Abstract CT201: Phase I study of 5-azacytidine and oxaliplatin in patients with advanced cancers relapsed or refractory to platinum compounds
Bibliographic record
Abstract
Abstract Purpose: To explore whether the hypomethylating agent 5-azacytidine (5-aza) restores platinum sensitivity. Experimental Design: Patients with advanced cancer relapsed/refractory to platinum compounds were treated with 5-aza 20-50 mg/m2/d IV (D 1-5) and oxaliplatin 15-30 mg/m2/d IV (D 2-5) (“3+3” design escalation phase followed by expansion phase; NCT01039155). PK studies were performed. Global DNA and gene-specific methylation changes (baseline to D12) in blood and tissue, tissue platinum level, and CTR1 (copper transporter involved in platinum uptake) expression were assessed (expansion phase). Results: Overall, 37 patients were treated (median age, 59 yrs; men, 49%; prior: oxaliplatin, 68%; carboplatin, 30%; cisplatin, 16%) (escalation, n=21; expansion, n=16). No DLT was noted at the maximum dose level tested (5-aza, 50 mg/m2/d; oxaliplatin 30 mg/m2/d; used in expansion phase). The most common adverse events were anemia (49% of pts.) and fatigue (32%). LINE-1 was measured (surrogate for global DNA methylation) in pre- and post-treatment blood samples (9 patients) and in tumor samples (7 patients). All blood samples showed reduction in global DNA methylation (baseline to D12) (median, -22%; range, [-32%, -12%], p<.0001). Paired tumor and blood pre- and post-treatment samples were available in 2 patients. In paired comparison, 1 patient had reduction in global methylation both in tumor and blood (-34% and -32%, respectively); and 1 patient had increased methylation in tumor (+52%) and decreased in blood (-22%). The mean cytoplasmic CTR1 score was 217.5 and 177.5 on D1 and D12, respectively (mean difference, -40; 95% CI: -69.1,-10.9; p=.02). The respective mean nuclear CTR1 score was 67.5 and 42.5 (mean difference, -25; 95% CI: -55.5,+5.5; p=.08). Oxaliplatin (D2) and 5-aza (D1 and 5) mean systemic exposure based on plasma AUCall resulted in a dose-dependent trend (oxaliplatin 15 to 30 mg/m2, 704.3 to 1149.0 hr·ng/mL; 5-aza 20 to 50 mg/m2, 112.5 to 404.5 [D1] and 143.7 to 426.5 hr·ng/mL [D5]). When the same dose of oxaliplatin was used with increasing doses of 5-aza from 25-50 mg/m2, a reduction in mean oxaliplatin exposure was noted (AUCinf: 1919.4 to 1455.9 hr·ng/mL). No significant differences in other non-compartmental modeled parameters estimated were observed. The total tumor oxaliplatin level was measured in 7 patients. The pre-dose levels ranged from <.25 to 5.8 µg/g tumor (median, .59). The post-dose levels increased 3- to 18-fold (median, 3.8) in 5 post-dose samples (mean difference, 1.48 µg/g; 95% CI: .01,2.95; p=.049). Two patients, having the highest pre-dose level, had unchanged levels. Two (5.4%) patients (colon, n=1; prostate, n=1) had stable disease and received 6 cycles of therapy. Conclusion: 5-aza combined with oxaliplatin was safe. Hypomethylation was inconsistent in tumor tissue, the CTR1 score decreased and the tumor oxaliplatin level increased. Citation Format: Apostolia M. Tsimberidou, Kirk Culotta, Ignacio Wistuba, Siqing Fu, Aung Naing, Gerald Falchook, Sarina Piha-Paul, Ralph Zinner, Jaime Rodriguez-Canales, Guangan He, Zahid H. Siddik, Jaroslav Jelinek, Woonbok Chung, Yang Ye, Rabih Said, Kenneth Hess, David J. Stewart, Razelle Kurzrock, Jean-Pierre Issa. Phase I study of 5-azacytidine and oxaliplatin in patients with advanced cancers relapsed or refractory to platinum compounds. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT201. doi:10.1158/1538-7445.AM2014-CT201
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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) | 0.003 | 0.001 |
| Bibliometrics | 0.000 | 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) | 0.005 | 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".