Pre-emptive Anakinra for Cytokine Event Reduction

Official title

Pilot Study of Pre-emptive Anakinra for the Prevention of Severe Cytokine Release Syndrome in Children and Young Adults With B-Acute Lymphoblastic Leukemia Receiving Chimeric Antigen Receptor (CAR) T Cells

Overview

Objectives: The primary objective of this study will be to evaluate the impact of pre-emptive use of anakinra on the rate of severe cytokine release syndrome (CRS) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for B-acute lymphoblastic leukemia (B-ALL) in children and young adults. Patient Population: Children and young adults \<25 years of age undergoing CAR T-cell therapy for B-ALL with bone marrow disease burden of ≥5% involvement or detectable peripheral blasts within 2 weeks of the initiation of lymphodepleting chemotherapy. Study Design: This is a pilot single arm study. The investigators will inquire into the efficacy and safety of using anakinra pre-emptively to reduce the rate of severe CRS in patients with \>/=5% bone marrow blasts or lymphoblasts in the peripheral blood. Treatment Plan: This is a single arm unblinded study in which patients will receive anakinra, 2.5 mg/kg (max 100mg), IV every 12 hours starting at the onset of persistent fever (fever \>38.5⁰ C x 2 occurrences separated by at least 4 hours in a 24 hour period). If there is persistence or progression of CRS, anakinra frequency will be increased to 2.5mg/kg IV (max 100mg), every 6 hours. Anakinra will be continued until 48 hours after resolution of CRS and ICANS, and at least 7 days post-CAR T infusion. If dose and frequency of anakinra is increased, the increased dose of anakinra will be continued until 48 hours after resolution of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) and at least 7 days post-CAR T infusion. For CRS worsening beyond dose escalation of anakinra, CRS will be managed as per standard of care management. Participants will be followed for 12 months following enrollment in the study and disease evaluations will be performed as per routine clinical care following CAR T-cell therapy.

Interventions

• Drug Anakinra (Kineret®)
  Pre-emptive Anakinra at the initial onset of CRS.

Primary outcome measures

• Rate of Severe CRS within 30 days of CAR T-cell infusion [Time frame: 30 days of CAR-T infusion]

Secondary outcome measures (8)

• Complete Remission Rate [Time frame: 28-35 days post CAR-T infusion]
• Overall and event-free survival [Time frame: Up to 12 months post CAR-T infusion]
• CRS and ICANS Severity [Time frame: Up to 12 months post CAR-T infusion]
• Immune effector cell-associated hematotoxicity (ICAHT) Severity [Time frame: Up to 12 months post CAR-T infusion]
• Use of tocilizumab or steroids [Time frame: Within 30 days post CAR T infusion]
• Infection severity [Time frame: Within 30 days post CAR T infusion]
• Inflammatory markers and cell turnover [Time frame: Within 30 days post CAR T infusion]
• Cell expansion and plasma cytokine profiles [Time frame: Within 35 days post CAR T infusion]

Eligibility criteria

• Patient consent and parental assent will be obtained.

NOTE: Signed consent form must be obtained prior to any study procedures. Labs, marrows or other procedures obtained during routine clinical care maybe used for eligibility if obtained within the protocol required windows.

• Patients or their parents/legally authorized representatives (LARs) must have the ability to understand and the willingness to sign a written informed consent document.
• The effects of Anakinra on the developing human fetus are largely unknown. For this reason, patients of child-bearing potential (POCBP) and their partners with sperm-producing reproductive capacity must agree to use adequate contraception from time of informed consent, for the duration of study participation, and for 90 days following completion of Anakinra therapy. Should a POCBP become pregnant or suspect they are pregnant while they or their partner are participating in this study, they should inform their treating physician immediately. Patients with sperm-producing reproductive capacity (PWSPRC) treated or enrolled on this protocol must also agree to use adequate contraception with partners of childbearing potential from time of informed consent, for the duration of study participation, and 90 days after completion of administration.

Note: A POCBP is any patient (regardless of gender, sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) with an egg-producing reproductive tract who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy
• Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)
• POCBP must have a negative serum or urine pregnancy test (women who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential)
• Patients who are between the age of 1 to 26 years
• Relapsed or refractory B-acute lymphoblastic leukemia

• 2nd or greater marrow relapse OR
• Central nervous system (CNS) relapse OR
• Any relapse after allogeneic hematopoietic stem cell transplant (HSCT) OR
• Refractory disease defined by not achieving an minimal residual disease (MRD)-negative complete remission (CR) after ≥ 2 chemotherapy cycles (1 cycle for relapsed patients) OR
• Ineligible for allogeneic HSCT because of:

