COPANLISIB IN PATIENTS WITH RELAPSED OR REFRACTORY INDOLENT B‐CELL LYMPHOMA (CHRONOS‐1)
Bibliographic record
Abstract
Introduction: Treatment options are limited for patients with relapsed/refractory indolent B-cell lymphoma. Copanlisib is an intravenously administered pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant activity against PI3K-α and PI3K-δ isoforms. We report results from a pivotal phase II study (NCT01660451, part B; CHRONOS 1). Methods: Patients with indolent B-cell non-Hodgkin lymphoma (follicular [FL], marginal zone [MZL], small lymphocytic and lymphoplasmacytoid/Waldenstrӧm macroglobulinemia) and relapsed after, or refractory to, ≥2 prior lines of treatment (including both rituximab and an alkylating agent) were eligible. Copanlisib (60 mg, IV) was intermittently administered on days 1, 8 and 15 of a 28-day cycle. The primary efficacy endpoint was objective tumor response rate (ORR) per independent radiologic review (Cheson et al. 2007). Archival tumor tissues were used for mRNA extraction and gene expression profiling. Results: The full analysis set comprised 142 treated patients. At the time of analysis, median duration of treatment was 22 weeks (range 1-105); 46 patients remained on treatment. The ORR was 59.2%, including 12.0% complete response (CR) and 47.2% partial response (PR), with 29.6% stable disease and 2.1% progressive disease. In the FL subset (n = 104), the ORR was 58.7%, (14.4% CR and 44.2% PR). In the MZL subset (n = 23), the ORR was 69.6%, (8.7% CR and 60.9% PR). Tumor shrinkage as best response was observed in 91% of evaluable patients (Figure). The estimated Kaplan-Meier (KM) median duration of response was 687 days (range 0-687). The KM-estimate of median PFS was 340 days (range 0-736). Gene expression analysis based on evaluable archival samples from 71 patients indicated that high expression of PI3K and B-cell receptor gene signatures was associated with response (p = 0.02 and p = 0.04, respectively). The most common treatment-related AEs (all grade/grade 3+) were transient hyperglycemia (49%/40%) and hypertension (29%/23%). Other AEs included neutropenia (25%/19%), diarrhea (18%/4%), lung infection (14%/11%), pneumonitis (7%/1.4%), and colitis (0.7%/0.7%). There were two non-fatal opportunistic infections. Laboratory toxicities of interest were principally grade-1, including elevated ALT (23% all-grade/19% grade-1) and AST (28%/25%). There were 6 deaths, with 3 attributed to copanlisib: lung infection, respiratory failure, and a thromboembolic event. Keywords: non-Hodgkin lymphoma (NHL); PI3K/AKT/mTOR.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".