IVIG for Infection Prevention After CAR-T-Cell Therapy

• ClinicalTrials.gov Identifier: NCT05952804
• Recruitment Status: Recruiting
• First Posted: July 19, 2023
• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: Takeda; National Cancer Institute (NCI)
• Information provided by (Responsible Party): Fred Hutchinson Cancer Center

Study Description

Brief Summary:

This phase II trial compares the effects of immunoglobulin replacement therapy with a placebo for preventing infectious complications in patients receiving CD19 chimeric antigen receptor (CAR)-T cell therapy. Hypogammaglobulinemia is a common complication in patients who receive CD19 CAR-T cell therapy. This is a condition in which the level of immunoglobulins (antibodies) in the blood is low and the risk of infection is high. Immunoglobulin replacement therapy works by replacing the body's IgG antibodies with donor blood product derived IgG antibodies that may help prevent infection. IgG antibodies are often depleted as a result of CAR-T therapy. Giving immunoglobulin replacement therapy may prevent infectious complications in patients receiving CD19 CAR-T cell therapy.

Condition or disease	Intervention/treatment	Phase
Lymphoma	Biological: Immune Globulin Infusion (Human), 10% Solution; Biological: Anti-CD19 CAR T Cells Preparation; Other: Saline; Procedure: Biospecimen Collection; Other: Survey Administration; Other: Electronic Health Record Review	Phase 2

Detailed Description:

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive immunoglobulin replacement therapy (IGRT) with intravenous immune globulin (IVIG) within 14 days prior to CD19 CAR-T-cell infusion. Patients then undergo CD19 CAR-T therapy. Patients receive IVIG monthly, starting 28 days after CD19 CAR-T therapy for up to 4 months in the absence of unacceptable toxicity, relapse of the underlying disease, or subsequent hematopoietic cell transplant. Patients also undergo blood sample collection throughout the study.

ARM II: Patients receive placebo with normal saline IV within 14 days prior to CD19 CAR-T treatment. Patients then undergo CD19 CAR-T-cell infusion. Patients receive normal saline monthly, starting 28 days after CD19 CAR-T therapy for up to 4 months in the absence of unacceptable toxicity, relapse of the underlying disease, or subsequent hematopoietic cell transplant. Patients also undergo blood sample collection throughout the study.

After completion of study treatment, patients are followed up monthly through up to 6 months after CD19 CAR-T-cell infusion.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Participants and study staff (except for site pharmacists) will be blinded to treatment arm assignments.
• Primary Purpose: Prevention
• Official Title: Immunoglobulin Replacement Therapy and Infectious Complications After CD19-Targeted CAR-T-Cell Therapy
• Estimated Study Start Date: June 10, 2024
• Estimated Primary Completion Date: July 31, 2027
• Estimated Study Completion Date: July 31, 2028

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I (therapeutic immune globulin); Patients receive IGRT with IVIG within 14 days prior to CD19 CAR-T treatment. Patients then undergo CD19 CAR-T therapy. Patients receive IVIG monthly, starting 28 days after CD19 CAR-T therapy for 4 months in the absence of unacceptable toxicity. Patients also undergo blood sample collection throughout the study.	Biological: Immune Globulin Infusion (Human), 10% Solution; Given IV; Other Name: GAMMAGARD LIQUID; Biological: Anti-CD19 CAR T Cells Preparation; Given CAR-T treatment; Other Name: CD19-targeting CAR-T Cells; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Other: Survey Administration; Ancillary studies; Other: Electronic Health Record Review; Ancillary studies
Placebo Comparator: Arm II (normal saline); Patients receive placebo with normal saline IV within 14 days prior to CD19 CAR-T treatment. Patients then undergo CD19 CAR-T therapy. Patients receive normal saline monthly, starting 28 days after CD19 CAR-T therapy for 4 months in the absence of unacceptable toxicity. Patients also undergo blood sample collection throughout the study.	Biological: Anti-CD19 CAR T Cells Preparation; Given CAR-T treatment; Other Name: CD19-targeting CAR-T Cells; Other: Saline; Given IV; Other Names: 7647-14-5; ISOTONIC SODIUM CHLORIDE SOLUTION; Sodium Chloride 0.9%; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Other: Survey Administration; Ancillary studies; Other: Electronic Health Record Review; Ancillary studies

Outcome Measures

Primary Outcome Measures :

1. Incidence rate of serious bacterial infections in the modified intention-to-treat (mITT) population [ Time Frame: From randomization through day 168 post chimeric antigen receptor (CAR) T-cell treatment (CARTx) ]
   Grade 2 or 3 bacterial infections. Only microbiologically confirmed infections will be included. Microbiological documentation of an infection consists of isolation of the pathogen by culture from a sterile (definite) or nonsterile (probable) site (if from a nonsterile site, the organism had to be clinically judged to be pathogenic). Will describe the number and type of infections in each study arm and calculate incidence rate estimates and 95% confidence intervals (CIs) for infections. Will compare serious bacterial infection IRs between study arms using negative binomial regression with an offset to account for days-at-risk. Will construct multivariable Cox proportional hazards models of time-to-first serious bacterial infection.

