Isatuximab, Bendamustine, and Prednisone in Refractory Multiple Myeloma

NCT04083898 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: 201910194
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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 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.

Conditions

Multiple Myeloma

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of regimen (Phase I only)

  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.

  Completion of first cycle of treatment for all participants enrolled in Phase I portion (estimated to be 9 months)

• Overall response rate (ORR) (Phase II only)

  -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 2016 response criteria.

  6 months

Secondary Outcomes (3)

• Number of adverse events experienced by participants (Phase I and Phase II)

  From start of treatment through 30 days after completion of treatment or initiation of new anti-myeloma therapy, whichever occurs first (estimated to be 7 months)

• Progression-free survival (PFS) (Phase II only)

  Up to 5 years after removal from study (estimated to be 5 years and 6 months)

• Overall survival (OS) (Phase II only)

  Up to 5 years after removal from study (estimated to be 5 years and 6 months)

Study Arms (4)

Phase I Dose Level 1: Isatuximab + Bendamustine + Prednisone

EXPERIMENTAL

-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; Drug: Bendamustine; Drug: Prednisone

Phase I Dose Level 2: Isatuximab + Bendamustine + Prednisone

EXPERIMENTAL

-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; Drug: Bendamustine; Drug: Prednisone

Phase I Dose Level 3: Isatuximab + Bendamustine + Prednisone

EXPERIMENTAL

-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; Drug: Bendamustine; Drug: Prednisone

Phase II: Isatuximab + Bendamustine + Prednisone

EXPERIMENTAL

-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; Drug: Bendamustine; Drug: Prednisone

Interventions

Isatuximab BIOLOGICAL

Isatuximab will be administered on a 28-day cycle

Phase I Dose Level 1: Isatuximab + Bendamustine + Prednisone; Phase I Dose Level 2: Isatuximab + Bendamustine + Prednisone; Phase I Dose Level 3: Isatuximab + Bendamustine + Prednisone; Phase II: Isatuximab + Bendamustine + Prednisone

Bendamustine DRUG

Bendamustine will be administered on a 28-day cycle as follows

Also known as: Bendeka, Treanda

Phase I Dose Level 1: Isatuximab + Bendamustine + Prednisone; Phase I Dose Level 2: Isatuximab + Bendamustine + Prednisone; Phase I Dose Level 3: Isatuximab + Bendamustine + Prednisone; Phase II: Isatuximab + Bendamustine + Prednisone

Prednisone DRUG

Prednisone will be administered on a 28-day cycle as follows

Also known as: Deltasone, Rayos, Prednisone Intensol

Phase I Dose Level 1: Isatuximab + Bendamustine + Prednisone; Phase I Dose Level 2: Isatuximab + Bendamustine + Prednisone; Phase I Dose Level 3: Isatuximab + Bendamustine + Prednisone; Phase II: Isatuximab + Bendamustine + Prednisone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• hour urine monoclonal protein ≥ 200 mg/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%
• Triple-class-refractory disease defined as both of the following:
• Previously received treatment with a proteasome inhibitor, an immunomodulatory drug, 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 most recent therapy.
• At least 6 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/mm\^3 (transfusions not permitted within 7 days of screening)

You may not qualify if:

• 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.
• Active hepatitis A, B, or C.
• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Sanofi: collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (1)

• Goldsmith SR, Slade MJ, Fiala M, Harding M, Crees ZD, Schroeder MA, Stockerl-Goldstein K, Vij R. A phase Ib trial of isatuximab, bendamustine, and prednisone in relapsed/refractory multiple myeloma. Ann Hematol. 2024 Nov;103(11):4557-4565. doi: 10.1007/s00277-024-05975-7. Epub 2024 Sep 4.

  PMID: 39227452 DERIVED

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Multiple Myeloma

Interventions

isatuximab; Bendamustine Hydrochloride; Prednisone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Ravi Vij, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 6, 2019
• First Posted: September 10, 2019
• Study Start: April 3, 2020
• Primary Completion: March 13, 2023
• Study Completion: March 7, 2024
• Last Updated: March 19, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)