A phase II study of durvalumab re-treatment +/- prednisone in patients who discontinued prior checkpoint therapy due to immune related toxicity (CCTG IND.238A).
Bibliographic record
Abstract
TPS2673 Background: Up to 18% of patients permanently discontinue immune checkpoint blockade (ICB) therapy following G3/G4 immune-related adverse events (irAEs) even if reversible / easily managed with replacement therapy or steroids. Safety concerns exist with ICB re-treatment. Given the potential benefit of ICB and evidence that patients with irAEs may exhibit greater efficacy, there is interest in ICB rechallenge following successful management of G3/G4 irAEs in patients who have had benefit, and trials to prospectively investigate ways to prevent irAE recurrence are needed. Durvalumab is a human monoclonal antibody of IgG1κ subclass that binds to PD-L1. Canadian Cancer Trials Group (CCTG) IND.238A is a phase 2, open label, multicentre study of durvalumab +/- prednisone rechallenge in patients who were benefitting from prior ICB but discontinued due to irAEs. Methods: Eligible patients have received prior anti-PD-(L)1 ICB alone or in combination with anti-CTLA-4 ICB, with or without chemotherapy/targeted therapy, and experienced either: 1) G3 or selected G4 irAEs (i.e. endocrinopathies manageable with replacement therapy; hematologic toxicity) that required drug discontinuation; 2) prolonged G2 irAEs where therapy was discontinued due to poor tolerability. Prior irAE must have resolved to ≤G1, patients must have completed steroid therapy and have documented RECIST 1.1 CR, PR, or prolonged SD (≥8 weeks) to initial ICB. Patients with prior (neo)adjuvant/consolidation ICB are eligible provided there has been ≥6-month treatment free interval before enrollment. Based on prior irAE, patients are allocated into either: 1) the High Risk cohort, receiving durvalumab (1500mg IV Q4W in all cohorts) + prednisone 0.5mg/kg/day for C1-2, or; 2) the Standard Risk cohort, where they are randomized to receive either durvalumab + prednisone 10mg/day for C1-2 (Cohort 2A) or durvalumab alone (Cohort 2B). Three to 6 patients are enrolled into each cohort initially, then each cohort expands up to a total of 60 evaluable patients (20 per cohort). Safety review takes place following enrollment of the 1st, 3rd, 6th and 10th patient in each cohort. Safety review occurs 4 weeks after the 1st patient treated on each cohort and subsequently once the last patient has been followed for at least 4 weeks. The primary endpoint is the incidence of treatment-related AEs (CTCAE v5.0), estimated as percentages of patients with each AE (90% exact CI will be calculated). Secondary objectives are ORR (RECIST 1.1 and iRECIST) and efficacy of corticosteroids in preventing recurrent or new ≥G2 irAEs (90% exact CI will be calculated). Exploratory endpoints include PFS / iPFS by Kaplan-Meier method, exploration of blood- and stool-based irAE biomarkers and PD-L1 expression. As of January 30, 2023, 12 of planned 60 patients have been enrolled. Clinical trial information: NCT03847649 .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".