A Phase II Trial of Low-Dose Interleukin-2 (IL-2) Added to Extra-Corporeal Photopheresis for Steroid-Refractory cGVHD
Condition: Chronic Graft-versus-host-disease
MeSH terms: Bronchiolitis Obliterans Syndrome; Graft vs Host Disease
Intervention: Extracorporeal Photopheresis (ECP); Interleukin-2
Intervention description: Participants receive ECP treatment twice a week for 16 weeks; Participants receive daily IL-2 injections starting Week 8 of study and ending at Week 16
Intervention MeSH terms: Interleukin-2
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: chronic graft-versus-host-disease

Summary:

      This research study is evaluating a combination of a therapy called Extra-corporeal
      Photopheresis (ECP) with a drug called Interleukin-2 (IL-2) as a possible treatment for
      chronic graft-versus-host-disease (GVHD) following allogeneic stem cell transplant.
    

Eligibility criteria:

        Inclusion Criteria:

        Participants must meet the following criteria on screening examination to be eligible to
        participate in the study:

          -  Recipients of 7-8/8 HLA matched adult donor allogeneic stem cell transplantation with
             myeloablative or non-myeloablative conditioning regimens.

          -  Participants must have steroid-refractory cGVHD. Steroid-refractory cGVHD is defined
             as having persistent signs and symptoms of cGVHD (Appendix D; section 17.4) despite
             the use of prednisone at ≥ 0.25 mg/kg/day (or 0.5 mg/kg every other day) for at least
             4 weeks (or equivalent dosing of alternate corticosteroids) without complete
             resolution of signs and symptoms. Patients with either extensive chronic GVHD or
             limited chronic GVHD requiring systemic therapy are eligible.

          -  Stable dose of corticosteroids for 4 weeks prior to enrollment

          -  No addition or subtraction of other immunosuppressive medications (e.g.,
             calcineurin-inhibitors, sirolimus, mycophenolate-mofetil) for 4 weeks prior to
             enrollment. The dose of immunosuppressive medicines may be adjusted based on the
             therapeutic range of that drug

          -  Patient age ≥18 years old. Because no dosing or adverse event data are currently
             available on the use of IL-2 in participants <18 years of age, children are excluded
             from this study.

          -  Estimated life expectancy greater than 3 months.

          -  ECOG performance status 0-2 (Appendix A; section 17.1).

          -  Participants must have adequate organ function as defined below:

               -  Hepatic: Adequate hepatic function (total bilirubin <2.0 mg/dl-exception
                  permitted in patients with Gilbert's Syndrome; AST (SGOT)/ALT (SGPT) ≤ 2x ULN),
                  unless hepatic dysfunction is a manifestation of presumed cGVHD. For patients
                  with abnormal LFTs as the sole manifestation of cGVHD, documented GVHD on liver
                  biopsy will be required prior to enrollment. Abnormal LFTs in the context of
                  active cGVHD involving other organ systems may also be permitted if the treating
                  physician documents the abnormal LFTs as being consistent with hepatic cGVHD, and
                  a liver biopsy will not be mandated in this situation.

               -  Renal: Serum creatinine within normal institutional limits or creatinine
                  clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels above
                  institutional normal.

               -  Pulmonary: FEV1 ≥ 50% or DLCO(Hb) ≥ 40% of predicted, unless pulmonary
                  dysfunction is deemed to be due to chronic GVHD.

               -  Adequate bone marrow function indicated by ANC>1000/mm3 and platelets>50,000/mm3
                  without growth factors or transfusions

               -  Cardiac: No myocardial infarction within 6 months prior to enrollment or NYHA
                  Class III or IV heart failure, uncontrolled angina, severe uncontrolled
                  ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or
                  active conduction system abnormalities. Prior to study entry, any ECG abnormality
                  at screening must be documented by the investigator as not medically relevant.

          -  The effects of IL-2 on the developing human fetus are unknown. For this reason and
             because chemotherapeutic agents are known to be teratogenic, women of child-bearing
             potential and men must agree to use adequate contraception (hormonal or barrier method
             of birth control; abstinence) prior to study entry and for the duration of study
             participation. Should a woman become pregnant or suspect she is pregnant while
             participating in this study, she should inform her treating physician immediately.

          -  Ability to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria:

        Participants who exhibit any of the following conditions at screening will not be eligible
        for admission into the study.

          -  Ongoing prednisone requirement >1 mg/kg/day (or equivalent).

          -  Concurrent use of calcineurin-inhibitors plus sirolimus. Either agent alone is
             acceptable.

          -  History of thrombotic microangiopathy, hemolytic-uremic syndrome or thrombotic
             thrombocytopenic purpura.

          -  Exposure to any new immunosuppressive medication in the 4 weeks prior to enrollment.

          -  Extra-corporeal Photopheresis (ECP) or rituximab therapy within 4 weeks prior to
             enrollment

          -  Any contraindication to ECP, i.e. contraindication to heparin or 8-MOP.

          -  Post-transplant exposure to any novel immunosuppressive medication (e.g., alemtuzumab)
             within 100 days prior to enrollment.

          -  Donor lymphocyte infusion within 100 days prior to enrollment.

          -  Active malignant relapse.

          -  Active uncontrolled infection.

          -  Inability to comply with IL-2 treatment regimen.

          -  Uncontrolled cardiac angina or symptomatic congestive heart failure (NYHA Class III or
             IV: Appendix C; section 17.3).

          -  Organ transplant (allograft) recipient.

          -  HIV-positive individuals on combination antiretroviral therapy are ineligible because
             of the potential for pharmacokinetic interactions with the agents used after
             allogeneic HSCT. In addition, these individuals are at increased risk of lethal
             infections. Appropriate studies will be undertaken in participants receiving
             combination antiretroviral therapy when indicated.

          -  Individuals with active hepatitis B or C are ineligible as they are at high risk of
             lethal treatment-related hepatotoxicity after HSCT.

          -  Other investigational drugs within 4 weeks prior to enrollment, unless cleared by the
             Principal Investigator.

          -  Pregnant women are excluded from this study because of the potential for teratogenic
             or abortifacient effects. Because there is an unknown but potential risk of adverse
             events in nursing infants secondary to treatment of the mother, breastfeeding should
             be discontinued.