A Study of Itacitinib for the Treatment of Chronic Graft Versus Host Disease (cGVHD)

A Pilot Study of INCB039110 (Itacitinib) for the Treatment of Steroid Refractory Chronic Graft-Versus-Host Disease

This study is being done in patients who have been receiving corticosteroids or other immunosuppressive therapies for the treatment of cGVHD for at least 6 months. The purpose of this study is to find out if itacitinib in combination with corticosteroids or other immunosuppressive therapies is safe and effective in people with cGVHD.

Graft versus host disease remains a major hurdle to improve allogeneic hematopoietic stem cell transplantation outcome, with cGVHD being associated with decreased quality of life. Suppression of the immune system with corticosteroids forms the basis of first-line therapy for management of GVHD, but sustained responses are usually seen in less than 50 percent of patients and there is no standard second- or third-line treatment for steroid refractory cGVHD. Identification of novel therapeutic targets are needed to improve outcomes. Therapeutic potential has been shown by a JAK inhibitor in the treatment of steroid refractory GVHD. Itacitinib is a novel, selective inhibitor of the JAK family of protein tyrosine kinases and will be studied here in patients with steroid refractory cGVHD.

Inclusion Criteria:

1. Written informed consent signed by the patient or legal guardian prior to any study-related screening procedures

2. Patients who have undergone allo-hematopoietic stem cell transplant(s) (HSCT) from any donor HLA type (related or unrelated donor with any degree of HLA matching) using any graft source (bone marrow, peripheral blood stem cells, or cord blood). Recipients of non-myeloablative, myeloablative, and reduced intensity conditions are eligible.

3. Active, clinically diagnosed, moderate or severe cGVHD per NIH Consensus Criteria:

   • Moderate cGVHD: at least 1 organ (except lung) with a score of 2, ≥3 organs involved with a score of 1 in each organ, or lung score of 1
   • Severe cGVHD: at least 1 organ with a score of 3, or lung score of 2 or 3

4. cGVHD must be refractory to steroids defined by at least one criteria:

   • Patient is refractory to glucocorticoid therapy at screening: ongoing treatment with prednisone equivalent ≥0.20 mg/kg/day x 4 weeks (wks) at screening and organ progression documented 4 wks after the initiation of this regimen
   • Patient is dependent on glucocorticoid therapy at screening: treatment with a prednisone equivalent mean dose ≥0.20 mg/kg/day received for 12 wks at screening
   • Patient is intolerant to glucocorticoids at screening: ongoing treatment with prednisone equivalent ≥0.20 mg/kg/day x 4 wks at screening and presence of at least one documented glucocorticoid toxicity

5. Evidence of myeloid and platelet engraftment (absolute neutrophil count ˃1,000/mm^3 and platelet count ˃25,000/mm^3). Use of growth factors or platelet transfusions is not allowed within 7 days before screening of laboratory assessment.

6. Patients must currently be receiving systemic or other immunosuppressive therapies for the treatment of cGVHD for a duration of ˃6 months prior to start of study treatment

7. Patients must be able to swallow and retain oral medication

8. Eastern Cooperative Oncology Group Performance Status score of 0, 1, or 2

9. Adequate hematologic function

10. Adequate renal function: creatinine clearance ≥30 mL/min measured or calculated by Cockcroft Gault equation

11. Patients willing to avoid pregnancy or father children based on 1 of the following:

    • Women of non-childbearing potential (i.e., surgically sterile by hysterectomy and/or bilateral oophorectomy OR ≥12 months of amenorrhea)
    • Women of childbearing potential who have a negative serum pregnancy test at screening and who agree to take appropriate precautions to avoid pregnancy from screening through safety follow-up.
    • Men who agree to take appropriate precautions to avoid fathering children from screening through safety follow-up. Male patients must also refrain from donating sperm during their participation in the study and for at least 3 months after completing the study.

12. Ability to understand the nature of this study and to comply with study and follow-up procedures

Exclusion Criteria:

1. Receiving concomitant JAK inhibitor for cGVHD; prior treatment with a JAK inhibitor for acute GVHD is permitted if treatment was stopped more than 60 days prior to study start. Patients are eligible if JAK inhibitors for treatment of cGVHD are stopped due to side effects and not due to refractoriness.

2. Treatment with any other investigational agent, device, or procedure, within 28 days (or 5 half-lives, whichever is longer) of enrollment. For previous study drugs where 5 half-lives is ≤28 days, a minimum of 10 days between termination of that study drug and administration of itacitinib is required.

3. Presence of current secondary malignancies with the exception of previously treated in situ carcinoma, cervical carcinoma Stage 1B or less, and noninvasive basal cell or squamous cell skin carcinoma.

4. Pregnant or nursing (lactating) women

5. Patients with relapsed primary malignancy, or who have been treated for relapse after the allo-HSCT was performed

6. History of progressive multifocal leukoencephalopathy

7. Evidence of the following infections:

   • Active uncontrolled bacterial, fungal, parasitic, or viral infection. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of infection progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
   • Known HIV infection
   • Active tuberculosis infection that developed after allo-HSCT
   • Active viral infection confirmed by polymerase chain reaction for the BK virus ( a polyoma virus), cytomegalovirus, Epstein-Barr virus, and human herpes virus 6
   • Active hepatitis B virus (HBV) or hepatitis C virus that requires treatment, or at risk for HBV reactivation (i.e., positive HBsAg)

8. Severe organ dysfunction unrelated to underlying GVHD including:

   • Cholestatic disorders or unresolved veno-occlusive disease of the liver (persistent bilirubin abnormalities not attributable to GVHD and ongoing organ dysfunction)
   • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral itacitinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowl resection)
   • Clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial infarction within 6 months of enrollment, New York Heart Association Class III or IV congestive heart failure, circulatory collapse requiring vasopressor or inotropic support, or arrhythmia that requires therapy
   • Significant respiratory disease that requires mechanical ventilation support or a resting O2 saturation ˂90 percent by pulse oximetry or FEV1 ˂30 percent

9. Patients requiring platelet transfusions to maintain a platelet count ˃25,000/mm^3

10. Any corticosteroid therapy for indications other than cGVHD at doses ˃1 mg/kg/day methylprednisone or equivalent within 7 days of study start

11. Patients receiving treatment with medications that interfere with coagulation or platelet function including, but not limited to, aspirin dose exceeding 81 mg/day and related drugs such as heparin or warfarin sodium. Use of low molecular weight heparin is allowed.

12. Known allergies, hypersensitivity, or intolerance to itacitinib or any of its excipients

13. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol