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771 Itacitinib and Corticosteroids As Initial Treatment for Chronic Graft-Versus-Host Disease: Phase 1/2 Results from Gravitas-309

Program: Oral and Poster Abstracts
Type: Oral
Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Novel Therapies for Graft-versus-Host Disease
Hematology Disease Topics & Pathways:
Research, clinical trials, Non-Biological therapies, Clinical Research, Combination therapy, Therapies
Monday, December 12, 2022: 11:00 AM

Annie Im, MD1, Daniel Wolff, MD2*, Corey Cutler, MD, MPH3*, Robert Zeiser, MD4, Nirav N. Shah, MD5, Ming Tony Tan, PhD6*, Jaime Sanz, MD7*, Haris Ali, MD8, Giuseppe Milone, MD9, Arjun D. Law, MD10*, Domenico Russo, MD11, Eva-Maria Wagner, MD12*, Olga Ivanova, PhD13*, Kevin Hou, PhD13*, Maureen Bleam, BS13*, Rodica Morariu-Zamfir, MD13* and Steven Z Pavletic, MD, MS14

1Univ. of Pittsburgh Cancer Institute, Pittsburgh, PA
2Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany
3Dana-Farber Cancer Institute, Boston, MA
4Department of Medicine I, Medical Center University of Freiburg, Freiburg, Germany
5Medical College of Wisconsin, Brookfield, WI
6Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center/Lombardi Comprehensive Cancer Center, Washington, DC
7Avinguda Fernando Abril Martorell, Hospital Universitario La Fe, Valencia, Valencia, Spain
8City of Hope Medical Center, Duarte, CA
9Hematology and BMT Unit, Azienda Ospedaliero Universitaria Policlinico "G.Rodolico-San Marco", Catania, Italy
10University Health Network, Princess Margaret Cancer Centre, Toronto, Canada
11Unit of Blood Diseases and Bone Marrow Transplantation, ASST Spedali Civili, University of Brescia, ASST Spedali Civili, Brescia, Italy
12Haematology and Oncology, University Medical Center, University Medicine Mainz, Mainz, Germany
13Incyte Corporation, Wilmington, DE
14National Cancer Institute, National Institutes of Health, Bethesda, MD

Background: Itacitinib is a potent, selective oral Janus kinase (JAK) 1 inhibitor with broad anti-inflammatory activity. GRAVITAS-309 was designed as a 2-part, multicenter, randomized trial to assess the efficacy and safety of itacitinib in combination with corticosteroids (CS) as first-line treatment for moderate or severe chronic graft-versus-host disease (GVHD). We describe preliminary results from the open-label, dose-finding portion of the study.

Methods: The study initially investigated itacitinib at doses of 200 mg once daily (qd; n=11) and 300 mg qd (n=10) in combination with CS. Both doses were well tolerated. The trial was then expanded to test itacitinib 400 mg qd and 300 mg twice daily (bid); the initial 300-mg qd cohort was expanded, and a CS monotherapy cohort was added (Figure 1). The expected CS starting dose was 0.5–1 mg/kg per day prednisone (or methylprednisolone equivalent) with a dose taper initiated on Day 14 or earlier during the second week of treatment and following published recommendations (Flowers and Martin. Blood. 2015;125[4]:606-15). Itacitinib dosage was initially reduced by 100 mg when given concomitantly with a strong CYP3A4 inhibitor (sCYP3A4i; eg, azole antifungals). A total of 140 patients (pts) (35/treatment group) with moderate or severe chronic GVHD were to be randomized 1:1 using chronic GVHD risk status (moderate vs severe) as a stratification factor. The primary objective was to identify the appropriate dose and schedule of itacitinib for further development. The data cutoff was January 31, 2022.

