A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies
Bibliographic record
Abstract
PURPOSE: UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors. EXPERIMENTAL DESIGN: Patients received irinotecan (75-125 mg/m(2) IV on days 1, 8, 15, 22) and UCN-01 (50-90 mg/m(2) IV on day 2 and 25-45 mg/m(2) on day 23 and subsequent doses) every 42 days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained. RESULTS: Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125 mg/m(2) on days 1, 8, 15, 22 and UCN-01 70 mg/m(2) on day 2 and 35 mg/m(2) on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 C(max) and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24 h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18 weeks, range 7-30 weeks). CONCLUSION: UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway.
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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 | 0.000 | 0.000 |
| 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".