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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
24
DI-Leu16-IL2 will be administered per dose and schedule specified in the arm.
City of Hope
Duarte, California, United States
St. Jude Hospital Yorba Linda
Fullerton, California, United States
University of Minnesota
Minneapolis, Minnesota, United States
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, United States
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).
Time frame: 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).
Time frame: 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.
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Joe Arlington Cancer Research and Treatment Center
Lubbock, Texas, United States
Time frame: 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.
Time frame: 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.
Time frame: Baseline, EOS (up to approximately 3 years)
Number of Participants With Anti-DI-Leu16-IL2 Antibodies
Time frame: First dose of study drug up to EOS (up to approximately 3 years)