Treatment of Relapsed or Refractory Lymphoma with the Oral Isotype-Selective Histone Deacetylase Inhibitor MGCD0103: Interim Results from a Phase II Study.
Bibliographic record
Abstract
Abstract Purpose: MGCD0103 is an oral inhibitor of histone deacetylases (HDACs) with isotype-selective activity against HDAC-1, -2, -3, and -11. MGCD0103 exhibits significant biological activity in preclinical models of hematopoietic cancers. Although several HDAC inhibitors have shown promising clinical activity in patients (pts) with T-cell lymphoid malignancies, the clinical activity of HDAC inhibitors have not been previously examined in B-cell lymphoma. The purpose of this study was to examine the efficacy and tolerability of MGCD0103 as monotherapy for the treatment of relapsed or refractory follicular and diffuse large B-cell lymphoma. Methods : This was an open-label, multi-center, phase II trial in adults (≥18 years) with relapsed or refractory lymphoma. The trial contained 2 cohorts of pts with diagnoses of either diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Eligibility required the presence of ≥1 site of measurable disease (≥2.0 cm) and an ECOG performance status of 0 or 1. Oral MGCD0103 was initially dosed at 110 mg 3× per week in 4-week cycles, with escalation to 135 mg or reductions to 85 and 60 mg permitted based on patient tolerance. Pts enrolled later in the trial had starting doses of 85 mg, with escalation to 110 mg and reductions to 60 and 40 mg permitted. On day 1 of cycle 1, blood samples were collected for PK analysis before dosing and at 0.5, 1, 2, 4, 6, and 24 hours. Results: To date, 38 pts (mean age, 60.3 ± 13.0 yrs; male, n=18) have been dosed: 19 with DLCBL and 19 with FL, all of whom have received prior Rituxan. Nineteen of 24 pts (79%) who had tumor size reassessed by CT scan after treatment initiation exhibited some tumor reduction; 12 (50%) exhibited >30% reduction and 7 (29%) exhibited >40% reduction. Twenty-five pts (1 pt has not yet had disease reassessed) were formally evaluable for clinical response; 16 (64%) have completed ≥3 cycles (12 weeks) of treatment. A CR was observed in 1 pt with FL after 2 cycles. PRs were observed in 2 pts with DLBCL after 2 and 4 cycles respectively and 1 pt with FL after 6 cycles. Twenty pts required dose reductions for management of toxicities. In 35 pts evaluable for safety, the most common non-hematologic toxicities were fatigue (24 pts), nausea (22), diarrhea (17), anorexia and decreased appetite (12), vomiting (10), and weight loss (9). Grade 3 toxicities occurred in 10 pts; fatigue and weight decrease being the most common. There were no grade 4 non-hematological toxicities. Hematological toxicities were minimal, with 1 pt requiring dose modification for thrombocytopenia and 2 for neutropenia. Significant inhibition of HDAC activity in PBMCs was seen in the majority of pts evaluated. Population PK (N=16) revealed: Cmax 119 ± 73 ng/ml, AUC (0–24) 715 ± 495 ng*hr/ml. Conclusions: Interim results from this ongoing trial suggest that single-agent MGCD0103 demonstrates significant anti-cancer activity in relapsed or refractory non-Hodgkin’s lymphoma (DLCBL and FL subtypes) and has a manageable side effect profile.
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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 | 0.002 | 0.001 |
| 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 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 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".