Interleukin-7 (CYT107) Treatment of Idiopathic CD4 Lymphocytopenia: Expansion of CD4 T Cells (ICICLE)

Interleukin-7 (CYT107) Treatment of Idiopathic CD4 Lymphocytopenia: Expansion of CD4 T Cells
(ICICLE) is a Phase I/IIa open-label, single arm clinical trial evaluating the safety
profile of glycosylated recombinant human interleukin-7 (rhIL-7) as an immunostimulatory
therapy in patients with idiopathic CD4 T cell lymphocytopenia (ICL) at risk of disease
progression. Secondary analyses will assess the immunostimulatory effects of rhIL-7 on T
cell number and function.

ICL was first characterized in the early 1990 s and is a primary immune disorder of CD4 T
cell lymphocytopenia (less than 300 cells/microL or less than 20% of lymphocytes), which is
not due to any known infectious process, exogenous medication, autoimmune cytopenia, or
other underlying disorder associated with lymphocytopenia. ICL patients are at risk for a
wide spectrum of opportunistic and other serious infections, autoimmune disorders, and other
types of lymphocytopenia. At present, no validated treatment exists for ICL, and treatment
is directed primarily toward infectious complications once they arise. A first-generation
form of rhIL-7 was shown in pre-clinical and Phase I studies in oncology and human
immunodeficiency virus (HIV)-infected patients to be well tolerated in repeated dose trials,
with long-lasting increases in both CD4 and CD8 T cells. CYT107 is a second-generation
rhIL-7 product made by Cytheris via a recombinant mammalian cell culture system.

DESIGN - Open-label, single-arm, Phase I/IIa interventional clinical trial. Participants
will be evaluated at baseline (prior to study treatment) and according to the protocol
follow-up schedule, receiving a total of 2 cycles of rhIL-7 (CYT107) during the induction
phase and up to 8 cycles during the maintenance phase. Safety assessments of rhIL-7 will be
the primary focus at each study visit, with secondary analyses of immune parameters,
including changes from baseline in T cell number and function at Weeks 24 and 48.

DURATION - Enrollment is expected to take 3 to 4 years. Each volunteer will be followed for
at least 48 weeks. Thus, total duration of the study will be approximately 5 years.

SAMPLE SIZE - Approximately 35-40 patients will be screened over a 3-year period to achieve
the desired sample of 18 ICL patients, allowing for a primary safety assessment of CYT107 in
this Phase I/IIa clinical trial, as well as exploring the immunomodulatory effects of
rhIL-7.

POPULATION - Men and women, aged greater than or equal to 18 years, with a confirmed
diagnosis of ICL (CD4 less than 300 cells/micromL or less than 20% of lymphocytes) deemed at
risk for complications due to concurrent CD8 T cell lymphocytopenia and/or history of
opportunistic or otherwise serious infection, without autoimmunity or hematologic or
lymphoid malignancy.

REGIMEN - During the induction phase, subjects will receive 2 cycles of subcutaneous rhIL-7
dosed once weekly for 3 weeks in a dose escalation fashion: 3 microg/kg (first 3
subjects-completed), 10 microg/kg (next 5 subjects-completed) and 20 microg/kg (last 5
subjects), with an additional 5 subjects at the highest achieved dose level. Cycles of
rhIL-7 will be administered starting at Week 1 and Week 24.

For subjects who tolerate the induction phase and elect to participate in the

maintenance phase, additional cycles of rhIL-7 may be offered at 3-6 month

intervals. These participants will receive rhIL-7 at the highest dose for which at

least 8 weeks of safety data for 5 subjects has been reviewed provided no more

than 1 DLT is reported.

-INCLUSION CRITERIA:

1. Age greater than or equal to 18 years

2. CD4 T cell count less than 300 cells/microL or less than 20% of total T lymphocytes
on 2 occasions at least 6 weeks apart (and at the time of screening) in the absence
of any illness accounting for CD4 lymphocytopenia

3. ICL diagnosis that indicates a risk for disease progression, defined as one or both
of the following:

- CD8 T cell lymphocytopenia (less than 180 cells/microL)

- History of opportunistic or otherwise significant infection (e.g., AIDS-defining
or highly morbid illnesses, such as Cryptococcus or Mycobacteria infection,
severe herpes zoster, JC virus causing progressive multifocal
leukoencephalopathy, Kaposi s sarcoma, or severe human papilloma virus
condylomata)

4. HIV-1 and HIV-2 seronegativity and below detection of HIV-1 viral load

5. HTLV-1 and HTLV-2 seronegativity

6. Adequate venous access, as determined by the study team, although participants unable
to undergo leukapheresis will not be excluded

7. Normal thyroid-stimulating hormone (TSH)

8. Negative serum or urine pregnancy test at time of study enrollment for women of
childbearing potential

9. Ability to understand and give informed consent

10. Capacity and willingness to adhere to study procedures, including scheduled follow-up
visits

11. Willingness to allow blood and tissue sample storage

12. Established primary care provider

EXCLUSION CRITERIA:

1. History of prior cytotoxic, chemotherapeutic, immunosuppressant (e.g., systemic
corticosteroids), immunomodulatory (e.g., IL-2, IL-7, interferon-gama), or growth
factor therapy within the last 6 months; chemotherapy or immunomodulatory therapy
given to treat an underlying disease or condition may be permitted at the protocol
team's discretion, provided diagnosis of ICL was established prior to starting this
treatment. The treatment has been stable for over 6 months and is being administered
at stable doses as maintenance therapy.

