Itacitinib (INCB039110) and Extracorporeal Photopheresis (ECP) for First-Line Treatment in Chronic GVHD
Condition: Chronic Graft-versus-host-disease
MeSH terms: Bronchiolitis Obliterans Syndrome; Graft vs Host Disease
Intervention: Itacitinib; Extracorporeal Photopheresis (ECP)
Intervention description: 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 Partial Response (PR) or better may continue itacitinib for up to 1 year.; 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention 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. (As this study was terminated after enrolling 3 patients, Part 2 of the planned study did not occur.)
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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.