itacitinib (INCB039110) / Incyte, Innovent Biologics - LARVOL DELTA

Mechanism of CRS: Critical Roles of IFN-γ, CD40L, and CD4 Cells. (TCT-ASTCT-CIBMTR 2025) - P1, P2 | "These observations led to two clinical trials testing itacitinib (NCT04071366) and duvelisib (NCT05044039) as CRS prophylaxis after CART19 infusion. Further, Lentiviral overexpression of CD40L in CD8 CART19 resulted in robust surface expression and secretion of CD40L as well as dramatic production of IL-6 by iDC (Data not shown). Together, our studies clearly implicate two major pathways that are necessary and sufficient for CRS: 1) IFN-γ/IFN-γR/JAK1/2 axis (both CD4 and CD8) and 2) CD40L/CD40 PI3Kg/d axis (exclusively CD4) and represent logical targets for future CRS mitigation strategies in vivo ."

IO biomarker • Hematological Disorders • Hematological Malignancies • Oncology • CD40LG • CD8 • CSF2 • GLI2 • IFNG • IL4 • IL6 • JAK1

Jak Inhibitor Itacitinib with Ptcy and Tacrolimus to Prevent Gvhd in a Myeloablative Fractionated Busulfan Regimen: A Phase 2 Trial (TCT-ASTCT-CIBMTR 2025) - P2 | "Background: Fractionating busulfan and giving it over a longer period, along with post-transplant cyclophosphamide (PTCy) graft versus host disease (GVHD) prophylaxis, reduces toxicity and allows for the safe administration of a myeloablative regimen in older patients. Based on the activity of ruxolitinib, a Jak inhibitor, in treating GVHD, we reasoned that a Jak inhibitor may prevent GVHD...Thiotepa 5 mg/kg was given on day -7 and fludarabine 30 mg/m 2 on days -6 to -3... These encouraging results warrant further studies to evaluate the role of JAK inhibitors to prevent GVHD, replacing MMF."

P2 data • Acute Graft versus Host Disease • Cardiovascular • Chronic Graft versus Host Disease • Chronic Lymphocytic Leukemia • Congestive Heart Failure • Febrile Neutropenia • Graft versus Host Disease • Heart Failure • Hematological Disorders • Hematological Malignancies • Hepatology • Immunology • Infectious Disease • Lymphoma • Multiple Myeloma • Myelofibrosis • Neutropenia • Novel Coronavirus Disease • Oncology • Otorhinolaryngology • Sinusitis

Hemophagocytic Syndrome Associated with CAR-T Cell Therapy (ASH 2024) - "on the use of drugs for cell therapy-related HLH at EBMT centers, common clinical combinations include corticosteroids + chemotherapy, corticosteroids + monoclonal antibodies + chemotherapy, corticosteroids + chemotherapy + cytokine blockade, corticosteroids + cytokine blockade, and corticosteroids alone. We introduce commonly used specific medications, including etoposide, emapalumab, the IL-six monoclonal antibody siltuximab, the anti-interleukin (IL)-six receptor monoclonal antibody tocilizumab, the interleukin-1 receptor antagonist anakinra, and JAK-one and JAK-two blockers such as ruxolitinib and the JAK-one inhibitor itacitinib, among others."

CAR T-Cell Therapy • IO biomarker • Hematological Disorders • Hematological Malignancies • Hemophagocytic lymphohistiocytosis • Hypertriglyceridemia • Immunology • Infectious Disease • Oncology • Rare Diseases • Rheumatology • Solid Tumor • Thrombocytopenia • IFNG

Itacitinib Pre-modulation in DLBCL Receiving CAR T Cell Therapy (clinicaltrials.gov) - P2 | N=27 | Recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2025 ➔ Apr 2026 | Trial primary completion date: Dec 2024 ➔ Apr 2025

CAR T-Cell Therapy • Trial completion date • Trial primary completion date • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CRP • JAK1

Final Analysis of Phase 2a Study of Adding Itacitinib to Tacrolimus/Sirolimus Gvhd Prophylaxis after Fludarabine/Melphalan-Based Conditioning Hematopoietic Cell Transplantation for Acute Leukemias, Myelodysplastic Syndrome (MDS), or Myelofibrosis (MF) (ASH 2024) - P2 | "Introduction : In a phase 2a clinical trial (NCT04339101), we hypothesized that adding Itacitinib, a potent and selective Janus kinases-1 inhibitor, to the standard tacrolimus/sirolimus (Tac/Siro) graft-vs-host-disease (GVHD) prophylaxis is safe and can potentially improve GVHD-free, relapse-free survival (GRFS). The study met the primary endpoint of 1-year GRFS at 54%, which is compared favorably to Tac/Siro or Tac/methotrexate as GVHD prophylaxis, similar to the results observed in PTCy/tacrolimus/MMF (BMT CTN 1703). The observed aGVHD rate was lower than our previously published historic data in patients receiving Tac/Siro alone (31% vs. 9%), half of the cases with grade 2-4 aGVHD were diagnosed after day +100 when itacitinib administration stopped per protocol therapy, indicating the need for further refinement in tapering strategy of Tac/Siro/itacitinib, potentially guided by the cytokine/cellular biomarkers identified in our study."

P2a data • Acute Graft versus Host Disease • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Oncology • Transplantation • IL10 • IL17A • TNFRSF1A

New drug tested to reduce side effect of ’half-matched’ stem cell transplants (ScienceDaily) - '"We have to be cautious about interpreting the results of a small study, but the rates of graft-versus-host disease were unexpectedly low," said senior author John F. DiPersio, MD, PhD....Half-matched transplants have increased dramatically in recent years, so improving the safety and effectiveness of this procedure is a big goal and has the potential to impact a lot of patients,' DiPersio said."

Media quote

Evaluation of Itacitinib Impact on TNFα Levels Following Immune Effector Cell (IEC) Therapy Using PKPD Modeling and Simulation Approaches (ASH 2024) - P2 | "Pharmacokinetic (PK) and PD modeling was applied to describe the inhibition of itacitinib on TNFα levels following CAR-T infusion.Objectives : The primary aim of the PKPD modeling analysis was to develop a mechanistic model to evaluate itacitinib anti-inflammatory action on systemic levels of TNFα following CAR-T therapy and itacitinib once-daily (QD) and twice-daily (BID) dosing regimens.Methods : The phase 2 study PKPD-evaluable population included 63 patients receiving CAR-T (axicabtagene ciloleucel) therapy for hematologic malignancies incorporating Part 1 (open-label; itacitinib 200 mg QD) and Part 2 (randomized, double-blind; itacitinib 200 mg BID vs placebo). The simulated BID regimen suppressed TNFα more effectively than QD, based on AUC metrics : 4391 pg∙hours/mL vs 2905 pg∙hours/mL.Conclusions : Aggregated TNFα profiles were adequately described by the integrated PKPD model incorporating CAR-T stimulatory dynamics with linear effect coupled with nonlinear..."

IO biomarker • Hematological Disorders • Hematological Malignancies • Oncology • JAK1 • TNFA

Rollover Study to Provide Continued Treatment for Participants With B-Cell Malignancies Previously Enrolled in Studies of Parsaclisib (INCB050465) (clinicaltrials.gov) - P2 | N=112 | Active, not recruiting | Sponsor: Incyte Corporation | Recruiting ➔ Active, not recruiting | N=200 ➔ 112

Enrollment change • Enrollment closed • Hematological Malignancies • Oncology

Contemporary Updates in the Prevention and Treatment of Graft-Versus-Host Disease. (PubMed, Curr Hematol Malig Rep) - "Clinical trials in preventing GVHD demonstrate lower rates of severe acute GVHD and chronic GVHD with post-transplant cyclophosphamide. For acute GVHD, lower risk acute GVHD appears amenable to steroid-sparing therapies, such as sirolimus and itacitinib. Combinations with novel agents such as itolizumab appear promising for high risk acute GVHD...For chronic GVHD requiring therapy beyond steroids, ruxolitinib, belumosudil, and ibrutinib are now available and should be considered. Increasingly, GVHD has become a manageable complication after allogeneic HCT potentially translating to greater success with allogeneic HCT in the future."

