Study to Evaluate the Role of Siltuximab in Treatment of Cytokine Release Syndrome (CRS) and Immune Effector Cell Associated Neurotoxicity (ICANS) Related to CAR-T Cell Therapy

• ClinicalTrials.gov Identifier: NCT04975555
• Recruitment Status: Recruiting
• First Posted: July 23, 2021
• Last Update Posted: December 20, 2022
• Sponsor: University of Alabama at Birmingham
• Information provided by (Responsible Party): Mayur Narkhede, University of Alabama at Birmingham

Study Description

Brief Summary:

This study will evaluate the use of siltuximab to decrease the severity of cytokine release syndrome (CRS) and immune effector cell-associated neurological syndrome (ICANS) in patients who will receive chimeric antigen receptor (CAR) T-cell therapy for the treatment of hematological malignancies.

Condition or disease	Intervention/treatment	Phase
Cytokine Release Syndrome; ICANS; Lymphoma, Non-Hodgkin; Multiple Myeloma; Acute Lymphoblastic Leukemia	Drug: Siltuximab	Phase 2

Detailed Description:

Patients eligible to receive CAR T-cell therapy for FDA-approved indications in hematological malignancies will be enrolled in this study on the day of CAR T-cell infusion. Patients will be followed until they develop grade 1 or higher CRS and/or ICANS. On developing these syndromes, siltuximab will be administered with close monitoring and follow-up for resolution of symptoms. If symptoms continue to worsen, then an additional dose of siltuximab will be given. If the symptoms leading to CRS do not resolve, then rescue tocilizumab will be administered. The study's primary endpoint is to assess the response rate of siltuximab in the resolution of CRS within 14 days. The study's secondary endpoint is to assess the response rate of siltuximab in the resolution of ICANS, the safety of siltuximab, and the overall response rate of CAR T-cell therapy.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Pilot Study to Evaluate the Role of Siltuximab in Treatment of Cytokine Release Syndrome (CRS) and Immune Effector Cell Associated Neurotoxicity (ICANS) Related to Chimeric Antigen Receptor T-Cell Therapy (CAR-T) in Hematological Malignancies
• Actual Study Start Date: November 15, 2021
• Estimated Primary Completion Date: December 31, 2024
• Estimated Study Completion Date: December 31, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Siltuximab; Patients who experience CRS/ICANS will receive this treatment	Drug: Siltuximab; Siltuximab is administered at the dose of 11mg/kg via intravenous infusion over 1 hour. If no resolution of CRS is achieved then a repeat dose of siltuximab at the dose of 11mg/kg via intravenous infusion over 1 hour will be given.

Outcome Measures

Primary Outcome Measures :

1. Participants with a complete response for cytokine release syndrome (CRS) [ Time Frame: Baseline through 14 days ]
   Participants who achieve a resolution of CRS. Resolution of CRS is defined as absence of symptoms leading to diagnosis of CRS for 24 hours.

Secondary Outcome Measures :

1. Participants with a response for Immune effector Cell Associated Neurotoxicity Syndrome (ICANS) [ Time Frame: Baseline through 28 days ]
   Participants who achieve a resolution or improvement in their ICANS. Complete response or partial response for ICANS is defined as either complete disappearance or decrease in the grade of severity as measured by ASTCT Consensus Grading for ICANS. The ASTCT grade is from 1 to 5 for ICANS with 1 being mild symptoms and 5 being severe symptoms.
2. Participants experiencing adverse events from Siltuximab [ Time Frame: Baseline through 28 days ]
   All Adverse Events (AE's) will be reported and evaluated using National Cancer Institute's Common Terminology Criteria (CTCAE) v5.0.
3. Participants with response to CAR T-cell therapy [ Time Frame: Baseline through day 90 ]
   This will be measured by using specific criteria's for Lymphoma, Multiple Myeloma or Acute Lymphoblastic Leukemia (ALL) [Based on the patients diagnosis]

