Itacitinib (INCB039110) and Extracorporeal Photopheresis (ECP) for First-Line Treatment in Chronic GVHD

Study Overview
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Brief Summary
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An open-label, Phase II trial designed to assess the recommended phase 2 dose (RP2D) of itacitinib in combination ECP and efficacy of the combination after 24 weeks of therapy. The trial will consist of two parts: Part One will assess the RP2D. For dose-finding purposes, the DLT evaluation period will be defined as the time from the first dose of itacitinib lead-in (7-day lead-in) to the last day of cycle one combination therapy (Cycle one day 28). Part Two will further describe and characterize the safety and efficacy of the regimen. The RP2D will be determined by a 3+3 dose de-escalation design. Should dose level one be deemed intolerable, enrollment will proceed at dose level -1. The RP2D will be affirmed according to the rules of the 3+3 dose de-escalation scheme (Section 4.2). Once an RP2D has been confirmed, Part 2 will open as an expansion cohort.

Official Title
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A Phase II Study of Itacitinib (INCB039110) and Extracorporeal Photopheresis (ECP) for First-Line Treatment in Chronic Graft Versus Host Disease

Conditions
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Chronic Graft-versus-host-disease

Intervention / Treatment
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* Drug: Itacitinib
* Device: Extracorporeal Photopheresis (ECP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: -Male or female subject aged ≥ 18 years. Active, clinically diagnosed, moderate or severe chronic GVHD as defined by the NIH Consensus Development Project Criteria (See Appendix 2). History of an allogeneic hematopoietic cell transplant with any conditioning regimen, donor, or graft source. Need for systemic treatment for chronic GVHD as assessed by the treating investigator. No previous systemic treatment for chronic GVHD. Note: Participants may be receiving immunosuppressants for the prophylaxis or treatment of acute GVHD, but these medications must have been stable for at least 2 weeks prior to the initiation of study therapy. Prednisone dose (or its equivalent) should be at doses of ≤0.25 mg/kg/d for at least 2 weeks prior to the initiation of study therapy. Topical or inhaled treatments for chronic GVHD are allowed. Any prior ECP treatments for the management of acute GVHD must have occurred > 4 weeks prior to the initiation of itacitinib treatment. Able to swallow and retain oral medication. Life expectancy > 24 weeks. Karnofsky performance status ≥ 60 Evidence of myeloid and platelet engraftment: Absolute neutrophil count ≥ 1000/mcL Platelet count ≥ 25,000/mcL Note: Use of growth factors and transfusion support is allowed during the study; however, growth factors and transfusion support to reach a minimum ANC or platelet count for inclusion are not allowed within the 7 days before the screening laboratory assessment. Adequate organ function as defined as: Hepatic: Total bilirubin ≤ 2 mg/dL AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN (unless of non-hepatic origin). AST/ALT ≤ 5 x ULN is acceptable if associated with chronic GVHD. Renal: ---eGFR ≥ 30 mL/min/1.73 m2 as calculated using the Modification of Diet in Renal Disease formula or by the Cockcroft-Gault formula: Males: ((140-age)×weight[kg])/(serum creatinine [mg/dL]×72) Females: (((140-age)×weight[kg])/(serum creatinine [mg/dL]×72))×0.85 Coagulation: PT/INR < 1.5 x ULN and PTT (aPTT) < 1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder). When treated with warfarin or other vitamin K antagonist, then INR ≤ 3 x ULN. Willingness to avoid pregnancy or father children based on the criteria below and as described in Section 5.4.2: Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy for at least 3 months OR ≥ 12 months of amenorrhea and at least 50 years of age). Woman of childbearing potential who has a negative serum pregnancy test at screening and negative urinary test before the first dose on Day 1 and who agrees 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 subject and their understanding confirmed. Men who agree to take appropriate precautions to avoid fathering children (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 subject and their understanding confirmed. Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines. Exclusion Criteria: Subjects with score 3 lung GVHD; or biopsy-proven bronchiolitis obliterans. Participants have uncontrolled manifestations of acute GVHD. Treatment with any investigational medication within ≤ 30 days or 5 half-lives, whichever is longer, before the first dose of study drug. Patients who have received any previous systemic treatment for chronic GVHD, including corticosteroids, prior to Cycle 1, Day 1. Note: Prior and concomitant use of Calcineurin-Inhibitors (CNIs) for prevention and treatment of acute GVHD, as well as topical/inhaled steroids, is acceptable. Received prior JAK inhibitor therapy for any indication ≤ 4 weeks prior to Cycle 1 Day 1. Patients with relapsed or progressive malignant disease or any post-transplant lymphoproliferative disease. Chronic GVHD occurring after a non-scheduled donor lymphocyte infusion (DLI) administered for pre-emptive treatment of malignancy recurrence. Participants who have received a scheduled DLI as part of their transplant procedure and not for management of malignancy relapse are eligible. Inability to swallow food or any condition of the upper gastrointestinal tract that precludes the administration of oral medications. Any contraindication for extracorporeal photopheresis (ECP) per the treating investigator's discretion. Subject has a concurrent illness which in the opinion of the investigator may interfere with the treatment and evaluation of the subject. Pregnant or currently breast-feeding. Note: INCB039110 is a JAK1 inhibitor with the potential for serious or life-threatening birth defects or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with INCB039110, breastfeeding should be discontinued if the mother is treated with INCB039110. These potential risks may also apply to other agents used in this study. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug and while on trial. Use of any prohibited concomitant medications as described in Section 6.5. A washout period of prohibited medications for a period of at least 5 half-lives or as clinically indicated should occur prior to the start of treatment. Inadequate recovery from toxicity and/or complications from major surgery before starting therapy. Unwillingness to be transfused with blood components during the study. History of other malignancy (not including the underlying malignancy that was the indication for the transplant), with the following exceptions: Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to Screening and felt to be at low risk for recurrence by the treating physician. Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease. Adequately treated cervical carcinoma in situ without current evidence of disease. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: Clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial infarction within 6 months of enrollment, NYHA Class III or IV congestive heart failure, circulatory collapse requiring vasopressor or inotropic support, or an arrhythmia that requires therapy. A clinically significant respiratory disease that requires mechanical ventilation support or ≥ 50% oxygen. Any uncontrolled active systemic infection or active infection requiring systemic treatment that was ongoing ≤ 7 days before screening. Subjects with acute infections requiring treatment should delay screening/enrollment until the course of therapy has been completed and the event is considered resolved. Prophylactic antibiotics will be permitted. Cholestatic disorders, or unresolved sinusoidal obstructive syndrome/ veno-occlusive disease of the liver (defined as persistent total bilirubin > 2 mg/dL, or abnormalities not attributable to GVHD and ongoing organ dysfunction). History of thromboembolic event within 1 month before study registration. HIV-infected patients on effective antiretroviral therapy with an undetectable viral load within 6 months are eligible for this trial. Active HBV or HCV infection that requires treatment, or at risk for HBV reactivation (i.e., positive HBsAg). Participants with negative HBsAg and positive total HBc antibody may be included if HBV DNA is undetectable at the time of screening. Participants who are positive for HCV antibodies are eligible only if PCR is negative for HCV RNA. Participants whose immune status is unknown or uncertain must have results confirming immune status before enrollment. Serology results performed less than or equal to 6 months prior to the first planned dose of itacitinib are acceptable for determining eligibility. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade ≥ 3). Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug/treatment and attending required study visits; pose a significant risk to the participant; or interfere with the interpretation of study data. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations) per the investigator's assessment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: The RP2D will be determined by a 3+3 dose de-escalation design. Once an RP2D has been confirmed, Part 2 will open as an expansion cohort.