A Study of De-immunized DI-Leu16-IL2 Administered Subcutaneously in Participants With B-cell NHL

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I/II Study of De-immunized DI-Leu16-IL2 Immunocytokine Administered Subcutaneously in Patients With B-cell Non-Hodgkin Lymphoma (NHL)

Conditions
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B-cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: DI-Leu16-IL2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Participants must have received prior rituximab-containing therapy. Evaluable disease. In the absence of lymphadenopathy, splenomegaly with defects or measurable extra-medullary disease is acceptable. Participants who have received a prior autologous stem cell transplant are eligible if the transplant occurred >6 months ago. Participants who have received a prior allogeneic stem cell transplant are eligible if: The transplant occurred >6 months ago There is no evidence of active graft versus host disease Systemic immunosuppressive agents (including corticosteroids) have not been received for at least 8 weeks Karnofsky performance scale ≥70% Life expectancy ≥12 weeks Adequate baseline functions: Serum creatinine ≤1.5 mg/deciliter (dL) Total white blood cell (WBC) count ≥3000/microliter (µL) or absolute neutrophil count (ANC) ≥1000/µL Absolute lymphocyte count ≥0.75 * 10^3/µL Platelet count ≥75,000/µL Hematocrit ≥25% or hemoglobin ≥9 grams/100 milliliters (mL) Alanine aminotransferase (ALT) <2.5 * upper limit of normal (ULN) Aspartate aminotransferase (AST) <2.5 * ULN Total bilirubin (TBili) <1.5 * ULN Sodium, potassium, and phosphorus levels no worse than grade 1 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. Electrocardiogram (12-lead ECG) QTc ≤480 millisecond (ms) Cardiac stress test (for example, stress thallium scan, stress echocardiography) with normal results if participant is suspected to have coronary artery disease. 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). Provide written informed consent prior to any screening procedures Exclusion Criteria: Evidence of central nervous system lymphoma or lymphomatous meningitis Prior treatment with interleukin 2 (IL2) within the last 5 years Type I hypersensitivity or anaphylactic reactions to murine proteins or to previous infusion of rituximab Pregnant or lactating female An immediate need for palliative radiotherapy or systemic corticosteroid therapy Known intercurrent infections (including hepatitis C virus and human immunodeficiency virus or other conditions), or clinical evidence of these conditions 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. Other significant active infection. Major surgery, chemotherapy, investigational agent, or radiation within 30 days of Day 1 Uncontrolled hypertension (diastolic greater to or equal to 100 millimeters of mercury [mmHg]) or hypotension (systolic less than or equal to 90 mmHg) History of repeated and clinically relevant episodes of syncope or other paroxysmal, ventricular, or other significant arrhythmias History of medically significant ascites requiring repetitive paracentesis Previous diagnosis of autoimmune disease (Exceptions: participants with autoimmune thyroiditis or vitiligo may be enrolled) Organ transplant recipient History of prior therapy or a serious, uncontrolled medical disorder that in the Investigator's opinion would impair participation in the study Known hypersensitivity to Tween-80 or human immunoglobulin Legal incapacity or limited legal capacity Participants with bulky lymph nodes (LNs) (≥10 centimeters [cm]) or marked splenomegaly (that is, extending into pelvis or crossing the midline). Circulating levels of rituximab >75.0 micrograms (µg)/mL

