Study of the Effect IL 7/ NT-I7 on CD4 Counts in Patients With High Grade Gliomas

PRIMARY OBJECTIVES:

Phase I: To determine the MTD (Maximum Tolerated Dose) and select optimal biological doses
(OBD) of NT-I7 in HGG patients with severe lymphopenia

Pilot Study: To test the effect of NT-I7 on CD4 counts compared to control

SECONDARY OBJECTIVES:

1. To determine the optimal biological dose of NT-I7

2. To evaluate the effect of concurrent dexamethasone

3. To evaluate the duration of effect on CD4 counts (up to 6 months)

4. To evaluate the total lymphocyte counts over time and serial T cell lymphocyte subtypes
and the effect on T cell repertoire (up to 6 months)

5. To evaluate the serial cytokine levels (up to 6 months)

6. To evaluate the impact of adjuvant temozolomide on NT-I7 effects on CD4 counts

7. To evaluate anti-drug antibodies

8. To evaluate the pharmacokinetic profile of NT-I7 after intramuscular administration in
this patient population

9. To evaluate the safety and toxicity of NT-I7 in patients with high grade glioma

OUTLINE: Patients are assigned to 1 of 2 groups depending on their use of dexamethasone.

GROUP A: Patients not on dexamethasone (or equivalent of an alternative corticosteroid), or
on a dose lower than a physiologic dose (=< 0.75 mg daily)

GROUP B: patients who require dexamethasone (or equivalent of an alternative corticosteroid)
=> 4 mg daily

Patients must have been on the group assignment dose of corticosteroids for at least 5 days
prior to the dose of NT-I7. Corticosteroid dose changes prior to the start of treatment are
allowed as long as they do not alter patient's group assignment.

PHASE I TREATMENT PLAN

All patients (both Groups A and B) will be given a single dose of NT-I7 by intramuscular
injection starting at 60 μg/kg, within one week after completing concurrent RT+TMZ and before
starting adjuvant TMZ treatment, during the standard post-radiation break. Following this
period, as per standard treatment, patients will go on to receive adjuvant temozolomide on
Days 1-5 of 28-day cycles for 6 cycles. There should be about six weeks between the study
injection and the start of adjuvant temozolomide; thus the start of adjuvant TMZ will be
approximately two weeks later than the usual start, which is 4 weeks post-end of radiation.
Patients who are delayed from receiving or are not able to receive adjuvant TMZ treatment may
continue on study; adjuvant TMZ treatment is not a requirement for participation.

PILOT STUDY TREATMENT PLAN

GROUP A: participants will be given either a placebo (NT-I7 diluent) or one dose of NT-I7 at
the Phase I Group A OBD by intramuscular injection within one week after completing
concurrent RT+TMZ and before starting adjuvant TMZ treatment, during the standard
post-radiation break.

GROUP B: participants will be given one dose of NT-I7 at the Phase I Group B OBD by
intramuscular injection within one week after completing concurrent RT+TMZ and before
starting adjuvant TMZ treatment, during the standard post-radiation break.

After completion of study treatment, patients are followed up every 2 months for 2 years and
then every 6 months thereafter.

Inclusion Criteria:

- Patients must have histologically confirmed high grade glioma by pathology (World
Health Organization [WHO] grade III and IV)

- Patients' post-operative treatment must have included at least 80% of standard
radiation and concomitant temozolomide; patients may not have received any other
prior chemotherapy, immunotherapy or therapy with biologic agent (including
immunotoxins, immunoconjugates, antisense, peptide receptor antagonists,
interferons, interleukins, tumor infiltrating lymphocytes [TIL],
lymphokine-activated killer [LAK] or gene therapy), or hormonal therapy for their
brain tumor; prior Gliadel wafers are allowed; glucocorticoid therapy is allowed

- Patients must have CD4 =< 300 cells/mm^3 in the last week (7 days) of standard
radiation + temozolomide treatment (58-60 Gy radiation with temozolomide 75 mg/m2
daily during radiation)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Total bilirubin =< institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase
[SGPT]) =< 2.5 x institutional upper limit of normal

- Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60
ml/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Activated partial thromboplastin time (APTT) or partial thromboplastin time (PTT)
=< 1.5 x institutional upper limit of normal

- Patients must have a Karnofsky performance status (KPS) >= 60% (i.e. the patient
must be able to care for himself/herself with occasional help from others)

- Patients must be able to provide written informed consent

- Women of childbearing potential must have a negative serum pregnancy test prior
to study entry; women of childbearing potential and men must agree to use two
birth control methods (either two barrier methods or a barrier method plus a
hormonal method) or abstinence prior to study entry and for the duration of study
participation (through at least 90 days after the last study injection); should a
woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately

- Patients must have no concurrent malignancy except curatively treated basal or
squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast,
or bladder; patients with prior malignancies must be disease-free for >= five
years

- Dexamethasone dose must be provided for treatment group assignment:

- Group A: patients not on dexamethasone or on a dose =< 0.75 mg daily (or
equivalent of an alternative corticosteroid)

- Group B: patients who require dexamethasone >= 4 mg daily (or equivalent of
an alternative corticosteroid) ** Patients must have been on the group
assignment dose of corticosteroids for at least 5 days prior to the dose of
NT-I7; corticosteroid dose changes prior to the start of treatment are
allowed as long as they do not alter patient's group assignment

Exclusion Criteria

- Patients receiving any other investigational agents are ineligible

- Patients with known hypersensitivity to NT-I7 or any component used in the
vehicle/formulation are ineligible

- Patients with 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, are ineligible

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with NT-I7

- Patients with human immunodeficiency virus (HIV) are excluded

- Patients with a known or screening-period-determined corrected QT (QTc) interval > 450
msec and patients who require a therapy with a drug known to prolong the QT/QTc
interval, are ineligible

- Patients with a history of or who currently have evidence of autoimmune disease (other
than autoimmune thyroid disease managed with thyroid hormone replacement or vitiligo)
including: myasthenia gravis, Guillain Barre syndrome, systemic lupus erythematosus,
multiple sclerosis, scleroderma, ulcerative colitis, Crohn's disease, autoimmune
hepatitis, Wegener's etc., are ineligible