A Phase I Study of the Histone Deacetylase Inhibitor MGCD0103 (MG-0103) Given as a Three-Times Weekly Oral Dose in Patients with Leukemia or Myelodysplastic Syndromes (MDS).
Bibliographic record
Abstract
Abstract MG-0103 is a novel non-hydroxamic acid inhibitor of human histone deacetylases (HDACs), with selectivity for the cancer-associated isoforms of class I HDACs. Deacetylation of histones by HDACs is postulated to inactivate tumour suppressor genes leading to neoplastic transformation, and therefore inhibition of this enzyme may result in antineoplastic activity. To study the safety and activity of MG-0103, we have developed a phase I open-label dose escalation study of MG-0103 administered orally, three-times weekly in patients with leukemia or MDS, with the primary endpoints being the determination of the maximum tolerated dose (MTD) and the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MG-0103. Eligibility criteria included appropriate performance status and renal and hepatic functions. Patients with relapsed/refractory leukemia or MDS and older patients with untreated AML/MDS were eligible. Eight patients have been enrolled at two dose levels (20 &40 mg/m2) so far. Their characteristics are: median age 70 years (range 33–79); all patients so far treated have AML; median number of prior therapies is 1 (range 0–3). All patients had complex cytogenetics including one elderly patient with t(8;21) that had not achieved CR with high dose ara-C-based therapy. MG-0103 has been well tolerated with no dose-limiting toxicities. No drug-related adverse events (AEs) >= Grade (Gr) 3 have been observed. The only Gr 2 drug-related AE has been heartburn (1 patient). All other drug-related AEs were grade 1. No cardiac abnormalities have been observed so far. Two of 3 patients at the first dose level have been treated for 3 or more cycles. PK evaluations are shown in the table below. Analysis of peripheral blood cell HDAC activity indicates that HDAC inhibition occurs in a dose-dependent manner. Enrolment is currently proceeding at a dose of 80 mg/m2. In summary, MG-0103 is a well-tolerated HDAC inhibitor in patients with AML at doses and exposures that result in target inhibition in peripheral blood. Dose 20 mg/m2 40 mg/m2 Pharmacokinectic characteristics AUC (0-∞) ng.hr/ml 260 +/− 10.8 528 +/−275 T 1/2 h 8.09 +/− 2.98 6.24 +/− 0.373
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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 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| 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".