Emapalumab Prevention of CAR-T Cell Associated Toxicities

A Phase 2 Trial of Emapalumab for the Prevention of CAR-T Cell Associated Toxicities

This research study involves assessing the impact of emapalumab as preventative management of CAR-T related cytokine release syndrome in participants with Non-Hodgkin's lymphoma (NHL).

The research study involves the following study interventions:

• Fludarabine and cyclophosphamide (Lymphodepleting Chemotherapy)
• Axicabtagene Ciloleucel
• Emapalumab

Study Overview

• Status: Recruiting
• Conditions: Follicular Lymphoma; Diffuse Large B Cell Lymphoma; Refractory Non-Hodgkin Lymphoma; High-grade B-cell Lymphoma; Primary Mediastinal Large B-cell Lymphoma; Large B-cell Lymphoma; Relapsed Non-Hodgkin Lymphoma
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Emapalumab; Drug: Fludarabine Phosphate; Drug: Axicabtagene Ciloleucel

Detailed Description

This is a phase 2 multi-center, open label study that is evaluating the safety and efficacy of emapalumab in preventing toxicities associated with axicabtagene ciloleucel in subjects with second- or third-line large B-cell non-Hodgkin's lymphoma.

A phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The U.S. Food and Drug Administration (FDA) has not approved emapalumab for the participants specific disease, but it has been approved for other uses.

The U.S. FDA has approved axicabtagene ciloleucel for the participants specific disease.

This research study procedures include screening for eligibility, study treatment including collection of T cells (leukapheresis), lymphodepleting chemotherapy, treatment with emapalumab and axicabtagene ciloleucel, and follow-up evaluations.

Once study treatment is completed, the participants will be followed for up to 24 months.

It is expected that about 28 people will take part in this research study.

• Study Type: Interventional
• Enrollment (Estimated): 28
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Matthew Frigault, MD; Phone Number: (617) 643-6175; Email: MFRIGAULT@partners.org

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Principal Investigator: Matthew Frigault, MD
      • Contact: Matthew Frigault, MD; Phone Number: 617-643-6175; Email: MFRIGAULT@partners.org
    • Boston, Massachusetts, United States, 02215
      • Not yet recruiting
      • Dana-Farber Cancer Institute
      • Contact: Caron Jacobson, MD; Phone Number: (617)-632-5847; Email: Caron_Jacobson@DFCI.HARVARD.EDU

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. Or adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
• At least 1 measurable lesion per Lugano at time of screening.
• At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy however steroids only require a 7-day washout.
• At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy at the time the subject is planned for leukapheresis (e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, etc).
• Age 18 or older
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

• Adequate renal, hepatic, pulmonary and cardiac function defined as:

  • ANC ≥1000/uL
  • Platelet count ≥50,000/uL
  • Absolute lymphocyte count ≥100/uL
  • Creatinine clearance (as estimated by Cockcroft Gault or CKD-EPI) ≥ 30 mL/min
  • Serum ALT/AST ≤2.5 per institutional ULN
  • Total bilirubin ≤1.5 mg/dl, except in subjects with Gilbert's syndrome.
  • Cardiac ejection fraction ≥ 40%, no clinically significant pericardial effusion, and no clinically significant ECG findings
  • Baseline oxygen saturation >92% on room air.
• Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential).
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years.
• History of Richter's transformation of CLL.
• Autologous stem cell transplant within 6 weeks of planned axicabtagene ciloleucel infusion.
• History of allogeneic stem cell transplantation.
• Presence of uncontrolled fungal, bacterial, viral, or other infection at time of screening.

• Known history of acute or chronic active hepatitis B or C infection. Subjects with history of hepatitis infection must have cleared their infection as determined by standard serological and genetic testing per current Infectious Diseases Society of America (IDSA) guidelines.