Journal • Review • Acute Graft versus Host Disease • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Transplantation

Itacitinib for Prevention of Graft-Versus-Host Disease and Cytokine Release Syndrome in Haploidentical Transplantation. (PubMed, Blood) - P1 | "Although post-transplant cyclophosphamide (PtCy) has improved graft vs. host disease (GvHD) prophylaxis in haplo-HCT, patients continue to experience life-threatening complications. Itacitinib, when added to standard GvHD prophylaxis, was well tolerated and resulted in low rates of CRS, acute and chronic GvHD, NRM and encouraging rates of GvHD-free relapse-free survival (GRFS) and OS after haplo-HCT. NCT03755414."

Cytokine release syndrome • Journal • Graft versus Host Disease • Hematological Disorders • Immunology • Inflammation • Oncology • Transplantation • IFNG • IL6 • JAK1

Itacitinib + Everolimus in Hodgkin Lymphoma (clinicaltrials.gov) - P1/2 | N=23 | Active, not recruiting | Sponsor: University of Pennsylvania | Trial primary completion date: Oct 2024 ➔ May 2024

Trial primary completion date • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Oncology

Itacitinib for the Treatment Steroid Refractory Immune Related Adverse Events Arising From Immune Checkpoint Inhibitors (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Douglas Johnson | N=25 ➔ 0 | Recruiting ➔ Withdrawn | Trial primary completion date: Apr 2026 ➔ Sep 2026

Adverse events • Checkpoint inhibition • Enrollment change • Trial primary completion date • Trial withdrawal • Hematological Malignancies • Oncology • Solid Tumor

Pluronic F127/lecithin PLGA nanoparticles as carriers of monocyte-targeted jakinibs: a potential therapeutic platform. (PubMed, Nanomedicine (Lond)) - "Aim: In this study, PLGA nanoparticles (PNPs) emulsified in Pluronic F127 (F127)/Lecithin (LEC) were designed to load Itacitinib (ITA), a selective JAK1 inhibitor, for targeting human monocytes.Materials & The physicochemical characteristics of empty and ITA-loaded F127/LEC PNPs were analyzed...ITA-F127/LEC PNPs significantly dampened monocyte activation. They also inhibited the monocyte's ability to promote T-cell proliferation and inhibited proinflammatory cytokine production. ITA-loaded F127/LEC PNPs showed potential for monocyte-targeted therapy, offering new avenues for disease treatment."

Journal

Rollover Study to Provide Continued Treatment for Participants With B-Cell Malignancies Previously Enrolled in Studies of Parsaclisib (INCB050465) (clinicaltrials.gov) - P2 | N=200 | Recruiting | Sponsor: Incyte Corporation | Trial completion date: Sep 2024 ➔ Sep 2027 | Trial primary completion date: Sep 2024 ➔ Sep 2027

Trial completion date • Trial primary completion date • Hematological Malignancies • Oncology

Study of INCB040093 in Subjects With Previously Treated B-Cell Malignancies (clinicaltrials.gov) - P1 | N=121 | Active, not recruiting | Sponsor: Incyte Corporation | Trial completion date: Aug 2024 ➔ Jan 2025 | Trial primary completion date: Aug 2024 ➔ Jan 2025

Trial completion date • Trial primary completion date • Hematological Malignancies • Oncology

Itacitinib for the Treatment of Bronchiolitis Obliterans Syndrome After Donor Hematopoietic Cell Transplant (clinicaltrials.gov) - P1 | N=8 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: May 2024 ➔ May 2025 | Trial primary completion date: May 2024 ➔ May 2025

Trial completion date • Trial primary completion date • Pulmonary Disease • Respiratory Diseases • Transplantation

NCI-2019-03203: Itacitinib and Alemtuzumab in Treating Patients with T-Cell Prolymphocytic Leukemia (clinicaltrials.gov) - P1 | N=15 | Completed | Sponsor: M.D. Anderson Cancer Center | Active, not recruiting ➔ Completed | Trial completion date: Dec 2026 ➔ Sep 2024 | Trial primary completion date: Dec 2026 ➔ Sep 2024

Trial completion • Trial completion date • Trial primary completion date • Hematological Malignancies • Leukemia • Oncology • Prolymphocytic Leukemia

