A Phase II Trial of Low-Dose Interleukin-2 (IL-2) Added to Extra-Corporeal Photopheresis for Steroid-Refractory cGVHD

A Phase II Trial of Low-Dose Interleukin-2 (IL-2) Added to Extra-Corporeal Photopheresis for Steroid-Refractory Chronic Graft-versus-Host-Disease

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.

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved IL-2 for the treatment of chronic GVHD but it has been approved for metastatic renal cell carcinoma (MCC) and metastatic melanoma. ECP is a standard of care treatment for chronic GVHD that has not responded to steroids.

Chronic GVHD is a medical condition that may occur after receiving bone marrow, stem cell or cord blood transplant from a donor. The donor's immune system may recognize (the host) as foreign and attempt to 'reject' it. This process is known as graft-versus-host disease.

Traditional standard therapy to treat chronic GVHD is prednisone (steroids). Participants on this trial have not responded to steroid therapy. The investigstors are looking to assess whether the combination of IL-2 and ECP therapy helps control chronic GVHD by stopping the donor's immune system from 'rejecting' the participant's body.

Participants will receive standard-of-care ECP treatment two times a week for 16 weeks. Each treatment will last approximately 2-3 hours. Starting after Week 8 of the ECP treatments, participants will give themselves or be given IL-2 through an injection under their skin. Participants will do this once every day for 8 weeks until the end of the 16-week ECP treatment. If a participant's GVHD worsens during the initial 8 weeks of ECP treatment, he or she has the option of starting IL-2 early.

If a participant's chronic GVHD improves at the end of the 16-week study duration, he or she may have the option of continuing the combination therapy of ECP and IL-2. Extended duration therapy is twice weekly ECP treatments plus daily IL-2 starting at the end of week 16. Participants may also have the option of continuing ECP treatments without IL-2 after the end of Week 16. If this is the case, participants will only be followed for one year from the start of therapy and will not have required study visits or tests.

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.