Secondary Outcome Measures :

1. Incidence rate of serious bacterial infections in ITT and per-protocol populations and of any serious infection or any infection after CD19 CARTx [ Time Frame: From randomization through day 168 post CARTx ]
   Will use similar analytic approaches as in the primary outcome analysis to evaluate secondary outcomes (any serious infection, any infection) and all outcomes in pre-specified populations (mITT, per-protocol, ITT). Will explore outcomes restricted to early (days 0-28) and later (days 29-168) post-CARTx time periods. Plot cumulative incidence curves of time-to-first serious bacterial infection by study arm. Incidence rate ratios, hazard ratios (HR), and their 95% CIs will be reported. Will use one-sided testing to determine whether the rate of infections is significantly lower in the immunoglobulin replacement therapy (IGRT) versus placebo arms.
2. Levels of total IgG, IgG subclasses, and total Streptococcus (S.) pneumoniae IgG [ Time Frame: From randomization through day 168 post CARTx ]
   Will graphically display mean total IgG levels, IgG subclasses, and S. pneumoniae IgG titers over time, stratified by study arm. Will use generalized estimating equations (GEE) models to compare means by randomization arm. Will test the association of each IgG metric as time-varying covariates with risk of subsequent infection (serious bacterial, any serious, any) at any time post-randomization and separately during early (days 0-28) and later (days 29-168) periods post-CARTx using Cox proportional hazard models. Model estimates will be presented as HRs with 95% CIs.
3. Health resource utilization (HRU) [ Time Frame: Up to 6 months post CARTx ]
   Will describe HRU metrics by study arm (overall and by relationship to study drug infusion or infection). Will compute rates (per 1000 person-days) for each metric (e.g., days alive and out of the hospital, days of antibiotics, outpatient visits, emergency room visits, hospitalizations, adverse events) and compare between study arms using rate ratios with p-values and 95% CIs calculated by Poisson or negative binomial regression.
4. Incidence and severity of cytokine release syndrome (CRS) and/or immune effector cell-associated neurotoxicity syndrome (ICANS) [ Time Frame: Up to 6 months post CARTx ]
   Will plot cumulative incidence curves, stratified by study arm, of any and grade >= 3 CRS, ICANS, or both, and compare hazard ratios using multivariable Cox proportional hazards models to adjust for stratification variables and potential confounders. To account for multiple comparisons, we will consider the Benjamini-Hochberg procedure for controlling the false discovery rate.
5. CAR T-cell expansion: Peak Plasma Concentration (Cmax) [ Time Frame: Up to 6 months post CARTx ]
   Will display and compare between study arms the distribution of Cmax based on flow cytometry and quantitative polymerase chain reaction (qPCR) at weekly intervals between days 0 and 28 after CAR-T cell infusion using the Wilcoxon rank-sum test.
6. CAR T-cell expansion: area under the curve (AUC) [ Time Frame: Up to 6 months post CARTx ]
   Will display and compare between study arms the area under the curve (AUC) 0-28 CAR-T cell values (log10 cells/uL) based on flow cytometry and quantitative polymerase chain reaction (qPCR) at weekly intervals between days 0 and 28 after CAR-T cell infusion using the Wilcoxon rank-sum test. The AUC 0-28 will be computed among log10-transformed CAR-T cell counts using a trapezoidal rule computational algorithm. Will use linear regression to test for differences in AUC 0-28 by study arm after adjusting for stratification variables (CAR-T cell product, site), disease burden (pre-lymphodepletion % bone marrow blasts; >= 5% versus < 5%), and other potential confounders.
7. CAR T-cell persistence [ Time Frame: Up to 6 months post CARTx ]
   Will display the distribution of CAR-T cell values (log10 copies/ug deoxyribonucleic acid) per study arm based on monthly qPCR results and compare results using similar approaches as described for expansion. Timing of the loss of CAR-T cell persistence will be defined as the date of the first of two consecutive CAR-T cell values < 10 copies/ug. Will compute the cumulative incidence of loss of persistence and evaluate the association with study arm by day 168 using a Cox proportional hazards model including similar adjustment factors as previously described.
8. CAR T-cell phenotype and function [ Time Frame: At day 14 post CARTx ]
   Compare CAR T-cell phenotype and function at day 14 after infusion between study arms. Cell subsets will be depicted using Uniform Manifold Approximation and Projection (UMAP), a dimension reduction technique to visualize and understand large, high dimensional datasets. Heatmaps will be created in R using the heatmap package to visualize differences in the proportion of patients with activated versus exhausted CAR-T cells and other select immune cell clusters, grouped for every marker and supervised by treatment arm. Will compare differences in absolute immune cell subset counts, the proportion of cell subsets with markers of activation versus exhaustion, and intracellular signaling (phospho-protein responses, stimulated and unstimulated) between study arms. Multivariable linear regression will be used to assess the relationship between treatment group and cell subset counts, as well as counts of activated versus exhausted cells, with adjustment for relevant confounders.
9. Immune cell subset phenotypes and functional makers [ Time Frame: At 6 months post CARTx ]
   Compare all immune cell subset phenotypes and functional makers at the end of the study between study arms. Cell subsets will be depicted using UMAP, a dimension reduction technique to visualize and understand large, high dimensional datasets. Heatmaps will be created in R using the heatmap package to visualize differences in the proportion of patients with activated versus exhausted CAR-T cells and other select immune cell clusters, grouped for every marker and supervised by treatment arm. Will compare differences in absolute immune cell subset counts, the proportion of cell subsets with markers of activation versus exhaustion, and intracellular signaling (phospho-protein responses, stimulated and unstimulated) between study arms. Multivariable linear regression will be used to assess the relationship between treatment group and cell subset counts, as well as counts of activated versus exhausted cells, with adjustment for relevant confounders.
10. IgA and IgM levels [ Time Frame: At 6 months post CARTx ]
    Compare IgA and IgM at end of study between study arms.
11. Health related quality of life (HRQOL) [ Time Frame: From baseline up to 6 months post CARTx ]
    Compare HRQOL between study arms. Assessment of quality of life using the Patient Short Form-36 HRQOL electronic questionnaire.

