A Study of De-immunized DI-Leu16-IL2 Administered Subcutaneously in Participants With B-cell NHL
A Study of De-immunized DI-Leu16-IL2 Administered Subcutaneously in Participants With B-cell NHL
This dose-escalation study is designed for determining the safety, tolerability,
 pharmacokinetics (PK), biological, and clinical activity of DI-Leu16-IL2 administered to
 participants with cluster of differentiation 20 (CD20) positive NHL that have failed standard
 rituximab-containing therapy.
The participants will be enrolled during dose escalation and during 2 expansion cohorts of up
 to 12 participants each.

 The dose escalation portion of the trial will incorporate a modified accelerated titration
 design. Therefore, the trial will enroll 3 participants per dose level with a doubling of the
 dose at each level during the accelerated stage of the study (skipping every other dose
 level). Once the first instance of any Grade 3 or higher treatment related toxicity (with
 some notable exceptions) is observed on the first cycle, the accelerated stage will end and
 the trial will revert to a conventional design using cohorts of 3 or 6 participants (standard
 3+3 design), with single step 2 milligrams (mg)/square meter (m^2) increments.

 To further explore the clinical efficacy, additional participants (up to 12 per cohort) may
 be enrolled at the optimal biologic dose (OBD) or maximum tolerated dose (MTD).

 At the end of the study, participants may be enrolled into an open-label extension study
 (AO-101-EXT [NCT02151903]), at the discretion of the investigator.
Inclusion Criteria:

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

 5. Participants 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 versus host disease

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

 6. Karnofsky performance scale ≥70%

 7. Life expectancy ≥12 weeks

 8. Adequate baseline functions:

 1. Serum creatinine ≤1.5 mg/deciliter (dL)

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

 3. Absolute lymphocyte count ≥0.75 * 10^3/µL

 4. Platelet count ≥75,000/µL

 5. Hematocrit ≥25% or hemoglobin ≥9 grams/100 milliliters (mL)

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

 7. Aspartate aminotransferase (AST) <2.5 * ULN

 8. Total bilirubin (TBili) <1.5 * 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, participants should have
 additional lung function testing to exclude clinically relevant restriction or
 obstruction. Participants 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 millisecond (ms)

 12. Cardiac stress test (for example, stress thallium scan, stress echocardiography)
 with normal results if participant is suspected to have coronary artery disease.

 9. Participants participating in the study are to use adequate birth control measures
 (abstinence, oral contraceptives, barrier method with spermicide or surgical
 sterilization) during the study. 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 (that is, has had menses at any time in the preceding 24
 consecutive months).

 10. 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 interleukin 2 (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. Participants who
 are seropositive only, that is, 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 millimeters of mercury
 [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: participants 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. Participants with bulky lymph nodes (LNs) (≥10 centimeters [cm]) or marked
 splenomegaly (that is, extending into pelvis or crossing the midline).

 19. Circulating levels of rituximab >75.0 micrograms (µg)/mL