Phase I study of H3B-6527 in hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC).
Bibliographic record
Abstract
4090 Background: Evidence suggests that hyperactivated fibroblast growth factor 4 (FGFR4) signaling pathway leads to enhanced tumor growth. Targeting FGFR4 may have therapeutic benefit in tumors with altered FGF19 signaling. A phase I study (NCT02834780) was undertaken to assess H3B-6527, a highly selective covalent FGFR4 inhibitor, in patients with HCC/ICC. Methods: Adults with advanced HCC/ICC, ECOG PS 0-1, well compensated liver function, who progressed after > one prior therapy, received H3B-6527 po daily (QD) or twice-daily (bid) on a 21-day cycle following a 3+3 design. Doses ranged from 300-2000mg QD or 500-700mg BID. Patients in dose escalation were treated regardless of FGF19 status. Patients in expansion had FGF19+ tumors by mRNA testing. Adverse events (AEs), and pharmacokinetics (PK) were assessed. Response was determined by RECIST 1.1/mRECIST imaging every 6 weeks. Results: Study enrollment is complete at 128 patients. Ninety HCC patients were treated (QD = 48, bid = 42). ICC enrollment was suspended after 38 patients due to limited efficacy. No dose-limiting toxicities were seen and no grade 4-5 treatment related AEs have been observed. Recommended Phase II dose for H3B-6527 is 1000mg QD based upon safety, efficacy, and PK data. Grade 3 TEAEs have occurred in 12.5% of patients on QD dosing. Treatment related TEAEs were seen in 62.5% of patients on the QD schedule, with diarrhea (45.8%), fatigue (12.5%), and nausea (12.5%) most frequent. Drug discontinuation due to AEs for QD dosing was 8.3%. Interim data analysis shows that, for HCC patients with >2 prior lines of therapy treated on QD schedule, overall survival was 10.6m, progression-free survival 4.1m, overall response rate 16.7% (all partial responses), and clinical benefit rate 45.8% (responders + durable stable disease >17 weeks). H3B-6527 Cmax and AUC were lower at 300 mg dose but then similar across 500–2000 mg doses. Following oral administration of 1000 mg fasted, H3B-6527 plasma concentration reached peak at a Tmax of ̃2-3 hours and then decayed exponentially, with terminal half-life of ̃4-5 hours. There was no accumulation following QD dose. Dosing with food did not meaningfully change H3B-6527 plasma exposure. Conclusions: H3B-6527 was well tolerated and demonstrated a favorable toxicity and safety profile and encouraging clinical activity in heavily pretreated HCC patients. Final trial results will be presented at conference. Clinical trial information: NCT02834780.
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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 | 0.003 | 0.005 |
| 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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".