A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma
Bibliographic record
Abstract
BACKGROUND: The current study was conducted to assess the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor effect of everolimus, a mammalian target of rapamycin inhibitor, in combination with sorafenib, a tyrosine kinase inhibitor, in patients with metastatic clear cell renal cell carcinoma. METHODS: Sequential cohorts of patients received escalating doses of everolimus and sorafenib in 28-day cycles in the absence of a dose-limiting toxicity (DLT) or disease progression were examined. RESULTS: Twenty patients with a median age of 65 years received therapy in 3 cohorts. Dose level 1 was comprised of everolimus at a dose of 2.5 mg daily and sorafenib at a dose of 400 mg twice daily (6 patients), dose level 2 was comprised of everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily (8 patients), and dose level 3 was comprised of everolimus at a dose of 10 mg daily and sorafenib at a dose of 200 mg twice daily (6 patients). DLTs included grade 4 (according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) hyperuricemia with grade 2 gout and grade 3 lipase associated with grade 2 pancreatitis at dose level 2, and grade 3 rash in 2 patients at dose level 3. Dose level 2 (everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily) was established as the maximum tolerated dose. Treatment-related adverse events occurring in >20% of patients included diarrhea, hand-foot syndrome, hypertension, hypophosphatemia, hypothyroidism, and rash. Five of 20 patients achieved Response Evaluation Criteria In Solid Tumors (RECIST)-defined partial responses, all of which occurred in patients without a history of prior systemic therapy. Seven of 8 patients treated at dose level 2 experienced a partial response or stable disease. Pharmacokinetic analysis revealed no interaction between everolimus and sorafenib. CONCLUSIONS: The combination of everolimus and sorafenib was associated with acceptable toxicity and evidence of antitumor activity in previously untreated patients with metastatic renal cell carcinoma.
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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 | 0.001 |
| 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) | 0.003 | 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".