A phase I study of sorafenib and RAD001 for metastatic clear cell renal cell carcinoma
Bibliographic record
Abstract
5104 Background: Both RAD001 and sorafenib have activity against advanced clear cell renal cell carcinoma (ccRCC). Inhibition of both mTOR and angiogenesis may improve outcomes; therefore, a phase I trial combining sorafenib and RAD001 was undertaken. Methods: Cohorts of 3 or 6 patients with ccRCC were treated with a 7 day run-in period of sorafenib 400 mg PO BID continuously followed by RAD001 (dose level I: 2.5 mg, dose level II: 5 mg) PO QD and sorafenib 400 mg PO BID continuously. Pharmacokinetic sampling of sorafenib was obtained on day -1, and of both RAD001 and sorafenib on day 15 of combination therapy. Dose-limiting toxicity (DLT) was defined as occurring within the first 28 days of therapy. Results: Fifteen patients with a median age of 65 (range 51–75) have been enrolled. Two patients were not evaluable for response or DLT evaluation. Five pts were treated with sunitinib previously. Zero of 6 pts on dose level 1 experienced a DLT. Two of 9 pts treated at dose level II have experienced protocol-defined DLTs (grade 4 uric acid and grade 3 lipase with grade 2 pancreatitis). Independently-reviewed best objective responses in 13 evaluable pts include 3 confirmed partial responses (10, 17+, and 23+ months), 6 stable disease (2+, 4+, 4.5, 6+, 13, and 23+ months), and 4 progressive disease. Steady state dosing of RAD001 demonstrated a steady state AUC0–24h of RAD001 of 193.3 (± 32.9) ng h/mL at a dosage of 5 mg QD, comparable to the single agent 5 mg QD steady state dosing AUC0–24h of 238 (± 77) ng h/mL, suggesting there is no pharmacokinetic interaction between RAD001 and sorafenib. Linear pharmacokinetics between the 2.5 and 5 mg QD dosages of RAD001 were observed. The AUC0–24h of sorafenib was not significantly changed by concomitant dosing with RAD001 with a steady state AUC0–24h of 134600 (±42072) ng h/mL pre-RAD001 and a post-sorafenib steady state AUC0–24h of 131451 (±53838) ng h/mL. Conclusions: Combination therapy with sorafenib and RAD001 is safe and feasible. No clinically relevant pharmacokinetic interaction was observed. Activity for the combination has been observed and a phase II study is planned at the 5 mg QD dosage of RAD001. No significant financial relationships to disclose.
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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) | 0.003 | 0.001 |
| Bibliometrics | 0.001 | 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) | 0.005 | 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".