itacitinib (INCB039110)

P1, N=15, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2026

P1, N=27, Terminated, Fred Hutchinson Cancer Center | Active, not recruiting --> Terminated; The study was terminated early with 27 out of 28 planned subjects enrolled. This decision was multifactorial, including slow enrollment in the last remaining cohort and a lack of evidence of clinical benefit.

P1, N=8, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=15 --> 8

P1, N=31, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P1, N=121, Active, not recruiting, Incyte Corporation | Trial completion date: Feb 2024 --> Aug 2024 | Trial primary completion date: Feb 2024 --> Aug 2024

P1, N=31, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting

P1, N=32, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Phase classification: P1a/1b --> P1

P1, N=55, Active, not recruiting, Washington University School of Medicine | Recruiting --> Active, not recruiting

P1, N=55, Recruiting, Washington University School of Medicine | Trial completion date: May 2024 --> Sep 2024 | Trial primary completion date: Feb 2024 --> Jun 2024

P1, N=30, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Feb 2027 --> Apr 2025 | Trial primary completion date: Feb 2027 --> Apr 2025

P1/2, N=23, Active, not recruiting, University of Pennsylvania | Trial completion date: Jan 2027 --> Jun 2027

P2, N=27, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Feb 2028 --> May 2026 | Trial primary completion date: Feb 2028 --> Jun 2024

P1, N=30, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

to evaluate the interactions between immune system components of healthy individuals and EVs derived from monocytic and lymphoid lineage cells generated in the presence of baricitinib (BARI) and itacitinib (ITA) and their possible effects. The higher proportion of arachidonic acid in the FA content of ITA-L/M-EVs could be related to the thrombosis described in patients treated with ITA. EVs also induced a decrease in the respiratory burst of neutrophils.

P1/2, N=59, Active, not recruiting, Incyte Corporation | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

P2/3, N=155, Terminated, Incyte Corporation | Active, not recruiting --> Terminated; The study was terminated due to insufficient efficacy to support moving into Part 2 of the study; there were no safety concerns that contributed to this decision.

P2, N=3, Terminated, University of Utah | Trial completion date: Oct 2025 --> Jan 2023 | Active, not recruiting --> Terminated; PI left institution

P1, N=27, Active, not recruiting, Fred Hutchinson Cancer Center | Trial completion date: Dec 2023 --> Mar 2024

In this phase I study, patients with advanced solid tumors treated with pembrolizumab (PD-1 inhibitor) and either itacitinib (JAK1 inhibitor) or parsaclisib (PI3Kδ inhibitor) experienced limited clinical activity beyond that expected with checkpoint inhibition alone and showed little effect on T-cell infiltration in the tumor. These results do not support continued development of these combinations.

P1/2, N=23, Terminated, Incyte Corporation | Active, not recruiting --> Terminated; Business Decision

P2, N=18, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting | N=100 --> 18

P2, N=25, Recruiting, Douglas Johnson | Initiation date: Oct 2023 --> Jan 2024

P2, N=15, Terminated, SCRI Development Innovations, LLC | Trial completion date: Jun 2024 --> Sep 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jun 2024 --> Sep 2023; Slow enrollment and PI departure

Kinase inhibitors blocking JAK activity, particularly Ruxolitinib a JAK1/2 inhibitor, have shown some efficacy in murine genetic models of HLH...In the absence of organ failure, fibrinogen<0.5 g/L, platelets<20 G/l, the need for ICU transfer, or etoposide treatment, HLH patients were considered non-severe... As first line treatment, itacitinib monotherapy provided encouraging clinical activity characterized by a high RR and durable response and no safety issues were notified. The second stage of HLH JAK is ongoing. Clinical trial information: NCT NCT05063110

GVHD prophylaxis was tacrolimus, mycophenolate mofetil, and post-transplant cyclophosphamide. Itacitinib with PB haplo-HCT was safe with low rates of acute and chronic GVHD, without increased risk of relapse or transplant related mortality. Severe CRS was not seen in this trial, and no anti-IL6 or steroid therapy was used. The addition of Jak inhibition to standard PtCy based GVHD prophylaxis was associated with encouraging rates of GRFS and OS on this pilot and expansion study.

The dose-finding, open-label, randomized portion of the study initially investigated itacitinib at 200 mg once daily (qd) and 300 mg qd in combination with CS (methylprednisolone or prednisone); both doses were well tolerated. Analysis of patient samples from GRAVITAS-309 revealed that serum elafin and DKK3 levels significantly correlated with skin GVHD scores, possibly reflecting the systemic origin of observed skin manifestations. Serum levels of osteopontin, CXCL9, and CXCL10 were specifically reduced by itacitinib in patients with cGVHD and may represent potential pharmacodynamic markers. Observed changes in different peripheral T-cell populations in patients' samples following itacitinib treatment were consistent with those reported in murine GVHD models, suggesting a potential role of naive CD4+ T cells in driving this disease.

P2; Trial completion date: Aug 2024 --> Jun 2025 | Trial primary completion date: Apr 2024 --> Dec 2024

P1, N=27, Active, not recruiting, Fred Hutchinson Cancer Center | Recruiting --> Active, not recruiting | Trial completion date: Jan 2025 --> Dec 2023 | Trial primary completion date: Jan 2024 --> Mar 2023

P2, N=111, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting | Trial completion date: Nov 2023 --> Jul 2023 | Trial primary completion date: Jun 2023 --> Feb 2023

P1a/1b, N=32, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting

P1, N=121, Active, not recruiting, Incyte Corporation | Trial completion date: Feb 2023 --> Feb 2024 | Trial primary completion date: Feb 2023 --> Feb 2024

P1, N=15, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P1a/1b, N=32, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Initiation date: Apr 2023 --> Jul 2023

P2, N=25, Not yet recruiting, Douglas Johnson | Trial completion date: Apr 2026 --> Aug 2026 | Initiation date: Mar 2023 --> Jul 2023 | Trial primary completion date: Apr 2025 --> Aug 2025

P2; Recruiting --> Active, not recruiting

P1, N=55, Recruiting, Washington University School of Medicine | Trial completion date: Sep 2023 --> May 2024 | Trial primary completion date: Jul 2023 --> Feb 2024

P2, N=27, Recruiting, H. Lee Moffitt Cancer Center and Research Institute

P1/2, N=59, Active, not recruiting, Incyte Corporation | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

Patients receiving commercial CAR-T products co-treated with itacitinib demonstrated kinetic parameters of CAR-T expansion similar to historical values. Functional marker expression and cytokine production suggest that JAK inhibition at the current study dose has no deleterious effect on CAR-T function. The current study will expand with a randomized, double-blind, placebo-controlled portion that will enroll patients with DLBCL receiving axi-cel with itacitinib (200 mg twice daily) vs placebo.

Early survival data including preliminary GRFS are promising. The study follow up is ongoing, and mature clinical data and immune reconstitution analyses will be updated.

P1, N=28, Recruiting, Fred Hutchinson Cancer Center | Trial completion date: Jun 2024 --> Jan 2025 | Trial primary completion date: Jun 2023 --> Jan 2024

Treatment-naïve pts with mNSCLC and PD-L1 expression ≥50% treated with pembrolizumab and a brief course of JAK inhibition starting at week 6 of treatment resulted in an ORR of 62% at 12 weeks and mPFS of 23.4 months. This novel combination was well tolerated. Interferon signaling modulation through JAK1 inhibition may help prevent resistance to anti-PD1 therapy and should be studied further in a randomized trial.