Results: 103 pts were enrolled and received at least one dose of itacitinib. The cohorts were well balanced for pt and disease characteristics. Median age was 57 years (range, 23–76) for the itacitinib cohorts and 59 years (range, 28–75) for the CS cohort. Approximately two-thirds of pts had moderate chronic GVHD. At the time of data cut, 39 (38%) pts in the itacitinib cohorts and 10 (28%) pts in the CS cohort continued study treatment. Median duration of study treatment was 27–28 weeks for the itacitinib cohorts (including 13–16 weeks of concomitant CS) and 17 weeks for the CS cohort. The itacitinib 300-mg bid dose cohort was discontinued early due to malignancy relapse occurring in 4/29 (14%) pts and more pts requiring dose reductions compared with the 400-mg qd and 300-mg qd cohorts (28% vs 17% and 8%, respectively), mostly due to cytopenias. Incidence of grade ≥3 treatment-emergent adverse events (AEs) was higher in the itacitinib cohorts than with CS (65% vs 31%) and were reported most commonly in the system organ classes of infections (44% vs 6%) and blood and lymphatic system disorders (23%–34% vs 6%). Cytomegalovirus (CMV) infections occurred in 10%–15% of pts in itacitinib cohorts (including CMV pneumonia [n=3], esophagitis [n=1], enteritis [n=1]) vs 3% with CS. The all-cause mortality rate was 14%–18% in itacitinib cohorts vs 11% with CS, with infections the leading cause.

The overall response rate (ORR) at 6 months was 46% (complete response [CR], 14%) with 300-mg qd and 53% (CR, 32%) with 400-mg qd, vs 36% (CR, 18%) with CS.

A preliminary exposure-response analysis showed a bell-shaped curve with maximum efficacy decreasing at higher exposures, consistent with increasing incidence of AEs. 60%–70% of patients received coadministration with a sCYP3A4i at any time point during study treatment, which increased itacitinib exposure across all doses, requiring dose reduction by 200 mg qd.

Conclusion: Preliminary results for first-line treatment of moderate or severe chronic GVHD showed an increase in ORR and CR rate with itacitinib + CS vs CS alone in both the 300-mg qd and 400-mg qd cohorts, at the expense of increased rates of cytopenias, infections, and mortality. This benefit:risk ratio does not support moving the combination of itacitinib + CS to a later phase of development in first-line therapy of chronic GVHD.

Disclosures: Im: Incyte: Research Funding; Abbvie: Consultancy; CTI Biopharma: Consultancy. Wolff: Incyte Corporation: Honoraria; Sanofi: Honoraria; Novartis: Honoraria, Research Funding; Behring: Honoraria. Cutler: Incyte Corporation: Consultancy, Honoraria; Equilium: Consultancy, Honoraria; Omeros: Consultancy, Honoraria; Mallinckrodt: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Jazz Educational: Consultancy, Honoraria; CTI Biopharma: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Cimeio: Membership on an entity's Board of Directors or advisory committees; Oxford Immune Algorithmic: Membership on an entity's Board of Directors or advisory committees. Zeiser: Novartis Pharmaceuticals: Consultancy; Magenta: Consultancy; Incyte Corporation: Consultancy; Celularity: Consultancy; Equilium: Consultancy; Daiichi: Consultancy. Shah: Novartis: Consultancy; Lilly Oncology: Consultancy, Honoraria; TG therapeutics: Consultancy; Kite Pharma: Consultancy; Miltenyi Biotec: Consultancy, Research Funding; Incyte Corporation: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy; Epizyme: Consultancy. Tan: Incyte Corporation: Consultancy. Ali: Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Law: Kite Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara: Research Funding; Sierra: Research Funding; Incyte Corporation: Research Funding; Jazz Educational: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wagner: Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Amgen: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Medac: Other: Travel Grant; Kite Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ivanova: Incyte Corporation: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Hou: Incyte Corporation: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Bleam: Incyte Corporation: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Morariu-Zamfir: Incyte Corporation: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Pavletic: Center for Cancer Research at the National Cancer Institute: Other: Clinical Research Development Agreements with Celgene, Actelion, Eli Lilly, Pharmacyclics and Kadmon Corporation, Research Funding.

*signifies non-member of ASH