Abstract 2706: Phase 2 study with pharmacokinetics (PK) analysis of sorafenib and vinorelbine in metastatic breast cancer
Bibliographic record
Abstract
Abstract Background Sorafenib (S) is an oral inhibitor of the Raf, VEGFR and PDGFR pathways that contribute to chemoresistance in cancer cells. The combination of S with chemotherapy agents (capecitabine, paclitaxel) in metastatic breast cancer (BC) resulted in improved progression-free survival. In preclinical models of BC, favorable effects were noted combining S and vinorelbine (V). S and V are both metabolized through hepatic isoenzymes CYP3A, with the potential of PK interactions. A previous phase 1b study documented the feasibility of this combination. We aimed to define the activity and safety of this regimen in advanced BC and to investigate PK interactions of the 2 drugs at full doses. Methods Eligible patients were affected by Her2 negative, chemotherapy-naive metastatic BC, with measurable (RECIST) disease, adequate renal, liver and bone marrow functions and LVEF Δ50%. Treatment included V (30 mg/m2 days 1, 8 every 21) + S (400 mg bid continuously), with dose reductions for grade 2-4 toxicities. Patients still benefiting after 8 cycles of treatment could continue on single-agent S. Six patients underwent PK analysis, starting treatment with S on day 4 of the first cycle, allowing for comparison of PK of each agent (V and S) administered alone versus during concomitant treatment with the other agent. Results 27 evaluable patients started on treatment, median age 57 (35-78); they received a median of 8 cycles to date (1-28), with 4 patients still on treatment. 44% of patients required at least one dose reduction for toxicity. One patient died of complicated sepsis after febrile neutropenia. Other significant toxicities included: febrile neutropenia (8%), uncomplicated Grade 3 (G3)-G4 neutropenia (60%); G3 fatigue (20%), hand-foot syndrome (12%), diarrhea (4%), enteritis (4%), hypertension (4%), asymptomatic increase of AST/ALT (16%), amylase (12%), lipase (8%), GGT (4%); G2 decrease in LVEF (4%), rash (16%), alopecia (20%). 33% of patients had a partial response, 85% experienced a clinical benefit (including stable disease after at least 4 cycles of treatment). Median progression-free survival was 5.5 months (95% CI 4.6-7.5). PK analysis showed no statistically significant interaction between S and N. Also the conversion of S to its metabolite S-N-oxide was not affected by the concomitant treatment with V. A non-significant trend was noticed for higher Cmax/AUC of V in the first 30 minutes after infusion when administered with ongoing treatment with S. Conclusions Combining S with V is feasible, but not devoid of toxicity, for which frequent dose reductions are necessary. A PK interaction could not be ruled out with the small sample size analyzed. More frail patients should start at a lower dose of both agents and we recommend close monitoring for the first 2 cycles, including amylase and lipase. Promising efficacy of this combination was observed, with a very high rate of disease control. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2706. doi:1538-7445.AM2012-2706
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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) | 0.001 | 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 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 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".