A Phase 1 Dose-Escalation Study of Irinotecan in Combination with 17-Allylamino-17-Demethoxygeldanamycin in Patients with Solid Tumors
Bibliographic record
Abstract
PURPOSE: Both heat shock protein 90 (Hsp90) and checkpoint kinase 1 (Chk1) have emerged as novel therapeutic targets. We conducted a phase I study of irinotecan and the Hsp90 inhibitor 17AAG, which can also down-regulate Chk1, in patients with solid tumors. EXPERIMENTAL DESIGN: During the dose escalation phase, patients received i.v. irinotecan followed by 17AAG once weekly for 2 weeks in a 21-day cycle. At the maximum tolerated dose (MTD), additional patients were enrolled to undergo pre- and post-17AAG tumor biopsies for pharmacodynamic evaluation. The pharmacokinetics of irinotecan, 17AAG, and their metabolites were characterized. Tumor p53 status as determined by immunohistochemistry was correlated with antitumor activity. RESULTS: Twenty-seven patients with a variety of solid tumors were enrolled. Four patients developed dose-limiting toxicity at dose level 4 (100 mg/m(2) irinotecan and 375 mg/m(2) 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The pharmacokinetics of 17AAG and its metabolite were not significantly affected by the coadministration of irinotecan, and vice versa. There was no partial response, although tumor shrinkage was observed in six patients. Five of 10 patients with p53-mutant tumor had stable disease as the best response compared with 2 of 6 patients with p53-wildtype tumor (P = 0.63). Evidence for Hsp90 inhibition by 17AAG, resulting in phospho-Chk1 loss, abrogation of the G(2)-M cell cycle checkpoint, and cell death could be shown in tumor biopsy samples obtained at the MTD. CONCLUSIONS: The combination of irinotecan and 17AAG can be given to patients with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m(2) irinotecan and 300 mg/m(2) 17AAG.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".