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

Phase 2

Terminated

Conditions: Chronic Graft-versus-host-disease

Interventions: Drug: Itacitinib
Device: Extracorporeal Photopheresis (ECP)

Registration Number: NCT04446182

Lead Sponsor: University of Utah

Brief Summary: 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 dose limiting toxicity (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. Once an RP2D has been confirmed, Part 2 will open as an expansion cohort.

As this study was terminated after enrolling three patients out of an anticipated target accrual of 58, Part Two of this study did not occur.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 3

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/microliter (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 absolute neutrophil count (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
  - alanine transaminase (AST)(SGOT)/aspartate aminotransferase (ALT)(SGPT) ≤ 2.5 × institutional upper limit of normal (ULN) (unless of non-hepatic origin). AST/ALT ≤ 5 x ULN is acceptable if associated with chronic GVHD.
- Renal:
  
  ---estimated glomerular filtration rate (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/ international normalized ratio (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 non-childbearing potential (i.e., 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 Janus kinase (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 Janus kinase 1 (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, New York Heart Association (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 hepatitis B virus (HBV) or hepatitis C virus (HCV) infection that requires treatment, or at risk for HBV reactivation (i.e., positive HBsAg). Participants with negative HBsAg and positive total hepatitis B core antigen (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 polymerase chain reaction (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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment: all patients	Extracorporeal Photopheresis (ECP)	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.
Treatment: all patients	Itacitinib	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.

Primary Outcome Measures

Name	Time	Method
Count of Participants With a Dose-limiting Toxicity (DLT) During the DLT Evaluation Period.	up to 38 days	Adverse events were assessed at each study visit from the first dose of itacitinib during the lead-in period (lead-in period = 5-10 days) until the last day of cycle one (each cycle = 28 days) of combination treatment with itacitinib and Extracorporeal Photopheresis (ECP). A DLT was defined as an Adverse Event (AE) that was 1) attributed as possibly, probably, or definitely related to itacitinib or to the combination of itacitinib and ECP, and 2) graded as "severe" or "life threatening" (grade 3 or 4) according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.
Count of Participants With a Response to Treatment at 24 Weeks of Treatment	24 weeks	Participants were assessed for chronic graft versus host disease (GVHD) severity per the NIH Consensus Development Project Criteria at baseline and after 24 weeks of treatment. The criteria evaluates 9 organ systems, and then defines a partial response (PR) as at least one organ system with improvement since baseline and no worsening in other organs. Complete response (CR) is defined as an improvement in all affected organ systems to having no GVHD symptoms in any organ system. All responses must occur without any secondary systemic immunosuppressive therapy, and no malignancy recurrence or death. Participants with a PR or CR are counted as a response for this outcome.