  • Patients should also be negative for latent Tb, CMV (NAT), EBV (NAT) and adenovirus (NAT) by PCR testing.
• No evidence of active CNS disease regardless of prior CNS history.
• History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage within 6 months of enrollment.
• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment.
• History of symptomatic pulmonary embolism within 3 months of enrollment; ongoing anticoagulation is allowed if beyond 3 months.
• Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.
• History of allergic reactions or severe immediate hypersensitivity reaction to any of the agents used in this study or compounds of similar chemical or biologic composition.
• Females who are pregnant or breastfeeding or female or male participants who are not willing to practice birth control from the time of consent through 6 months after the completion of axicabtagene ciloleucel
• In the investigators judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.
• History of autoimmune disease requiring ongoing systemic immunosuppression. Steroids are allowed up to 5mg predinosine-equivalent for adrenal insufficiency.
• Patients anticipated to require canakinumab, JAK inhibitors, TNF inhibitors, and tocilizumab for non-CAR-T management of baseline autoimmune/inflammatory disease at the time of emapalumab initiation.
• Receipt of a BCG vaccine within 12 weeks prior to Screening.
• Receipt of a live or attenuated live (other than BCG) vaccine within 4 weeks prior to screeing.
• Participants who are receiving any other investigational agents for this condition.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Emapalumab; Leukapheresis will happen within approximately 5 days of eligibility confirmation. Emapalumab is given as a single dose on Day -1 by intravenous infusion over about 1 hour. Lymphodepleting Chemotherapy with cyclophosphamide and fludarabine will occur once a day for 3 days (Days -5 through Day -3) by intravenous infusion over about 2-4 hours. Axicabtagene ciloleucel will be given once on Day 0 by intravenous infusion over about 30 minutes.

Drug: Cyclophosphamide; Alkylating agent; Drug: Emapalumab; An interferon gamma (IFNγ) blocking antibody; Other Names: Gamifant; Human anti-interferon gamma (IFNγ) monoclonal antibody; Drug: Fludarabine Phosphate; Purine antagonist antimetabolite; Drug: Axicabtagene Ciloleucel; Autologous treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of grade 2+ CRS per ASTCT	Assessed using American Society for Transplantation and Cellular Therapy (ASTCT). All participants will be monitored and assessed for grade 2+ cytokine release syndrome (CRS) for 24 months after post treatment.	Day -1 to 24 months post treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate and severity of ICANS as per ASTCT	Assessed using American Society for Transplantation and Cellular Therapy (ASTCT). The rate and severity of immune cell associated neurotoxicity syndrome (ICANS) within the first 30 days of infusion.	30 days
Objective response rate (ORR)	The incidence of either a complete response or a partial response by Lugano. All subjects that do not meet the criteria for an objective response by the analysis data cutoff date will be considered non-responders.	Day -1 to 24 months post treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of response (DOR)	Among subject who experience an objective response the date of their first objective response to disease progression per Lugano or death regardless of cause. Subjects not meeting the criteria for progression or death by the analysis data cutoff date will be censored at their last evaluable disease assessment date and their response will be noted as ongoing.	From First Objective Response until date of first documented disease progression or date of death from any cause, assessed up to 24 months post treatment
Progression-free Survival (PFS)	The time from the axicabtagene ciloleucel infusion date to the date of disease progression per Lugano or death from any cause. Subjects not meeting the criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date.	From Day 0 until date of first documented disease progression or date of death from any cause, assessed up to 24 months post treatment
Overall survival (OS)	The time from axicabtagene ciloleucel infusion to the date of death. Subjects who have not died by the analysis data cutoff date will be censored at their last contact date.	From Day 0 until documented date of death from any cause, assessed up to 24 months post treatment

Collaborators and Investigators

• Sponsor: Marcela V. Maus, M.D.,Ph.D.
• Collaborators: Swedish Orphan Biovitrum
• Investigators: Principal Investigator: Matthew Frigault, MD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2024
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2027

Study Registration Dates

• First Submitted: August 5, 2024
• First Submitted That Met QC Criteria: August 8, 2024
• First Posted (Actual): August 12, 2024

Study Record Updates

• Last Update Posted (Estimated): November 14, 2025
• Last Update Submitted That Met QC Criteria: November 12, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Second Line Large B-cell Non-Hodgkin's Lymphoma; Third Line Large B-cell Non-Hodgkin's Lymphoma
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, B-Cell; Lymphoma; Hemic and Lymphatic Diseases; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Lymphoma, Follicular; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Hydrocarbons; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Cyclophosphamide; Antibodies, Monoclonal; fludarabine phosphate; axicabtagene ciloleucel; Emapalumab
• Other Study ID Numbers: 24-317

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: Contact the Partners Innovations team at http://www.partners.org/innovation
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• 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.: No