Strategies to Mitigate CAR T-Cell-Associated Cytokine Release Syndrome and Neurologic Toxicity (ICBMT 2024) - "Past and current strategies to improve the safety profile of axi-cel will be reviewed: prophylactic tocilizumab, dexamethasone, anakinra, and earlier interventions. I will spotlight promising data from a recent clinical trial investigating the JAK-1 inhibitor itacitinib to prevent CRS and ICANS after axi-cel treatment (Frigault et al., ASH Abstract...Lastly, I will share our experience with anakinra to prevent CRS and ICANS in patients with large B-cell lymphoma receiving the CD19 CAR T-cell product lisocabtagene maraleucel on an investigator-initiated clinical trial (Liang et al., Tandem Meeting Abstract...2023). Learning objectives: - Identify clinical and laboratory factors associated with severe CRS and ICANS - Recognize differences in the toxicity profile across distinct CAR T-cell products - Become acquainted with current toxicity prophylactic strategies"

CAR T-Cell Therapy • Cytokine release syndrome • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Infectious Disease • Inflammation • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Safety and efficacy of itacitinib, a selective JAK1 inhibitor, in advanced hepatocellular cancer: Phase 1b trial (JAKAL). (PubMed, Future Oncol) - P1 | "Tumor biopsies and blood samples will be taken for presence of JAK1 mutations.Activation of JAK/STAT pathway drives HCC development and is associated with immunotherapy resistance. Itacitinib is hypothesized to be safe and effective in HCC patients that have progressed after first-line therapies.Clinical Trial Registration: EudraCT: 2017-004437-81 NCT04358185 (ClinicalTrials.gov)."

IO biomarker • Journal • Metastases • P1 data • Fibrosis • Gastroenterology • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Liver Cancer • Liver Cirrhosis • Oncology • Solid Tumor

Phase II Study of Pembrolizumab and Itacitinib for Patients with Metastatic NSCLC Expressing PD-L1: Long-Term Follow up (IASLC-WCLC 2024) - P2 | "Conclusions : Treatment-naïve pts with mNSCLC and PD-L1 expression ≥50% treated with pembrolizumab and a brief course of JAK inhibition achieved an ORR of 62% at 12 weeks and improvement in mPFS and mOS compared to historical controls (Keynote 24: mPFS 10.3 mo, mOS 30 mo). Interferon signaling modulation through JAK1 inhibition may help prevent resistance to anti-PD1 therapy and should be studied further in a randomized trial."

Clinical • IO biomarker • Metastases • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • JAK2 • PD-L1

Itacitinib Pre-modulation in DLBCL Receiving CAR T Cell Therapy (clinicaltrials.gov) - P2 | N=27 | Recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Nov 2026 ➔ Dec 2025

CAR T-Cell Therapy • Trial completion date • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CRP • JAK1

NCI-2022-03765: Adding Itacitinib to Cyclophosphamide and Tacrolimus for the Prevention of Graft Versus Host Disease in Patients Undergoing Hematopoietic Stem Cell Transplants (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Apr 2024 ➔ May 2026 | Trial primary completion date: Apr 2024 ➔ May 2026

Post-transplantation • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Myelomonocytic Leukemia • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Transplantation

haplo-HCT: Study of Itacitinib for the Prophylaxis of Graft-Versus-Host Disease and Cytokine Release Syndrome After T-cell Replete Haploidentical Peripheral Blood Hematopoietic Cell Transplantation (clinicaltrials.gov) - P1 | N=55 | Completed | Sponsor: Washington University School of Medicine | Active, not recruiting ➔ Completed | Trial completion date: Sep 2024 ➔ May 2024

Cytokine release syndrome • Trial completion • Trial completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Graft versus Host Disease • Hematological Malignancies • Hodgkin Lymphoma • Immunology • Inflammation • Leukemia • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • CD34

Itacitinib, Tacrolimus, and Sirolimus for the Prevention of GVHD in Patients With Acute Leukemia, Myelodysplastic Syndrome, or Myelofibrosis Undergoing Reduced Intensity Conditioning Donor Stem Cell Transplantation (clinicaltrials.gov) - P2 | N=59 | Active, not recruiting | Sponsor: City of Hope Medical Center | Phase classification: P2a ➔ P2 | Trial completion date: May 2024 ➔ Dec 2024

Phase classification • Trial completion date • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Oncology • Transplantation

Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients. (PubMed, Science) - "Patients with persistent inflammation refractory to itacitinib showed progressive CD8 T cell terminal differentiation and progressive disease. Thus, JAK inhibition may improve the efficacy of anti-PD-1 immunotherapy by pivoting T cell differentiation dynamics."

Journal • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD8 • JAK1