Abstract CT311: Results of a phase I/IIa dose-escalation study of the combination of decitabine and genistein against advanced solid tumors
Bibliographic record
Abstract
Abstract Background: Epigenetic aberrations, including DNA hypermethylation of tumor suppressor genes are a common feature in solid tumors. Thus, targeting epigenetic pathways is a promising approach for cancer chemotherapy. However, only occasional proof-of-principle responses can be seen in solid tumors. The activity of hypomethylating drugs, such as decitabine could be improved by a treatment combination. Preclinical studies have suggested that adding genistein, a natural isofavone may synergize with demethylating drugs and improve treatment results. Methods: Here, we describe a phase I/IIa dose-escalation study of decitabine with a fixed dose of genistein. Primary objective of the phase I trial was to determine the Maximum Tolerated Dose (MTD) and to evaluate pharmacokinetic parameters in patients with advanced solid tumor. The objective of the phase IIa was to assess its efficacy in lung cancer. Decitabine was administered over 10-hours at increasing doses (60, 120, 240 mg/m2) with continuous administration of genistein 300 mg/day orally. Treatment was repeated every 4 to 6 weeks. Results: For the phase I, ten patients with advanced solid tumors were recruited. The recommended dose of decitabine (for the phase IIa) was 120 mg/m2 with neutropenia as limiting side effect. Decitabine at 120 mg/m2 and genistein produced plasma levels of 0.62 ± 0.06 μM and 8.5 ± 5.6 μM, respectively. The drug combination was well tolerated and produced stable disease for more than 7 months (7-14 months) in 50% of the patients. One patient had a 50% reduction in tumor burden after 6 months of therapy. In the phase IIa trial against advanced lung cancer, patients progressed rapidly, within 2 months of treatment mainly because of the apparition of new lesions in the liver. Conclusion: The combination of decitabine and genistein is well-tolerated in advanced solid tumors and shows interesting anticancer effects. This study on decitabine and genistein warrants future investigations to address this issue of liver metastasis in advanced lung cancer. Citation Format: Noël J. Raynal, Elie Kassouf, Luc Daigneault, Patrick Colin, Isabelle Plante, Guylaine Lassonde, Richard Momparler, Michel Charbonneau, Normand Blais. Results of a phase I/IIa dose-escalation study of the combination of decitabine and genistein against advanced solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT311. doi:10.1158/1538-7445.AM2015-CT311
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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) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 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".