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment: all patients<br>Patients will self-administer itacitinib every morning regardless of food. ECP will be administered twice weekly on consecutive days for 8 weeks per institutional standards. At the end of 8 weeks of combination therapy, patients will start a standard ECP taper schedule and itacitinib will be continued at the assigned dose level. After six cycles of therapy, itacitinib may be tapered at the treating investigator's discretion as described below. | Drug: Itacitinib<br>* All eligible patients will begin study therapy with approximately a week lead-in of itacitinib monotherapy at scheduled dose. Itacitinib will be taken daily at scheduled dose for a total of six cycles. itacitinib may be tapered as deemed appropriate by the treating investigator. Patients will remain on study therapy as long as treatment discontinuation criteria are not met. Patients with PR or better may continue itacitinib for up to 1 year.<br>Device: Extracorporeal Photopheresis (ECP)<br>* ECP will begin after itacitinib lead in period. At the end of 8 weeks of combination therapy, patients will start a standard ECP taper schedule. Patients achieving PR or better after 6 cycles of itacitinib may continue treatment with itacitinib for up to 1 year. Thereafter, itacitinib may be tapered at the treating investigator's discretion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| rate of dose-limiting toxicities during the defined DLT evaluation period. | assess an appropriate dose of itacitinib in combination with Extracorporeal Photopheresis (ECP) in patients with moderate or severe chronic GVHD. | up to 35 days | 
| Overall response rate (ORR) at 24 weeks (at Cycle 7 Day 1 visit) as determined by the NIH Consensus Development Project Criteria (ORR is defined as CR + PR) without secondary systemic immunosuppressive therapy and no recurrent malignancy or death | assess the clinical efficacy of itacitinib in combination with ECP in subjects with moderate or severe chronic GVHD treated at the Recommended Phase 2 Dose (RP2D). | up to 35 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events (AEs) and serious adverse events (SAEs) will be collected assessed by CTCAE, version 5.0 for the duration of treatment. | assess the safety of itacitinib in combination with ECP. | 6-12 months | 
| • Overall response rate at 1-year as determined by the NIH Consensus Development Project Criteria, without secondary systemic immunosuppression and no recurrent malignancy or death | assess long term response and efficacy | 1 year | 
| • Failure Free Survival (FFS) at 24 weeks and 1-year as defined as the time from the initiation of study therapy until treatment failure defined as the initiation of secondary therapy for chronic GVHD, malignancy relapse, or death from any cause | assess long term response and efficacy | 24 weeks and 1 year | 
| proportion of patients who have withdrawn all immunosuppressants at 1-year. | assess long term response and efficacy | 1 year | 
| • Overall response rate at 24 weeks, as determined by the NIH Consensus Development Project Criteria, stratified by concurrent predisone (or equivalence) use: 0 mg/kg/d, ≤ 0.25mg/kg/d, and > 0.25mg/kg/d. | assess long term response and efficacy | 24 weeks | 
| mean cumulative prednisone dose used up to 24 weeks | assess long term response and efficacy | 24 weeks | 
| • Organ-specific response rates at 24 weeks and 1-year as determined by the NIH Consensus Development Project Criteria | assess long term response and efficacy | 24 weeks and 1 year | 
| • Change in NIH global score of chronic GVHD from baseline to 24 weeks and 1-year after the initiation of the protocol therapy | assess long term response and efficacy | 1 year | 
| Duration of response (DOR), interval between the date of initial documentation of a response (PR or better), and the time of progression from the best response, start of a new therapy for cGVHD (including corticosteroids), or death from any cause | assess long term response and efficacy | up to 1 year | 
| • Clinician-reported chronic GVHD activity assessment at baseline, 24 weeks, and 1-year | assess long term response and efficacy | week 0, 24 weeks, 1 year | 
| • Patient-reported chronic GVHD severity assessment at baseline, 24 weeks, and 1-year. | assess long term response and efficacy | week 0, 24 weeks, 1 year | 
| • 24 week and 1-year non-relapse mortality (NRM) defined as the proportion of participants who died due to causes other than a relapse of their primary hematologic disease | assess long term response and efficacy | 24 weeks and 1 year | 
| • Relapse rate (RR) of malignant and non-malignant hematologic diseases, defined as the proportion of participants whose underlying disease relapses at 24 weeks and 1-year | assess long term response and efficacy | 24 weeks and 1 year | 
| • Overall survival (OS) as defined as the time from the initiation of study therapy until death from any cause at 24 weeks and 1-year | assess long term response and efficacy | 24 weeks and 1 year |