FCBP) must agree to refrain from becoming pregnant
             while on study drug and for 3 months after discontinuation from study drug, and must
             agree to use adequate contraception including hormonal contraception, (e.g. birth
             control pills, etc.), barrier method contraception (e.g. condoms), or abstinence
             during that time frame. Men engaging in sexual intercourse with a FCBP must agree to
             use adequate contraception including hormonal contraception, (e.g. birth control
             pills, etc), barrier method contraception (e.g. condoms), or abstinence while on study
             drug and for 3 months after discontinuation from study drug

          -  Ability to understand and willing to sign a written informed consent document.

        Exclusion Criteria:

          -  Prior exposure to isatuximab or bendamustine

          -  History of plasma cell leukemia or MM CNS involvement.

          -  Receiving renal replacement therapy, hemodialysis, or peritoneal dialysis.

          -  Diagnosed with another concurrent malignancy requiring treatment.

          -  Known active hepatitis A, B, or C. Antibody testing not required for screening.

          -  Known intolerance to infused protein products, sucrose, histidine, polysorbate 80 or
             known hypersensitivity to any of the components of study therapy.

          -  Receiving any other investigational agents within 14 days prior to enrollment.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac
             arrhythmia.

          -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
             pregnancy test within 14 days of study entry.

          -  Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or
             they have a history of AIDS-defining opportunistic infection within the 12 months
             prior to registration. Concurrent treatment with effective ART according to DHHS
             treatment guidelines is recommended.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of regimen (Phase I only)
Time Frame:Completion of first cycle of treatment for all participants enrolled in Phase I portion (estimated to be 9 months)
Safety Issue:
Description:The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 participants of a cohort (of 2 to 6 participants) experience dose limiting toxicity (DLT) during the first cycle of treatment. Dose escalation will proceed until the MTD has been reached or until the maximum dose of each drug is tested (Dose Level 3). If no more than 1 DLT is observed at dose levels 1, 2 and 3, level 3 will be declared the recommended phase II dose (RP2D) and the MTD will remain undefined.

Secondary Outcome Measures

Measure:Number of adverse events experienced by participants (Phase I and Phase II)
Time Frame:From start of treatment through 30 days after completion of treatment (estimated to be 7 months)
Safety Issue:
Description:Participants will be evaluated for toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 5.0.
Measure:Progression-free survival (PFS) (Phase II only)
Time Frame:Up to 5 years after removal from study (estimated to be 5 years and 7 months)
Safety Issue:
Description:Progression-free survival (PFS) will be defined as time from Cycle 1 Day 1 to disease progression or relapse. Any patient who expires, withdraws, or is lost to follow-up prior to disease progression or relapse will be censored at last follow-up. Patients who are removed from study therapy prior to progression or relapse will be censored at the time of initiation of subsequent anti-myeloma treatment.
Measure:Overall survival (OS) (Phase II only)
Time Frame:Up to 5 years after removal from study (estimated to be 5 years and 7 months)
Safety Issue:
Description:Overall survival (OS) will be defined as time from Cycle 1 Day 1 to death due to any causes. Patients who are alive at the time of data analyses will be censored on the last known alive date. Patients who are removed from study therapy prior death will be censored at the time of initiation of subsequent anti-myeloma treatment.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Washington University School of Medicine

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