760 Interim PK/PD, safety and efficacy data of monotherapy dose escalation of a phase 1/2 study with MDNA11 in patients with advanced solid tumors
Bibliographic record
Abstract
<h3>Background</h3> MDNA11 is an albumin-fused long-acting IL-2 agonist with enhanced affinity for IL-2Rb and no binding to IL-2Ra, resulting in potent CD8<sup>+</sup> T and NK cell activation, limited Treg increase and reduced toxicities.<sup>1</sup> ABILITY (A Beta-only IL-2 ImmunoTherapY) is a Phase 1/2 study evaluating the safety, pharmacokinetic (PK), pharmacodynamic (PD) and preliminary clinical activity of MDNA11 as monotherapy and in combination with Prembrolizumab in pre-treated patients with advanced solid tumors. <h3>Methods</h3> The dose-escalation phase of ABILITY uses a modified 3+3 design to determine the recommended dose for expansion (RDE). Patients received a fixed dose of 3, 10 or 30 μg/kg (dose levels 1–3; DL1–3) by intravenous infusion on a Q2W schedule. Step-up dosing was implemented starting at DL4 where patients received 2 or 3 priming doses prior to the target dose of 60 μg/kg (DL4), 90 μg/kg (DL5) or 120 μg/kg (DL6). Primary endpoints include incidence and severity of adverse events (AEs). Secondary endpoints include assessment of PK, PD and tumor response per RECISTv1.1 and iRECIST <h3>Results</h3> As of June 22, 2023, twenty dose limiting toxicity (DLT)-evaluable patients have been dosed with MDNA11 during monotherapy dose escalation (3–120 μg/kg). Tumor types enrolled included melanoma (n=11), renal cell carcinoma (n=2), pancreatic ductal adenocarcinoma (PDAC; n=2), sarcoma (n=2), tonsillar squamous cell carcinoma (n=1), gastro-esophageal adenocarcinoma (n=1) and lung adenocarcinoma (n=1). PK analysis showed dose-dependent increase in MDNA11 exposure. Immune profiling showed robust lymphocyte expansion, including increase in CD8<sup>+</sup> T and NK cells and limited change in Tregs. There were no DLTs observed. The most common AEs were infusion related reaction (65%) comprising pyrexia (50%), nausea (45%), chills (35%), fatigue (30%) and diarrhea (25%), with the majority being grade 1–2 and resolved within 48–72 hours. Transient (~ 1week duration) transaminases increase was seen in 25% of patients. Tumor response was evaluated in 19 patients. Single-agent activity included stable disease (SD) observed in 6 patients, including a melanoma patient with SD beyond 1.5 year, and an ongoing partial response (PR) in a PDAC patient who had previously progressed on immune checkpoint inhibitor and is currently continuing on MDNA11 for > 1 year. <h3>Conclusions</h3> MDNA11 is well tolerated with no DLTs up to target dose of 120 μg/kg on a Q2W schedule. Evidence of clinical activity includes SD in 6 of 19 patients in addition to a durable PR in a PDAC patient. Data analysis is ongoing to inform RDE selection. <h3>Acknowledgements</h3> We are grateful to all patients participating in this study. <h3>Trial Registration</h3> NCT: 05086692 <h3>Reference</h3> Merchant R, Galligan C, Munegowda MA, <i>et al</i>. Fine-tuned long-acting interleukin-2 superkine potentiates durable immune responses in mice and non-human primate. 2022;<b>10</b>:e003155. <h3>Ethics Approval</h3> The study was conducted with approval from institutional ethics committee and informed consent from participants.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".