Emapalumab Prophylaxis of Bispecific T-Cell Engagers (BiTEs) Associated CRS and ICANS

A Phase II Study of the Interferon Gamma Inhibitor Emapalumab for Prophylaxis of Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome in Patients With Lymphoma and Multiple Myeloma Receiving Bispecific T-Cell Engagers

The purpose of this study is to evaluate emapalumab as a prophylactic therapy in preventing cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in patients with hematologic malignancies receiving bispecific antibodies (BsAbs) as outpatient. The primary objectives of this study are to evaluate the efficacy, safety, and feasibility of prophylaxis with the interferon gamma (IFN-У -γ) inhibitor Emapalumab in preventing CRS and/or ICANS in patients receiving bispecific antibody therapy for hematologic malignancies.

Inclusion Criteria:

1. Disease Criteria:

   1. Adult patients (≥18 years) with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or that relapsed after first-line chemoimmunotherapy not eligible for high-dose therapy/autologous stem cell transplantation (HDT-ASCT) or Chimeric Antigen Receptor T- cell (CAR-T) therapy, or adult patients with relapsed/refractory (R/R) LBCL after two or more lines of systemic therapy, who are planned to receive a commercially approved bispecific antibody therapy (e.g. epcoritamab, glofitamab). This includes:

      • Diffuse large B-cell lymphoma (DLBCL) not otherwise specified,
      • Primary mediastinal large B-cell lymphoma,
      • High-grade B-cell lymphoma,
      • DLBCL arising from follicular lymphoma.

   2. Adult patients with R/R multiple myeloma (MM) who have received multiple lines of therapy and are planned to receive a commercially approved bispecific antibody therapy. These prior therapies will typically include a proteasome inhibitor (e.g., bortezomib, carfilzomib), an immunomodulatory drug (e.g., lenalidomide, pomalidomide), and an anti-CD38 monoclonal antibody (e.g., daratumumab).

2. Treatment Eligibility:

   1. At least measurable disease per Lugano Criteria (for B-cell lymphomas) or per International Myeloma Working Group (IMWG) criteria (for multiple myeloma) at the time of screening.
   2. 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 bispecific antibody therapy, except for systemic inhibitory/stimulatory immune checkpoint therapy. Steroids require only a 7-day washout.
   3. At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, etc.) before the planned bispecific therapy.

3. Performance Status:

   1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

4. Organ Function:

   1. Adequate renal, hepatic, pulmonary, and cardiac function, defined as:
   2. Absolute neutrophil count (ANC) ≥ 1000/µL,
   3. Platelet count ≥ 50,000/µL,
   4. Hgb > 7, and standard pre-medications are allowed per standard of care guidelines
   5. Patients eligible to receive the bispecifics per institutional guidelines.
   6. Absolute lymphocyte count ≥ 100/µL
   7. Creatinine clearance (as estimated by Cockcroft Gault or CKD-EPI) ≥ 30 mL/min,
   8. Serum ALT/AST ≤ 2.5 times institutional upper limit of normal (ULN),
   9. Total bilirubin ≤ 1.5 mg/dL, except in subjects with Gilbert's syndrome,
   10. Cardiac ejection fraction ≥ 40%, no clinically significant pericardial effusion, and no clinically significant ECG findings (current status)
   11. Baseline oxygen saturation > 92% on room air.

5. Reproductive Status:

   1. 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.
   2. Women of Childbearing Potential (WOCBP) must agree to use one highly effective method of contraception, including hormonal contraceptives (e.g. combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine device (IUD) or intrauterine system (IUS); vasectomy or tubal ligation; and one effective method of contraception, including male condom, female condom, cervical cap, diaphragm or contraceptive sponge or abstain from heterosexual intercourse for the duration of study participation and for six months after the last bispecific antibody dose..
   3. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment.

6. 6. Consent:

   1. Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

1. Other Malignancies:

   a. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, breast) unless disease-free for at least 2 years.

   b. History of Richter's transformation of chronic lymphocytic leukemia (CLL).

2. Stem Cell Transplantation:

   1. Autologous stem cell transplant within 6 weeks of planned bispecific antibody therapy.
   2. History of allogeneic stem cell transplantation within 6 months of planned bispecific antibody.

3. Infections:

   1. Presence of uncontrolled fungal, bacterial, viral, or other infections at the time of screening.
   2. Patients with uncontrolled hepatitis B or C infection. Subjects with positive Hepatitis B or C serology should be started on appropriate antiviral therapy prior to Emapalumab infusion.
   3. Patients must be negative for tuberculosis (TB). Subjects positive for latent tuberculosis prior to study must be started on or have completed with appropriate treatment prior to emapalumab infusion.
   4. Patients must be negative for active cytomegalovirus (CMV, NAT), Epstein-Barr virus (EBV, NAT), and adenovirus (NAT) by PCR testing.

4. Central nervous system (CNS) Disorders:

   a. Evidence of active CNS disease, regardless of prior CNS history. b. History or presence of CNS disorder such as seizure disorder or cerebrovascular ischemia/hemorrhage within 6 months of enrollment.

5. Cardiac and Pulmonary Events:

   1. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of enrollment.
   2. History of symptomatic pulmonary embolism within 3 months of enrollment (ongoing anticoagulation is allowed if beyond 3 months).

6. Autoimmune Disease:

   a. History of autoimmune disease requiring ongoing systemic immunosuppression. Steroids are allowed up to 5mg prednisone-equivalent for adrenal insufficiency.

   b. Patients anticipated to require canakinumab, Janus kinase (JAK) inhibitors, Tumor necrosis factor (TNF) inhibitors, or tocilizumab for baseline autoimmune/inflammatory disease at the time of bispecific antibody therapy initiation.

7. Vaccination:

   1. Receipt of a Bacillus Calmette-Guérin (BCG) vaccine within 12 weeks prior to screening.
   2. Receipt of any live or attenuated live vaccine (other than BCG) within 4 weeks prior to screening.

8. Investigational Agents:

   a. Participants receiving any other investigational agents for their condition.

9. Pregnancy or Breastfeeding:

   a. Females who are pregnant or breastfeeding, or participants unwilling to use birth control during the study and for 6 months after bispecific therapy.

10. Inability to Participate:

    1. In the investigator's judgment, subjects unlikely to complete all protocol required study visits or procedures, including follow-up visits, or comply with study participation requirements.