• Comorbid disease
• Other contraindications to allogeneic HSCT conditioning
• No suitable donor
• Prior HSCT
• Declines HSCT as the therapeutic option after documented discussion, with expected outcomes, about the role of HSCT with a HSCT physician
• Documentation of CD19+ tumor expression in the bone marrow, peripheral blood, cerebrospinal fluid (CSF), or tumor tissue by flow cytometry at relapse, or a recent sample in the case of refractory disease. If the patient has received CD19-directed Pre-emptive anakinra for severe CRS prevention therapy, the flow cytometry should be obtained after this therapy to show CD19 expression.
• Adequate organ function defined as:

• Alanine aminotransferase (ALT) < 500 U/L
• Bilirubin ≤2.0 mg/dL
• Minimum pulmonary reserve defined as ≤Grade 1 dyspnea, pulse oximetry >92% on room air; diffusing capacity of the lungs for carbon monoxide (DLCO) ≥40% (corrected for anemia) if pulmonary function tests (PFTs) are clinically appropriate as determined by the treating investigator.
• Left ventricular shortening fraction ≥ 28% or ejection fraction ≥40% confirmed by echocardiography (ECHO), or adequate ventricular function documented by imaging or a cardiologist.
• Serum creatinine below the values in the below table, based on age/sex assigned at birth: Maximum Serum Creatinine (mg/dL) Age (years) Male Female 1 to <2 0.6 0.6 2 to <6 0.8 0.8 6 to <10 1.0 1.0 10 to <13 1.2 1.2 13 to <16 1.5 1.4 ≥16 1.7 1.4
• Bone marrow disease burden of ≥5% or peripheral blasts within 2 weeks of the start of lymphodepleting chemotherapy
• Receiving commercially available tisagenlecleucel

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Ann & Robert H. Lurie Children's Hospital of Chicago — Chicago

Publications

• Gazeau N, Liang EC, Wu QV, Voutsinas JM, Barba P, Iacoboni G, Kwon M, Ortega JLR, Lopez-Corral L, Hernani R, Ortiz-Maldonado V, Martinez-Cibrian N, Martinez AP, Maziarz RT, Williamson S, Nemecek ER, Shadman M, Cowan AJ, Green DJ, Kimble E, Hirayama AV, Maloney DG, Turtle CJ, Gauthier J. Anakinra for Refractory Cytokine Release Syndrome or Immune Effector Cell-Associated Neurotoxicity Syndrome afte PMID 37031746
• Hines MR, Knight TE, McNerney KO, Leick MB, Jain T, Ahmed S, Frigault MJ, Hill JA, Jain MD, Johnson WT, Lin Y, Mahadeo KM, Maron GM, Marsh RA, Neelapu SS, Nikiforow S, Ombrello AK, Shah NN, Talleur AC, Turicek D, Vatsayan A, Wong SW, Maus MV, Komanduri KV, Berliner N, Henter JI, Perales MA, Frey NV, Teachey DT, Frank MJ, Shah NN. Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-L PMID 36906275
• Rejeski K, Subklewe M, Aljurf M, Bachy E, Balduzzi A, Barba P, Bruno B, Benjamin R, Carrabba MG, Chabannon C, Ciceri F, Corradini P, Delgado J, Di Blasi R, Greco R, Houot R, Iacoboni G, Jager U, Kersten MJ, Mielke S, Nagler A, Onida F, Peric Z, Roddie C, Ruggeri A, Sanchez-Guijo F, Sanchez-Ortega I, Schneidawind D, Schubert ML, Snowden JA, Thieblemont C, Topp M, Zinzani PL, Gribben JG, Bonini C, S PMID 37300386
• Kineret. Package Insert. Biovitrum AB. December 18th.
• Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;2 PMID 30592986
• Strati P, Jallouk A, Deng Q, Li X, Feng L, Sun R, Adkins S, Johncy S, Cain T, Steiner RE, Ahmed S, Chihara D, Fayad LE, Iyer SP, Horowitz S, Nastoupil LJ, Nair R, Hassan A, Daoud TE, Hawkins M, Rodriguez MA, Shpall EJ, Ramdial JL, Kebriaei P, Hong DS, Westin JR, Neelapu SS, Green MR. A phase 1 study of prophylactic anakinra to mitigate ICANS in patients with large B-cell lymphoma. Blood Adv. 2023 PMID 37389847
• Liang EC, Albittar A, Portuguese AJ, Huang JJ, Wuliji N, Wu Q, De Los Reyes J, Pin N, Torkelson A, Kirchmeier DR. Planned Interim Analysis of a Phase 2 Investigator-Initiated Trial of Anakinra to Prevent CRS and Neurotoxicity after Treatment with Lisocabtagene Maraleucel. Transplantation and Cellular Therapy. 2024;30(2):S179-S80.
• Frigault MJ, Gallagher KM, Wehrli M, Valles B, Casey K, Lindell K, Trailor M, Cho H, Brown JL, Horick NK. A phase II trial of anakinra for the prevention of CAR-T cell mediated neurotoxicity. Blood. 2021;138:2814.

Identifiers

NCT: NCT06703216 · 2024-7158

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