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

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ClinicalTrials.gov Identifier: NCT04083898
Recruitment Status : Not yet recruiting
First Posted : September 10, 2019
Last Update Posted : September 10, 2019
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Biological: Isatuximab Drug: Bendamustine Drug: Prednisone Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 37 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of Isatuximab, Bendamustine, and Prednisone in Penta-Refractory Multiple Myeloma
Estimated Study Start Date : December 31, 2019
Estimated Primary Completion Date : July 31, 2021
Estimated Study Completion Date : July 31, 2026


Arm Intervention/treatment
Experimental: Phase I Dose Level 1: Isatuximab + Bendamustine + Prednisone
-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.
Biological: Isatuximab
Isatuximab will be administered on a 28-day cycle

Drug: Bendamustine
Bendamustine will be administered on a 28-day cycle as follows
Other Names:
  • Bendeka
  • Treanda

Drug: Prednisone
Prednisone will be administered on a 28-day cycle as follows
Other Names:
  • Deltasone
  • Rayos
  • Prednisone Intensol

Experimental: Phase I Dose Level 2: Isatuximab + Bendamustine + Prednisone
-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.
Biological: Isatuximab
Isatuximab will be administered on a 28-day cycle

Drug: Bendamustine
Bendamustine will be administered on a 28-day cycle as follows
Other Names:
  • Bendeka
  • Treanda

Drug: Prednisone
Prednisone will be administered on a 28-day cycle as follows
Other Names:
  • Deltasone
  • Rayos
  • Prednisone Intensol

Experimental: Phase I Dose Level 3: Isatuximab + Bendamustine + Prednisone
-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.
Biological: Isatuximab
Isatuximab will be administered on a 28-day cycle

Drug: Bendamustine
Bendamustine will be administered on a 28-day cycle as follows
Other Names:
  • Bendeka
  • Treanda

Drug: Prednisone
Prednisone will be administered on a 28-day cycle as follows
Other Names:
  • Deltasone
  • Rayos
  • Prednisone Intensol

Experimental: Phase II: Isatuximab + Bendamustine + Prednisone
-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.
Biological: Isatuximab
Isatuximab will be administered on a 28-day cycle

Drug: Bendamustine
Bendamustine will be administered on a 28-day cycle as follows
Other Names:
  • Bendeka
  • Treanda

Drug: Prednisone
Prednisone will be administered on a 28-day cycle as follows
Other Names:
  • Deltasone
  • Rayos
  • Prednisone Intensol




Primary Outcome Measures :
  1. 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) ]
    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.

  2. Overall response rate (ORR) (Phase II only) [ Time Frame: 6 months ]
    -ORR defined as the proportion of patients meeting the criteria for partial response, very good partial response, complete response, or stringent complete response per IMWG criteria.


Secondary Outcome Measures :
  1. 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) ]
    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.

  2. 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) ]
    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.

  3. Overall survival (OS) (Phase II only) [ Time Frame: Up to 5 years after removal from study (estimated to be 5 years and 7 months) ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04083898


Contacts
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Contact: Ravi Vij, M.D. 314-454-8304 rvij@wustl.edu

Locations
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United States, Missouri
Washington University School of Medicine Not yet recruiting
Saint Louis, Missouri, United States, 63110
Contact: Ravi Vij, M.D.    314-454-8304    rvij@wustl.edu   
Principal Investigator: Ravi Vij, M.D.         
Sub-Investigator: Camille Abboud, M.D.         
Sub-Investigator: John DiPersio, M.D., Ph.D.         
Sub-Investigator: Mark Fiala, MSW         
Sub-Investigator: Armin Ghobadi, M.D.         
Sub-Investigator: Scott Goldsmith, M.D.         
Sub-Investigator: Mark Schroeder, M.D.         
Sub-Investigator: Keith Stockerl-Goldstein, M.D.         
Sub-Investigator: Geoffrey Uy, M.D.         
Sub-Investigator: Peter Westervelt, M.D., Ph.D.         
Sponsors and Collaborators
Washington University School of Medicine
Sanofi
Investigators
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Principal Investigator: Ravi Vij, M.D. Washington University School of Medicine

Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT04083898     History of Changes
Other Study ID Numbers: 19-x314
First Posted: September 10, 2019    Key Record Dates
Last Update Posted: September 10, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Bendamustine Hydrochloride
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Prednisone
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action