Phase I/II Study of De-immunized DI-Leu16-IL2 Immunocytokine Administered Subcutaneously in Patients With B-cell NHL

An open-label, dose-escalation trial of the safety, tolerability, pharmacokinetics (PK),
biological, and clinical activity of DI-Leu16-IL2 administered to patients with CD20
(B-lymphocyte antigen CD20) positive Non-Hodgkin Lymphoma (NHL) that have failed standard
rituximab-containing therapy. Following peripheral blood B cell depletion with rituximab (if
needed) each patient will receive DI-Leu16-IL2 administered as a subcutaneous (SC) injection
for three consecutive days every three weeks (21 day cycle). Three to six (3-6) patients will
be enrolled in each cohort. Patients may receive 6 cycles of DI-Leu16-IL2 approximately
thrice weekly for 3 weeks for a total of 18 doses.

Approximately 66 patients will be enrolled in this study at approximately 6 investigational
centers in the U.S. Forty-two (42) patients will be enrolled during dose escalation (Phase 1)
and 2 expansion cohorts of 12 patients each (Phase 2).

Following completion of the Phase I portion of the trial and review of the safety, response
and correlative immune data it has been elected to have 2 expansion cohorts of 12 patients
each at 2 mg/m2.

- Diffuse Large B-Cell Lymphoma (DLBCL) that is relapsed or refractory to standard therapy

- All other CD20-expressing B-cell NHL that is relapsed or refractory to standard therapy.
As mentioned above Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
with peripheral blood leukemia/lymphoma cells and high-grade lymphomas (i.e.
Lymphoblastic Lymphoma/Burkitt's Lymphoma) are excluded

At the end of the study, patients may be enrolled into an open-label extension study (Study
AO-101-EXT), at the discretion of the investigator.

Study Primary Endpoints

1. To determine the maximum tolerated dose (MTD) of DI-Leu16-IL2 administered SC following
peripheral blood B cell depletion with rituximab in patients with B-cell NHL.

2. To investigate the optimal biologic dose (OBD) of DI-Leu16-IL2 following peripheral
blood B cell depletion with rituximab in patients with B-cell NHL, which may differ from
the MTD.

3. To describe the toxicities associated with the proposed DI-Leu16-IL2 regimen.

Study Secondary Endpoints

1. To evaluate the immunogenicity as measured by the induction of DI-Leu16-IL2-specific
antibodies.

2. To evaluate the PK of DI-Leu16-IL2 (achieved in the primary portion of the study).

3. To measure the response rate at the MTD (and/or OBD) associated with the proposed
therapy and survival endpoints of the enrolled patients.

Inclusion Criteria:

1. Patients with CD20-expressing B-cell NHL that is relapsed or refractory to standard
therapy. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with peripheral blood
leukemia/lymphoma cells and high-grade lymphomas are excluded

2. Patients must have received prior rituximab-containing therapy.

3. Evaluable disease. In the absence of lymphadenopathy, splenomegaly with defects or
measurable extra-medullary disease is acceptable

4. Patients who have received a prior autologous stem cell transplant are eligible if the
transplant occurred > 6 months ago.

5. Patients who have received a prior allogeneic stem cell transplant are eligible if:

1. The transplant occurred > 6 months ago

2. There is no evidence of active graft vs host disease

3. Systemic immunosuppressive agents (including corticosteroids) have not been
received for at least 8 weeks

6. Age ≥18 years

7. Karnofsky performance scale ≥70%

8. Life expectancy ≥12 weeks

9. Adequate baseline functions:

1. Serum creatinine ≤ 1.5 mg/dl

2. Total white blood cell count (WBC) ≥ 3000/µl, or absolute neutrophil count (ANC)
≥ 1000/µl

3. Absolute lymphocyte count ≥0.75 x 10^3/µl

4. Platelet count ≥75,000/µl

5. Hematocrit ≥ 25% or hemoglobin ≥9 g/100 mL

6. Alanine aminotransferase (ALT) <2.5 x upper limit of normal (ULN)

7. Aspartate aminotransferase (AST) <2.5 x UNL

8. Total bilirubin (TBili) <1.5 x ULN

9. Sodium, potassium, and phosphorus levels no worse than grade 1

10. Chest x-ray (CXR) or computed tomography CT within 4 weeks prior to Day 1 with no
evidence of pulmonary congestion, pleural effusions, pulmonary fibrosis, or
significant emphysema. If results are questionable, patients should have
additional lung function testing to exclude clinically relevant restriction or
obstruction. Patients must have a forced expiratory volume (FEV-1) and Diffusing
Capacity of the Lung for Carbon Monoxide (DLCO) of at least 65% and 50% of
expected, respectively.

11. Electrocardiogram (12-lead ECG) QTc ≤ 480 ms

12. Cardiac stress test (e.g., stress thallium scan, stress echocardiography) with
normal results if patient is suspected to have coronary artery disease.

10. Patients participating in the study are to use adequate birth control measures
(abstinence, oral contraceptives, barrier method with spermicide or surgical
sterilization) during study participation. Females of childbearing potential must have
a negative serum pregnancy test on the days of dosing. A female of childbearing
potential is a sexually mature woman who: 1) has not undergone a hysterectomy or
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive
months.

11. Provide written informed consent prior to any screening procedures

Exclusion Criteria:

1. Evidence of central nervous system lymphoma or lymphomatous meningitis

2. Prior treatment with IL2 within the last 5 years

3. Type I hypersensitivity or anaphylactic reactions to murine proteins or to previous
infusion of rituximab

4. Pregnant or lactating female

5. An immediate need for palliative radiotherapy or systemic corticosteroid therapy

6. Known intercurrent infections (including hepatitis C virus and human immunodeficiency
virus or other conditions), or clinical evidence of these conditions

7. Actively infected with or chronic carriers of hepatitis B virus as demonstrated by
positive hepatitis B core antibody or hepatitis B surface antigen. (Patients who are
seropositive only, i.e. surface antibody positive [HbsAb], are permitted)

8. Other significant active infection.

9. Major surgery, chemotherapy, investigational agent, or radiation within 30 days of Day
1

10. Uncontrolled hypertension (diastolic greater to or equal to 100 mmHg) or hypotension
(systolic less than or equal to 90 mmHg)

11. History of repeated and clinically relevant episodes of syncope or other paroxysmal,
ventricular, or other significant arrhythmias

12. History of medically significant ascites requiring repetitive paracentesis

13. Previous diagnosis of autoimmune disease (Exceptions: patients with autoimmune
thyroiditis or vitiligo may be enrolled)

14. Organ transplant recipient

15. History of prior therapy or a serious, uncontrolled medical disorder that in the
Investigator's opinion would impair participation in the study

16. Known hypersensitivity to Tween-80, or human immunoglobulin

17. Legal incapacity or limited legal capacity

18. Patients with bulky lymph nodes (LNs) (≥10 cm) or marked splenomegaly (i.e. extending
into pelvis or crossing the midline).

19. Circulating levels of rituximab > 75.0 µg/ml