Phase I/II Study of the Oral Isotype-Selective Histone Deacetylase (HDAC) Inhibitor MGCD0103 in Combination with Azacitidine in Patients (pts) with High-Risk Myelodysplastic Syndrome (MDS) or Acute Myelogenous Leukemia (AML).
Bibliographic record
Abstract
Abstract Aberrant DNA methylation and histone code alterations are common in leukemia. The oral isotype-selective HDAC inhibitor MGCD0103 and the DNA methyltransferase inhibitor azacitidine have been shown to have synergistic antileukemia activity in preclinical models. Both agents have single-agent clinical activity in MDS and AML (Garcia-Manero, ASCO, 2006 & Silverman, JCO, 2002). Based on this, we have developed a Phase I/II study of the combination in leukemia. Patients with relapsed/refractory MDS (10% or more marrow blasts) or AML, or untreated older patients with AML are eligible. Adequate performance status, renal and hepatic functions are required. Azacitidine is administered at its approved dose/schedule: 75 mg/m2 SC daily x 7 every 28 days. MGCD0103 was started on day 5 of azacitidine and was given as an oral dose 3 times a week without adjusting for body weight, without interruption. The phase I portion of the study design followed a classic “3+3” model and only MGCD0103 was dose escalated. Three dose levels of MGCD0103 have been studied so far: 35, 60 and 90 mg. Twelve patients have been registered in this study. The median age is 61 (range 45–85). All, but 1 patient with MDS, had AML. All patients had relapsed or refractory disease. A total of 24 cycles have been administered, mean = 2.0 (range 1–4). Only 1 patient has experienced dose limiting toxicity: grade 3 vomiting at a dose of 90 mg of MGCD0103. Otherwise, the combination has been very well tolerated and the MTD has not yet been defined, with dosing currently ongoing at the approximate MTD of single agent MGCD0103: 110 mg orally three times a week without interruption. Preliminary PK data indicate that the t1/2 for azacitidine is less than 2 h, and does not appear to be affected by MGCD0103. Likewise, MGCD0103 pharmacokinetic characteristics do not appear to be affected by azacitidine. The majority of patients exhibited substantial reduction in HDAC activity during treatment with the combination. Analysis of DNA methylation is ongoing. Two patients have achieved response: 1 complete remission after 4 courses of therapy (in an older patient in first relapsed AML with an initial CR duration of 11 months and multiple cytogenetic abnormalities). A second older patient with refractory AML achieved a complete marrow CR (marrow blasts less than 5%) but died from pneumonia (not drug-related) after the second course of therapy on day 28 before peripheral count recovery. In conclusion, the combination of azacitidine with MGCD0103 is safe in patients with advanced AML/MDS. The combination has encouraging safety, PK, and clinical activity profiles. The study continues at the MTD of single agent MGCD013 in combination with azacitidine. Once the MTD of the combination is documented, the study will continue as a phase II study in this patient population.
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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) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| 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) | 0.003 | 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".