Phase Ib and dose-expansion study of GSK3326595, a PRMT5 inhibitor as monotherapy and in combination with pembrolizumab in patients with advanced cancers
Bibliographic record
Abstract
Background Protein arginine methyltransferase 5 (PRMT5) inhibition often leads to a decrease in cell growth and survival in cancer cell lines. GSK3326595 is a first-generation PRMT5 inhibitor. Patients and Methods METEOR-1 was a first-in-human, open-label, multicenter, three-part phase 1 study (NCT02783300) in patients with solid tumors and non-Hodgkin lymphoma (NHL). Objectives of part 1 were to determine the recommended phase 2 dose (RP2D), assess safety, evaluate preliminary clinical activity, and study the pharmacokinetics of oral GSK3326595 monotherapy. Part 2 enrolled patients at the RP2D to further evaluate clinical activity and safety. Part 3 explored the RP2D of GSK3326595 with pembrolizumab. Results A total of 288 patients were treated. In part 1, 69 patients received QD or BID GSK3326595 in doses ranging from 12.5-600 mg/day. In part 2, 218 patients received either 400 mg or 300 mg QD, with the RP2D amended from 400 mg to 300 mg QD due to toxicities. In part 3, 10 patients received GSK3326595 at 100 mg/day with pembrolizumab 200 mg intravenously every 3 weeks. Pharmacokinetics revealed that GSK3326595 was rapidly absorbed (T max : 2-3 hours), with a mean terminal half-life of 4-6 hours. Dose-dependent increases in plasma exposure (C max and AUC) were observed with both QD and BID dosing. The most common adverse events (AEs) at the RP2D included fatigue (57%), nausea (48%), and anemia (48%). Four partial responses (PRs) were observed in part 1 at doses of 200 mg (n=2), 300 mg (n=1), and 400 mg (n=1). Two complete responses and 1 PR were seen in NHL (ie, follicular [n=2] lymphoma, diffuse large B-cell lymphoma [n=1]), 1 PR in adenoid cystic carcinoma, and 1 PR in HR+ breast cancer in part 2. No responses were observed in part 3. Conclusions GSK3326595 monotherapy demonstrated modest antitumor activity. Further research in ACC and NHL is warranted.
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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 | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.005 |
| Insufficient payload (model declined to judge) | 0.004 | 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".