Results of ACCURACY: A phase 2 trial of AL101, a selective gamma secretase inhibitor, in subjects with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) harboring Notch activating mutations (Notch <sup>mut</sup> ).
Bibliographic record
Abstract
6046 Background: Notch signaling plays a key role in ACC tumorigenesis. Notch mut are found in ̃20% of ACC tumors, which are aggressive with a poor prognosis. Approved or standard therapies for relapsed/metastatic ACC are lacking, regardless of Notch status. Investigational drug AL101, a γ-secretase inhibitor, blocks Notch signaling and inhibits tumor growth in Notch mut patient-derived ACC xenografts. AL101 has clinical activity at 4 mg once weekly (QW) with a disease control rate (DCR) of 68% (15% partial response, (PR)) and appears to be well tolerated. An additional cohort of 42 patients was enrolled at 6 mg QW, and here we update the final results of the trial. Methods: ACCURACY is an open-label, multicenter phase 2 study of AL101 (4 and 6 mg intravenous QW) in subjects with R/M ACC with Notch1-4 mut (ASCO ‘19, Abstr TPS6098). Subjects required evidence of disease progression within 6 months of entry or newly diagnosed metastatic disease and an ECOG performance status of 0-1. The primary endpoint was overall response rate (ORR) by RECIST v1.1 (or modified MD Anderson bone criteria), as assessed by investigators. Secondary endpoints were ORR by central review, duration of response, and safety. The study provided ≥80% power to detect an increase of the ORR from 8% to 25% using a type I error of 5%. Results: A total of 82 subjects were enrolled in the study. The data cutoff date used was Oct 25, 2021. Most common (≥20%) treatment-related adverse events of all grades in the study were diarrhea (78%; grade 3 (gr3) 10%), fatigue (67%; gr3 6%), nausea (60%; gr3 7%). Pharmacokinetics (PK) and blood pharmacodynamics (PD) both displayed a dose dependent change in AL101 plasma concentration and modulation of Notch target gene expression (Hes1 and Hes4), respectively. Of the 77 evaluable subjects, there were 9 PRs (12%) and 44 SDs (57%) for a disease control rate of 69%. Conclusions: Investigational drug AL101 at both 4 and 6 mg QW appears to be well tolerable in Notch mut R/M ACC. Additional efficacy and PK/PD data will be presented Clinical trial information: NCT03691207. Disposition and baseline characteristics of subjects treated with AL101 a . 4 mg QW 6 mg QW Treated, n 45 37 Gender, n (%)MaleFemale 20 (44)25 (56) 24 (57)18 (43) Median age, years 50 59 Race, n (%)WhiteBlackAsianOther/not reported 31 (69)4 (9)2 (4)8 (18) 33(79)2 (5)1 (2)6 (14) Prior systemic therapy, n (%) 27 (60) 19 (51) Disease status at screening, n (%) b MetastaticLocal recurrenceTreatment naïve and metastatic 42 (93)15 (33)4 (9) 36 (86)11 (28)6 (14) Most common sites of metastases, n (%) b LungBoneLiver 22 (49)13 (29)8 (18) 22 (52)15 (36)13 (31) QW=once weekly. a Data cutoff Oct 25, 2021. b Subjects may select more than 1 category.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.004 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".