Clinical benefit was noted in the earlier portion of the trial; hence, participants were not enrolled in 2 expansion cohorts and the study was terminated early.

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

Safety population included all enrolled participants who received at least 1 dose of study drug.

First dose of study drug up to EOS (up to approximately 3 years)

Safety population included all enrolled participants who received at least 1 dose of study drug.

Clinical benefit was noted in the earlier portion of the trial; hence, participants were not enrolled in 2 expansion cohorts and the study was terminated early.