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Patients who are planned to receive chimeric antigen receptor T-cell therapy as per the United States Food and Drug Agency (USFDA) approved indications for Diffuse large B-cell lymphoma (DLBCL), Mantle cell lymphoma (MCL), Follicular lymphoma (FL), Primary mediastinal large B-cell lymphoma (PMBCL), High grade B-cell lymphoma, DLBCL arising from follicular lymphoma, Multiple myeloma and B-cell precursor acute lymphoblastic leukemia
• Patients with hepatitis C virus (HCV) can be included if they have completed therapy for hepatitis C with undetectable HCV RNA viral load.
• Patients with Hepatitis B can be included if they are on suppressive therapy for hepatitis B infection and with no detectable viral load.
• Adequate organ function as defined below unless attributed to disease involvement.Acceptable window for assessing adequate organ function is 7 days to 30 days before planned CAR T-cell infusion with day 0 as the planned day of CAR T-cell infusion.Adequate liver function (bilirubin < 2mg/dL, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) <3 x ULN), adequate kidney function (crcl > 30ml/min using Cockcroft-Gault, based on actual weight) and adequate hematological parameters (Absolute neutrophil count ≥ 1,000/µL, Hemoglobin > 8, Platelet Count ≥ 50,000/ µL)
• Patients able to tolerate washout periods for therapies prior to CAR T-cell infusion. Systemic therapy: Washout period is 2 weeks prior to CAR T-cell infusion. Radiation therapy: Washout period is 1 week prior to CAR T-cell infusion. Corticosteroids: The washout period is 5 days prior to CAR T-cell infusion.
• A negative urine pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling on this trial.
• For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 4 months after infusion of siltuximab.
• For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner
• Willing and able to participate in all required evaluations and procedures in this study protocol including receiving intravenous administration of the investigational product and being admitted, when required, for at least 24 hours during investigational product administration.

Exclusion Criteria:

• Subjects requiring ongoing daily corticosteroid therapy at a dose of > 10 mg of prednisone per day (or equivalent). Pulsed corticosteroid use for disease control is acceptable.
• Active autoimmune disease requiring immunosuppressive therapy is excluded unless discussed with the principal investigator (PI)
• Pregnant women are excluded from this study.
• Evidence of ongoing systemic bacterial, or fungal or viral infection, except localized fungal infection of skin or nails.
• Patients with ongoing or past HIV infection.

Contacts and Locations

Contacts

Contact: Mayur Narkhede; 205-934-2248; msnarkhede@uabmc.edu

Locations

United States, Alabama

University of Alabama at Birmingham; Recruiting

Birmingham, Alabama, United States, 35294

Principal Investigator: Mayur S Narkhede, M.D

Sub-Investigator: Amitkumar Mehta, M.D

Sub-Investigator: Gaurav Goyal, M.D

Sub-Investigator: Susan Bal, M.D

Sub-Investigator: Pankit Vachhani, M.D

Sub-Investigator: Smith Giri, M.D

Sponsors and Collaborators

University of Alabama at Birmingham

Investigators

• Principal Investigator: Mayur S Narkhede; University of Alabama at Birmingham

More Information

• Responsible Party: Mayur Narkhede, Assistant Professor, University of Alabama at Birmingham
• ClinicalTrials.gov Identifier: NCT04975555
• Other Study ID Numbers: IRB-300007103
• First Posted: July 23, 2021
• Last Update Posted: December 20, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: To Be determined

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mayur Narkhede, University of Alabama at Birmingham:

Siltuximab; Chimeric Antigen Receptor T-cell Therapy; Cytokine release syndrome; Immune effector Cell associated Neurotoxicity Syndrome; Lymphoma; Multiple Myeloma; Acute lymphoblastic Leukemia

Additional relevant MeSH terms:

Multiple Myeloma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Neurotoxicity Syndromes; Syndrome; Cytokine Release Syndrome; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease; Pathologic Processes; Leukemia; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Nervous System Diseases; Poisoning; Chemically-Induced Disorders; Systemic Inflammatory Response Syndrome; Inflammation