Study of Individual Adult and Pediatric Patient Dose-escalated Interleukin-2 Therapy for Refractory Chronic GVHD

This research study is a Phase I clinical trial, which tests the safety of an investigational
intervention and also tries to define the appropriate dose of the investigational
intervention to use for further studies. "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
cGVHD but it has been approved for metastatic renal cell carcinoma (MCC), and metastatic
melanoma.

Chronic GVHD is a medical condition that may occur after the participant has received bone
marrow, stem cell or cord blood transplant. The donor's immune system may recognize the
participant's body (the host) as foreign and attempt to 'reject' it. This process is known as
graft-versus-host-disease. Traditional standard therapy to treat cGVHD is prednisone
(steroids). Interleukin-2 (IL-2) is a natural protein involved with regulation of white blood
cells (WBCs). WBCs are part of the immune system.The investigators looking to see whether
IL-2 helps control chronic GVHD by stopping the donor's immune system from 'rejecting' the
participant's body.

This study will look to see if increasing the dose level of study drug every two weeks can be
administered safely without severe or unmanageable side effects in participants that have
cGVHD. Depending on how well you tolerate your initial dose level and subsequent dose levels,
your study drug dose level may be increased a maximum of two times. These increases in dose
levels will occur two weeks apart. All participants on the study will start at the same dose
level.

Study Drug: You will administer, or have someone else administer if you are unable to
yourself, IL-2 through an injection under your skin. You should rotate the injection site, if
possible. You will do this once every day for 8- weeks.

During the first 8 weeks of IL-2, you will continue to take steroids and other immune
suppressing medications without changing the dose your doctor has set for you while you are
on IL-2. After 8 weeks of I L-2 therapy, your doctor may reduce the amount of steroids you
take.

If your cGVHD improves after 8 weeks on dose-escalated IL-2, you may have the option of
continuing extended duration therapy. Extended duration therapy is daily IL-2 treatment
starting at the end of week 8. You will be re-assessed every 6 months while on extended
duration IL-2 to determine if IL-2 therapy should continue, at the discretion of the treating
physician.

Drug Diary: Each day of the first 8 weeks you take IL-2 and each day during extended-duration
IL-2 (if applicable); you will be asked to document in a drug diary when you took the drug
and where you injected it. The diary will also ask if the entire syringe was injected, and if
there were other issues related to IL-2. You will be asked to return your drug diary to
clinic every 2 weeks for the first 8 weeks of IL-2 and at least every 8 weeks for extended
duration IL-2.

Chronic GVHD Assessments: While you are on study, a member of the study team will examine you
to evaluate your cGVHD. These assessments may include examination of your skin,
joints/muscles, eyes, mouth, lungs, and gastrointestinal system (for example, whether you
have experienced any nausea, vomiting, diarrhea, difficulty swallowing). The investigators
will also look at the range of motion of different body parts (for example, your arms).

Inclusion Criteria

- Recipient of 7-8/8 HLA-matched (HLA-A, -B, -C, -DRB1) allogeneic hematopoietic stem
cell transplantation

- Participants must have steroid-refractory cGVHD despite use of 2 or more agents.
Steroid-refractory cGVHD is defined as having persistent signs and symptoms of cGVHD
(Appendix C, D) 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 glucocorticoids)
without complete resolution of signs and symptoms. Participants with either extensive
or limited chronic GVHD requiring systemic therapy are eligible.

- Stable dose of glucocorticoids 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.

- Participants must have adequate organ function as defined below:

- Hepatic: Adequate hepatic function (total bilirubin ≤ 2.0 mg/dl-exception
permitted in participants with Gilbert's Syndrome; AST (SGOT)/ALT (SGPT) ≤ 2x
institutional ULN), unless hepatic dysfunction is a manifestation of presumed
cGVHD. For participants 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.

- Pulmonary: FEV1 ≥ 50% or DLCO(Hb) ≥ 40% of predicted, unless pulmonary
dysfunction is deemed to be due to chronic GVHD.

- Renal: Serum creatinine ≤ institutional ULN or creatinine clearance ≥ 60
mL/min/1.73 m2 for participants with creatinine levels above institutional
normal.

- Pediatric patients must have creatinine clearance ≥ 60 mL/min/1.73 m2 regardless
of serum creatinine level.

- Adequate bone marrow function indicated by absolute neutrophil count (ANC)
≥1000/mcL and platelets ≥ 50,000/mcL 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.

- Karnofsky/Lansky performance status ≥ 60% (Appendix A)

- Age ≥ 2 years. In our institutional experience and according to published reports, the
incidence of cGVHD in children aged less than 2 years is rare. 41 Daily SC injections
of low-dose IL-2 have been used in pediatric post-HSCT patients as young as 2 years.
39 Prolonged daily SC injections of other drugs such as low molecular weight heparin
and insulin are commonly administered and well tolerated in the young pediatric
population with the use of the Insuflon® indwelling SC catheter. The use of the
Insuflon® indwelling SC catheter for IL-2 administration is not required for all
pediatric patients and their use will depend on the preference of the patient and
provider

- The effects of IL-2 on the developing human fetus are unknown. For this reason and
because chemotherapeutic agents are known to be teratogenic, participants of
child-bearing and child-fathering potential 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 female become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately. Males treated or enrolled on this protocol must
also agree to use adequate contraception prior to the study, for the duration of study
participation, and 4 months after completion of IL-2 administration.

- Ability to understand and/or the willingness of participant or their parent/legally
authorized representative to sign a written informed consent document.

Exclusion Criteria:

- Participants with ongoing prednisone (equivalent) dose requirement > 1 mg/kg/day (or
equivalent).

- Participants with concurrent use of calcineurin-inhibitor plus sirolimus (either agent
alone is acceptable).

- Participants with new immunosuppressive medication, extra-corporeal photopheresis or
rituximab therapy initiated in the 4 weeks prior.

- Participant with post-transplant exposure to donor lymphocyte infusion (DLI), or
T-cell or IL-2 targeted medication (e.g. ATG, alemtuzumab, basiliximab, denileukin
diftitox) within 100 days prior.

- Other investigational drugs within 4 weeks prior to enrollment, unless cleared by the
Principal Investigator. Previous fixed-dose IL-2 therapy that was discontinued prior
to 4 weeks is permitted.

- Participants with active malignant relapse or recrudescence of their prior hematologic
disorder.

- Participants with inability to comply with IL-2 treatment regimen.

- 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.

- History of severe allergic reactions attributed to compounds of similar chemical or
biologic composition to IL-2.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Individuals with active uncontrolled hepatitis B or C are ineligible as they are at
high risk of lethal treatment-related hepatotoxicity after HSCT.

- 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.