Secondary Outcome Measures

Name	Time	Method
Count of Participants Who Experience Adverse Events (AEs) and Serious Adverse Events (SAEs) During Study Treatment	during study treatment - up to 1 year	Adverse events were assessed at each study visit per CTCAE v5 criteria. This objective counts the number of participants who experienced 1) any adverse event of any severity, or 2) any serious adverse event that was possibly, probably, or definitely related to itacitinib or to combination treatment with itacitinib and ECP.
Count of Participants With a Response to Treatment After One Year of Treatment	1 year	Participants were assessed for chronic graft versus host disease (GVHD) severity per the NIH Consensus Development Project Criteria at baseline and after one year of treatment. The criteria evaluates 9 organ systems, and then defines a partial response (PR) as at least one organ system with improvement since baseline and no worsening in other organs. Complete response (CR) is defined as an improvement in all affected organ systems to having no GVHD symptoms in any organ system. All responses must occur without any secondary systemic immunosuppressive therapy, and no malignancy recurrence or death. Participants with a PR or CR are counted as a response for this outcome.
Count of Participants With Failure Free Survival (FFS) at 24 Weeks and 1 Year	24 weeks and 1 year	Failure Free Survival (FFS) is defined as the number of participants at 24 weeks and at 1 year who have not experienced treatment failure. Treatment failure is defined as the initiation of secondary therapy for chronic GVHD, malignancy relapse, or death from any cause.
Count of Participants Who Have Withdrawn All Immunosuppressants at 1 Year	1 year	Immunosuppressive therapy is common for participants with GVHD. This objective counts the number of participants who were able to discontinue all immunosuppressants by 1 year of treatment and follow-up.
Count of Participants With a Response to Treatment at 24 Weeks of Treatment Stratified by Concurrent Prednisone Use	24 weeks	Participants were assessed for chronic graft versus host disease (GVHD) severity per the NIH Consensus Development Project Criteria at baseline and after 24 weeks of treatment. The criteria evaluates 9 organ systems, and then defines a partial response (PR) as at least one organ system with improvement since baseline and no worsening in other organs. Complete response (CR) is defined as an improvement in all affected organ systems to having no GVHD symptoms in any organ system. All responses must occur without any secondary systemic immunosuppressive therapy, and no malignancy recurrence or death. Participants with a PR or CR are counted as a response for this outcome. Participants were also evaluated for the amount of prednisone (or other steroids converted by prednisone equivalence) they were using at the time of the response. This outcome is the same as outcome # 2, but has been stratified by prednisone use.
Mean Cumulative Prednisone Used up to 24 Weeks	24 weeks	This outcome assessed the cumulative amount of prednisone (or other steroids converted to prednisone equivalence) used by participants up to 24 weeks of treatment.
Count of Participants With Organ-specific Responses at 24 Weeks	24 weeks	Participants were assessed for chronic graft versus host disease (GVHD) severity per the NIH Consensus Development Project Criteria at baseline and after 24 weeks of treatment. The criteria evaluate 9 organ systems, and for each organ, defines changes in symptoms to qualify as a partial response (PR), complete response (CR), or progressive disease (PD) in that organ. In general, PR in an organ indicates partial improvement after prior involvement of that organ. CR indicates improvement to no symptoms after prior involvement. PD indicates worsening of symptoms in the organ system. Lack of response indicates that the organ system was involved at both baseline and 24 weeks, but did not improve or deteriorate sufficiently to qualify for PR, CR, or PD. No involvement/Not evaluable indicates that the organ system never had any GVHD symptoms or was not able to be evaluated.
Count of Participants With Organ-specific Responses at 1 Year	1 year	Participants were assessed for chronic graft versus host disease (GVHD) severity per the NIH Consensus Development Project Criteria at baseline and after 1 year of treatment. The criteria evaluate 9 organ systems, and for each organ, defines changes in symptoms to qualify as a partial response (PR), complete response (CR), or progressive disease (PD) in that organ. In general, PR in an organ indicates partial improvement after prior involvement of that organ. CR indicates improvement to no symptoms after prior involvement. PD indicates worsening of symptoms in the organ system. Lack of response indicates that the organ system was involved at both baseline and 24 weeks, but did not improve or deteriorate sufficiently to qualify for PR, CR, or PD. No involvement indicates that the organ system never had any GVHD symptoms.
Mean NIH Global GVHD Score at 24 Weeks	24 weeks	Participants were assessed for chronic graft versus host disease (GVHD) severity per the NIH Consensus Development Project Criteria at baseline and after 24 weeks of treatment. One data point in the criteria is an overall global rating of the participant's GVHD, ranging from 0 (no GVHD) to 3 (severe GVHD). The baseline global score is reported in the baseline characteristics.
Duration of Response (DOR)	up to 1 year	DOR was measured as the interval between the date of initial documentation of a response (PR or better), and the date of progression, start of a new therapy for chronic GVHD (cGVHD) (including corticosteroids), or death from any cause.
Mean Clinician-evaluated GVHD Severity Score at 24 Weeks and 1 Year	at 24 weeks and 1 year	Participants were assessed for chronic graft versus host disease (GVHD) severity per the NIH Consensus Development Project Criteria at baseline, after 24 weeks of treatment, and after one year of treatment. One data point in the criteria is a general rating the severity of the participant's GVHD symptoms, ranging from 0 (GVHD symptoms not at all severe) to 10 (most severe GVHD symptoms possible). The baseline severity score is reported in the baseline characteristics.
Mean Participant-reported cGVHD Symptom Severity Score at 24 Weeks and at 1 Year	24 weeks and 1 year	Participants were asked to rate their own symptoms for chronic graft versus host disease (cGVHD) severity per the NIH Consensus Development Project Criteria at baseline, after 24 weeks of treatment, and after one year of treatment. One data point in is a general rating of the severity of the participant's GVHD symptoms, ranging from 0 (GVHD symptoms not at all severe) to 10 (most severe GVHD symptoms possible). The baseline severity score is reported in the baseline characteristics.
Count of Participants With Non-relapse Mortality (NRM)	24 weeks and 1 year	NRM is defined as death due to causes other than a relapse of their primary hematologic disease. This outcome reports the number of participants who were deceased at 24 weeks and at 1 year after the start of treatment whose death meets the definition of NRM.
Count of Participants With Relapse at 24 Weeks and 1 Year	24 weeks and 1 year	Relapse is defined as re-activation of the participant's primary hematologic malignancy after it has been in remission. This outcome reports the number of participants who had experienced relapse at 24 weeks and at 1 year after start of treatment.
Count of Participants Alive at 24 Weeks and 1 Year	24 weeks and 1 year	This outcome measures overall survival (OS), meaning the number of participants who remain alive at 24 weeks and at 1 year from start of treatment.