A phase I study of the EZH2 inhibitor tazemetostat in pediatric subjects with relapsed or refractory INI1-negative tumors or synovial sarcoma.
Bibliographic record
Abstract
TPS10587 Background: Tazemetostat is a potent and selective inhibitor of the histone methyltransferase enhancer of zeste-homolog 2 (EZH2), the catalytic subunit of the polycomb repressive complex 2 (PRC2). EZH2 is responsible for trimethylation of lysine 27 on histone H3, which results in chromatin remodelling and repressed transcription. Aberrant EZH2 activity has been implicated as an oncogenic driver in non-Hodgkin lymphoma and other malignancies. The SWI/SNF complex also remodels chromatin, activates transcription, and acts in opposition to PRC2. Oncogenesis from mutation and/or loss of the SWI/SNF subunit INI1 in cancers such as malignant rhabdoid tumor (MRT) or SMARCA4 loss in ovarian “small cell carcinoma, hypercalcemic type” is associated with anticancer activity of EZH2 inhibition in preclinical models. This has translated into objective responses of promising durability in subjects (subjs) whose solid tumors exhibited either INI1 or SMARCA4 loss in the tazemetostat phase I adult study. Methods: This phase I, multi-center dose escalation (DEsc) and dose expansion (DExp) study administers tazemetostat twice daily (BID) using an oral suspension formulation in pediatric subjs age 6 months to 21 years. Approximately 24 subjs will be dosed using a “Rolling 6” DEsc design at a starting dose of 240 mg/m2 BID. Following DEsc, a DExp cohort will enroll up to 20 subjs. Eligible malignancies includerhabdoid tumors (MRT, atypical teratoid rhabdoid tumor, rhabdoid tumor of the kidney, MRT of ovary) that are INI1 or SMARCA4 negative, synovial sarcoma, and other INI1 negative tumors including epithelioid sarcoma, renal medullary carcinoma, myoepithelial carcinoma, and others. Response assessments are evaluated every 8 weeks using RANO or RECIST 1.1. Primary endpoints include dose-limiting toxicities/maximum tolerated dose (DEsc) and overall response rate (ORR) (DExp). Secondary endpoints include ORR (DEsc), progression-free survival, overall survival, safety/tolerability, PK and duration of response for confirmed responders. The first subj was dosed in January 2016 in the US with additional sites to be opened in Canada, the EU and Australia (NCT02601937). Clinical trial information: NCT02601937.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".