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:

• Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent
• For patients with medical incapacity or impaired consciousness such that they are not able to give fully informed voluntary consent, the subjects' legal representative must sign an institutional review board (IRB) approved informed consent document prior to the initiation of any screening or study-specific procedures
• Participants must be 18 years of age or older
• Participants will receive an Food and Drug Administration (FDA)-approved CD19-CAR T-cell product for the treatment of lymphoma. Patients receiving an FDA-approved product are eligible even if the product is being administered as part of a clinical trial or expanded access program (e.g., product is 'out of specification'; concomitant anti-tumor treatment such as acalabrutinib)
• Serum total IgG =< 400 mg/dL within the prior three months
• SUBSEQUENT INFUSIONS: Received an FDA-approved CD19-CAR T-cell product for the treatment of lymphoma.

Exclusion Criteria:

• Selective IgA deficiency
• Prior serious adverse event/s related to intravenous immune globulin (IVIG) administration
• Known serious allergy to any component of IVIG
• Has a history or current evidence of any condition, therapy, lab abnormality, or other circumstance that might confound the results of the study or interfere with the patient's ability to participate for the full duration of the study or would put the patient at undue risk as judged by the investigator, such that it is not in the best interest of the patient to participate in this study
• SUBSEQUENT INFUSIONS: Ongoing symptoms of cytokine release syndrome (CRS) and/or immune effector cell-associated neurotoxicity syndrome (ICANS) meeting criteria for grade 3 or higher
• SUBSEQUENT INFUSIONS: Selective IgA deficiency
• SUBSEQUENT INFUSIONS: Has a history or current evidence of any condition, therapy, lab abnormality, or other circumstance that might confound the results of the study or interfere with the patient's ability to participate for the full duration of the study or would put the patient at undue risk as judged by the Investigator, such that it is not in the best interest of the patient to participate in this study
• SUBSEQUENT INFUSIONS: Receipt of additional therapy for persistence or relapse of the patient's primary malignancy
• SUBSEQUENT INFUSIONS: Receipt of bone marrow transplant (allogeneic or autologous)
• SUBSEQUENT INFUSIONS: Any serious adverse event (SAE), clinically significant adverse event (AE), severe laboratory abnormality, intercurrent illness, or other medical condition that indicates to the Investigator that continued participation is not in the best interest of the participant

Contacts and Locations

Contacts

Contact: Joshua Hill, MD; 206-667-6504; jahill@fredhutch.org

Locations

United States, California

City of Hope Cancer Center; Not yet recruiting

Duarte, California, United States, 91010

Principal Investigator: Sanjeet Dadwal, MD

United States, Florida

Moffitt Cancer Center; Not yet recruiting

Tampa, Florida, United States, 33612

Principal Investigator: Frederick Locke, MD

United States, Massachusetts

Massachusetts General Hospital Cancer Center; Not yet recruiting

Boston, Massachusetts, United States, 02114

Principal Investigator: Matthew Frigault, MD

United States, New York

Memorial Sloan Kettering Cancer Center; Not yet recruiting

New York, New York, United States, 10065

Principal Investigator: Miguel-Angel Perales, MD

United States, Washington

Fred Hutch/University of Washington Cancer Consortium; Recruiting

Seattle, Washington, United States, 98109

Contact: Joshua Hill, MD 206-667-6504 jahill@fredhutch.org

Principal Investigator: Joshua Hill, MD

Sponsors and Collaborators

Fred Hutchinson Cancer Center

Takeda

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Joshua Hill, MD; Fred Hutch/University of Washington Cancer Consortium

More Information

• Responsible Party: Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT05952804
• Other Study ID Numbers: RG1123550; NCI-2023-04889 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 20082 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ); R01CA276040 ( U.S. NIH Grant/Contract )
• First Posted: July 19, 2023
• Last Update Posted: May 13, 2024
• Last Verified: February 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Additional relevant MeSH terms:

Pharmaceutical Solutions; Immunoglobulins; Antibodies; gamma-Globulins; Immunoglobulins, Intravenous; Rho(D) Immune Globulin; Immunologic Factors; Physiological Effects of Drugs