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DI-Leu16-IL2 0.5 mg/m^2<br>Participants will receive DI-Leu16-IL2 0.5 mg/m^2 subcutaneously (SC) for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles. | Drug: DI-Leu16-IL2<br>* DI-Leu16-IL2 will be administered per dose and schedule specified in the arm.<br>|
| Experimental: DI-Leu16-IL2 1.0 mg/m^2<br>Participants will receive DI-Leu16-IL2 1.0 mg/m^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles. | Drug: DI-Leu16-IL2<br>* DI-Leu16-IL2 will be administered per dose and schedule specified in the arm.<br>|
| Experimental: DI-Leu16-IL2 2.0 mg/m^2<br>Participants will receive DI-Leu16-IL2 2.0 mg/m^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles. | Drug: DI-Leu16-IL2<br>* DI-Leu16-IL2 will be administered per dose and schedule specified in the arm.<br>|
| Experimental: DI-Leu16-IL2 4.0 mg/m^2<br>Participants will receive DI-Leu16-IL2 4.0 mg/m^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles | Drug: DI-Leu16-IL2<br>* DI-Leu16-IL2 will be administered per dose and schedule specified in the arm.<br>|
| Experimental: DI-Leu16-IL2 6.0 mg/m^2<br>Participants will receive DI-Leu16-IL2 6.0 mg/m^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles. | Drug: DI-Leu16-IL2<br>* DI-Leu16-IL2 will be administered per dose and schedule specified in the arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of DI-Leu16-IL2 | The MTD was determined based on toxicities from the first 2 cycles of treatment. The MTD was the highest dose tested with no more than 1 participant out of 6 experienced a dose-limiting toxicity (DLT). All non-hematologic adverse events (AEs) and all hematologic AEs of greater than Grade 3 were considered relevant to determining DLTs. DLTs included absolute lymphocyte count (ALC) Grade 3 and 4 (if ALC does not resolve to baseline grade according to Common Terminology Criteria for Adverse Events (CTCAE) v4 within 5 days post the final injection per cycle of DI-Leu16-IL2), and absolute neutrophil count (ANC) Grade 3 (If ANC does not resolve to at least Grade 2 within 5 days post the final injection per cycle of DI-Leu16-IL2) and Grade 4 (any). | First 2 cycles of treatment (each cycle = 21 days) | 
| Number of Participants With a DLT | All non-hematologic AEs and all hematologic AEs of greater than Grade 3 were considered relevant to determining DLTs. DLTs included ALC Grade 3 and 4 (if ALC does not resolve to baseline grade according to CTCAE v4 within 5 days post the final injection per cycle of DI-Leu16-IL2), and ANC Grade 3 (If ANC does not resolve to at least Grade 2 within 5 days post the final injection per cycle of DI-Leu16-IL2) and Grade 4 (any). | First 2 cycles of treatment (each cycle = 21 days) | 
| Number of Participants With Best Overall Response (BOR) Assessed Per International Workshop for Non-Hodgkin Lymphoma (NHL) Response Criteria | BOR included complete response (CR), unconfirmed CR (CRu), partial response (PR), stable disease (SD), and progressive disease (PD). CR: 1) Disappearance of all detectable clinical and radiological evidence of disease; 2) lymph nodes (LN) regressed to normal size; 3) other organs (spleen, liver, kidneys) that were enlarged before therapy must have decreased in size; 4) clear bone marrow (BM) infiltrate. CRu: must meet CR criteria 1 and 3, as well as ≥1 of following: residual LN mass >1.5 cm in greatest transverse diameter; individual nodes that were previously confluent regressed by >75% in sum of product diameters (SPD); or indeterminate BM. PR: 6 largest dominant nodes or nodal masses decreased by ≤50% in SPD; no increase in size of other nodes; liver or spleen; splenic and hepatic nodules regressed ≥50% in SPD; and no new disease. SD: less than a PR but not PD. PD: 50% increase from nadir in SPD of any abnormal node for PR or nonresponders and appearance of any new lesion. | First dose of study drug until first appearance of CR, CRu, PR, SD, or PD (up to 6 months) | 
| Tumor Measurement: Percent Change From Baseline in Sum of Product of Diameters at the End of Study | Sum of product diameters sums the product of the 2 tumor measurements on each lesion. If only 1 measurement was available, it was used as the longest length and the product of the lengths in the sum. Baseline value is the last non-missing measurement prior to receiving study drug injection. None of the participants were considered evaluable in 'DI-Leu16-IL2 0.5 mg/m^2' arm for this outcome measure at the end of study, and therefore, data were not collected for that arm. | Baseline, end of study (EOS) (up to approximately 3 years) | 
| Tumor Measurement: Percent Change From Baseline in Sum of Longest Diameters at the End of Study | Sum of longest diameters is the sum of the longest measured length of each tumor lesion. Baseline value is the last non-missing measurement prior to receiving study drug injection. None of the participants were considered evaluable in 'DI-Leu16-IL2 0.5 mg/m^2' arm for this outcome measure at the end of study, and therefore, data were not collected for that arm. | Baseline, EOS (up to approximately 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Anti-DI-Leu16-IL2 Antibodies |  | First dose of study drug up to EOS (up to approximately 3 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NHL, Immunocytokine, Lymphoma, Non-Hodgkin, B-cell, IL (interleukin)