Itacitinib or Ruxolitinib to Improve Efficacy in Patients with Diffuse Large B-Cell Lymphoma Receiving Treatment with CAR T-cell Therapy
This phase II tests how well itacitinib or ruxolitinib works in combination with axicabtagene ciloleucel (axi-cel) chimeric antigen receptor (CAR) T-cell therapy in treating patients with diffuse large b-cell lymphoma (DLBCL). CAR T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient’s blood. Then the gene for a special receptor that binds to a certain protein on the patient’s cancer cells is added to the T cells in the laboratory. The special receptor is called a CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers, including DLBCL. Patients with DLBCL who express high levels of systemic inflammation may have worse outcomes with axi-cel than patients with low systemic inflammation. Giving a JAK1 inhibitor, such as itacitinib or ruxolitinib, may reduce tumor and systemic inflammation, and improve how well axi-cell therapy works in treating DLBCL.
Inclusion Criteria
- Patients with a histologically confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL) who plan to receive treatment at the Moffitt Cancer Center will be eligible
- Adult males or females who are 18 years of age or older at time of signing informed consent
- Must have ability to comprehend and the willingness to sign written informed consent for study participation
- Eligible to receive CAR-T cell therapy (axicabtagene ciloleucel) for DLBCL and histological variants approved by the standard of care label, which states: * “YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of: ** Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. ** 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. **Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma”
- Patients must have a serum ferritin level above 400 ng/mL and C-reactive protein level above 2 mg/dL (20 mg/L) at screening
- Eastern Oncology Cooperative Group (ECOG) performance status 0 to 2
- The effects of itacitinib and/or ruxolitinib on the developing human fetus are unknown. For this reason and because Janus kinase (JAK) inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation as outlined in criteria below: * Men must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through safety follow up and must refrain from donating sperm during this period. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the participants in their understanding confirmed * Women of childbearing potential must have a negative serum pregnancy test at screening and before the first dose of Day 1 and must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through safety follow up. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the participants and their understanding confirmed * Women of non-childbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR >= 12 months of amenorrhea) are eligible
- Patients must be ineligible for stem cell transplant at screening on the basis of active lymphoma
- Platelets >= 50 x 10^9/L
- Hemoglobin >= 8g/dL
- Neutrophils >= 0.5 x 10^9/L
- Alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN) for age, < 5 x ULN in the presence of liver metastases
- Aspartate aminotransferase (AST) < 2.5 x ULN for age, < 5 x ULN in the presence of liver metastases
- Total bilirubin < 1.5 x ULN or < 3 x ULN in the presence of documented Gilbert’s syndrome unconjugated hyperbilirubinemia)
- Renal creatinine clearance >= 30 mL/minute based on Cockcroft-Gault formula
- Cardiopulmonary cardiac left ventricular ejection fraction (LVEF) >= 40% confirmed by ECHO/multigated analysis
- Adequate pulmonary function =< Grade 2 dyspnea and =< Grade 2 hypoxia per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0
Exclusion Criteria
- Patients who are currently receiving or who have received any investigational study agent =< 4 weeks prior to screening visit are ineligible
- Prior treatment with chimeric antigen receptor (CAR) T-cell therapy
- Participants with clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial infarction within 6 months from screening, New York Health Association III or IV heart failure, and circulatory collapse requiring vasopressor or inotropic support
- Patients with a history of symptomatic thrombosis events (stroke, pulmonary embolism, or deep vein thrombosis) within 3 months of enrollment
- Participants with arrhythmias that are not stable on a medical management program within 2 weeks of screening are also excluded
- Evidence of active uncontrolled/untreated infection (viral, bacterial, fungal, opportunistic) of any origin
- Participants with a known history or prior diagnosis of immunologic or inflammatory/autoimmune disease affecting the central nervous system (CNS), and unrelated to their disease under study or previous treatment
- Known positive human immunodeficiency virus (HIV) status
- Participants with evidence of active and/or chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy, if indicated
- Participants with a history of hepatitis C virus (HCV) infection, HCV must have been treated and cured
- Participants with a history of active tuberculosis
- Participants who require the concurrent use of chronic systemic steroids or immunosuppressant medications. Steroids should not be given within 5 days prior to leukapheresis. Concomitant bridging steroids are allowed after leukapheresis
- Known hypersensitivity or severe reaction to itacitinib, ruxolitinib, similar compounds, or excipients
- Participants who have not recovered from adverse events (AEs) due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1), with the exception of stable Grade 2 peripheral neuropathy and/or any grade alopecia
- Pregnant or nursing (breast-feeding) women are excluded from this study because there is an unknown but potential risk to using itacitinib (stage I) or ruxolitinib (stage II) in pregnant or nursing women
- Any condition that would, in the investigator’s judgement, interfere with full participation in the study, including administration of itacitinib (stage I) or ruxolitinib (stage II) and attending required study visits (if outpatient); pose a significant risk to the participant; or interfere with interpretation of study data
- Inability of the participant to swallow and retain oral medication
- Participants receiving any medications or substances that are strong inhibitors of CYP3A4 are ineligible. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product
Additional locations may be listed on ClinicalTrials.gov for NCT05757219.
Locations matching your search criteria
United States
Florida
Tampa
PRIMARY OBJECTIVES:
I. To assess safety, tolerability, and efficacy of oral JAK inhibition in conjunction with axicabtagene ciloleucel (Axi-cel) CAR-T-cell therapy in subjects with diffuse large B-cell lymphoma (DLBCL).
II. To investigate whether a pre-modulation strategy using oral JAK inhibition, in conjunction with axi-cel, improves the proportion of patients who are alive and have not progressed at the landmark of 6 months after axi-cel from 25% to 45% in patients who express high levels of systemic inflammation.
SECONDARY OBJECTIVES:
I. To investigate the effect of pre-modulation with oral JAK inhibition on occurrence of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS).
II. To determine the overall response rate (ORR) at 6 months in patients treated with oral JAK inhibition and axicabtagene ciloleucel.
III. To investigate the effect of pre-modulation with oral JAK inhibition on systemic inflammation and the DLBCL tumor microenvironment.
IV. To compare the efficacy and safety of itacitinib versus ruxolitinib pre-modulation in patients receiving axi-cel.
OUTLINE: Patients are assigned to 1 of 2 stages.
STAGE 1: Patients undergo apheresis. Patients then receive itacitinib orally (PO) once daily (QD) after apheresis on approximately days -28 to +30, fludarabine intravenously (IV) and cytarabine IV on day -5 to -3 and receive axicabtagene ciloleucel IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography (ECHO) or multi-gated acquisition scan (MUGA) during screening and imaging with positron emission tomography (PET) and computed tomography (CT) throughout the study. Patients may also undergo optional tumor biopsies on study.
STAGE 2: Patients undergo apheresis. Patients then receive ruxolitinib PO QD after apheresis on approximately days -27 to +30, fludarabine IV and cytarabine IV on day -5 to -3 and receive axicabtagene ciloleucel IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA during screening and imaging with PET and CT throughout the study. Patients may also undergo optional tumor biopsies on study.
After completion of study treatment, patients are followed up at day +30, 60, 90, 180, and at 12, 18 and 24 months.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMoffitt Cancer Center
Principal InvestigatorMichael David Jain
- Primary IDMCC-21892
- Secondary IDsNCI-2023-01299
- ClinicalTrials.gov IDNCT05757219