2. History of prior participation in another investigational intervention study within
the last 6 months. Co-enrollment in other NIAID stem cell mobilization protocols will
be permitted at the protocol team s discretion, but CYT107 may be dosed no sooner
than 6 months after last dose of that protocol s medications have been given.

3. Active uncontrolled opportunistic infection at the time of enrollment

4. Current or recent history (less than 28 days prior to screening) of a viral,
bacterial, parasitic or fungal infection requiring hospitalization and/or systemic
treatment, other than long-term maintenance pharmacotherapy

5. Serious illness requiring systemic treatment and/or hospitalization within 56 days (8
weeks) of screening, unless the subject is clinically stable, in the opinion of the
Principal Investigator, and has completed therapy or has been on appropriate therapy
for greater than 28 days (4 weeks) prior to screening

6. Current or history of hematologic or lymphoid (lymphoma) malignancy

7. Established or planned pregnancies or refusal to use effective birth control (e.g.,
barrier methods, oral contraceptives, intrauterine devices) for the duration of study
involvement, regardless of gender

8. Concurrent breastfeeding

9. Renal insufficiency (e.g., estimated glomerular filtration rate less than 60
mL/min/1.73 m(2))

10. Any of the following screening laboratory abnormalities: platelets less than 100,000
cells/microL; lipase greater than 1.5 times the ULN; AST, ALT, or alkaline
phosphatase greater than 2.5 times the ULN; total bilirubin greater than 1.5 times
the ULN

11. History of splenectomy or hematologic disease associated with hypersplenism, such as
alpha- or beta-thalassemia, hereditary spherocytosis, Gaucher s disease, or
autoimmune hemolytic anemia

12. Cirrhosis of any origin, including alcoholic or non-alcoholic steatohepatitis, either
suspected by history or histologically proven

13. History of hepatitis B or C infection, i.e., positive hepatitis B surface antigen,
positive anti-hepatitis B core antibody with a detectable hepatitis B DNA viral load,
positive anti-hepatitis C antibody and/or detectable hepatitis C RNA viral load
(subjects who became negative for hepatitis B DNA or hepatitis C RNA following
anti-viral treatment will not qualify for study treatment)

14. Need for anticoagulant medication (e.g., warfarin, heparin), other than aspirin,
clopidogrel, or other antiplatelet agent as CYT107 may co-precipitate with heparin if
taken together.

15. Active drug or alcohol use or dependence that, in the opinion of the investigator,
would interfere with adherence to study requirements (subjects must agree to refrain
from substance abuse use during the entire course of the study)

16. Past or current psychiatric illness that, in the opinion of the investigator, would
interfere with protocol adherence or the ability and willingness to give written
informed consent

17. Current autoimmune conditions requiring systemic (oral, injection, or other
parenteral) therapy, as well as psoriasis and optic neuritis regardless of treatment
and/or a diagnosis of systemic lupus erythematous based on the screening
rheumatologic work up.

18. Cardiac, pulmonary, thyroid, renal, hepatic, neurological (central or peripheral)
disease or disorder of hemostasis requiring therapy and considered to be significant
by the protocol team

19. History of cardiovascular disease, arrhythmias, or clinically significant ECG
abnormalities, including a corrected QT interval (QTc) greater than or equal to 470
milliseconds

20. Family history consistent with an inherited cardiomyopathy or arrhythmia such as the
following:

- Arrhythmogenic Right Ventricular Dysplasia (ARVD)

- Brugada syndrome (BrS)

- Congenital Long QT (LQT)

- Congenital Short QT intervals (SQT)

- Early Repolarization Syndrome

- Idiopathic Ventricular Fibrillation (IVF)

21. Uncontrolled hypertension (i.e., resting systolic blood pressure greater than160 mmHg
or resting diastolic blood pressure greater than 90 mmHg), despite pharmacologic
antihypertensive treatment, confirmed with a second blood pressure measurement done
later in the same day.

22. Evidence of circulating neutralizing anti-IL-7 antibodies (prior to initial rhIL-7
administration)

To be eligible for rhIL-7 administration, all Exclusion Criteria are prohibited. However,
for the purpose of performing baseine pre-IL-7 procedures certain Exclusion Criteria
designed to minimize specific complications from rhIL-7 (e.g., autoimmune or
lymphoproliferative complications) but that do not increase the risk associated with these
procedures are permitted, as baseline procedures will be done prior to IL-7
administration: #6, #11, through #13, #17, #18, #20, #22.