Phase I study of isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 given as three-times weekly oral dose in patients (pts) with advanced solid tumors
Bibliographic record
Abstract
3007 Background: MGCD0103 is a novel isotype-selective inhibitor of human HDACs. Deacetylation of histones by HDACs is postulated to inactivate tumor suppressor genes leading to neoplastic transformation. Inhibition of these enzymes might restore normal growth control. Methods: A phase I trial of MGCD0103, given as a three-times weekly oral dose 2 out of every 3 weeks, has been performed in pts with advanced solid tumors. Main endpoints are safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) assessments of HDAC activity and histone acetylation status in buffy coat white cells. Results: Five dose levels have been evaluated (mg/m2): 12.5, 20, 27, 36, and 45. As of January, 2006, 28 pts have been enrolled with the following demographics: M:F = 18:10; median age (range) = 60 (29–75); ECOG 0:1:2 = 9:13:1 (n = 23); primary tumor sites: colorectal (8), renal (5), lung (4), others (11); prior chemotherapy, radiotherapy, immunotherapy were given to 22, 12 and 2 pts, respectively (n=23). A total of 62 cycles have been administered, with median = 2 and range=1–7 cycles. MGCD0103 has been well tolerated; most common AEs (23 pts): grade 1–3 fatigue (91% of pts), grade 1–2 nausea and vomiting (70 and 48%), anorexia (26%), constipation (39%). Disease stabilization > 2 cycles has been observed in 3 renal cell cancer pts (4, 6, and 7 cycles) and 1 colorectal cancer pt (4 cycles). Preliminary PK analyses demonstrated intra-pt PK variability, however co-administration of acidic carbonated beverage (protocol amendment) appears to reduce variability without altering average Cmax or AUC (0–24) comparing Day 1 with Day 14. There was little accumulation or decrease in concentrations with extended dosing, and t1/2 was dose-independent at 7.7–11.3 hr. (±0.6–1.6). PD data reveal dose-dependent maximal inhibition of HDAC activity in patients co-administered an acidic beverage. Conclusions: At doses evaluated MGCD0103 appears tolerated and exhibits favourable PK and PD. [Table: see text]
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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) | 0.002 | 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) | 0.002 | 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".