Phase II trial of pharmacodynamically (PDally)-guided optimal biologic dose titration (OBDT) of sorafenib (S) in combination with metronomic cyclophosphamide (mC) in advanced neuroendocrine tumors (aNET)
Bibliographic record
Abstract
3526 Background: There is a paucity of reliable PD assays for guiding individual OBDT. PD effects of kinase inhibitors have been previously measured in static tissues. We developed a dynamic flow-cytometric PD assay that quantitates RAF signal transduction capacity (STC) based on the differential MEK´s phosphor-status in stimulated vs. basal conditions (phosphor-shift [PS]) in PBMCs. In a pilot study of 7 patients (pt) with advanced solid tumors in a phase I trial (unpublished data) the % of PS inhibition (I) 7 days after starting S at 400 mg BID showed a 10-fold interpatient variation and correlation with TTP. PDGFR-B/VEGFR2 blockade plus mC showed synergistic effect in the RIP1-Tag2 mouse NET model (J Clin Oncol. 23:939) In this phase II trial of aNET a double antiagniogenic strategy is undertaken: PD-guided OBDT of S + mC. Methods: Eligibility criteria included: unresectable NET with documented PD within 6 months prior to entry; ECOG 0–2; unlimited prior therapy but S; octreotide allowed. Therapy: pt start run-in phase with S at 200mg bid + 50 mg QD fixed dose of mC. After 7 d they escalate to 400 mg BID of S regardless of RAF STC assay results. RAF STC and toxicity are then assessed Q14d, escalating S at 200 mg BID increments until any of the following is achieved: a) 90% RAF STC I; b) maximum S dose of 800 mg BID; or c) intolerable Gr 2 or G3+ toxicity. Once S dose is determined based on these criteria, cycle 1 begins. Design: Simon 2-stage optimal; P0 = 0.05 P1 = 0.2; α =0.05 β = 0.1. Results: Accrual: 10 pt M:F = 6:4, islet cell:carcinoid = 5:5, age median 56 (40–79), ECOG 0:1 = 5:5. S doses (mg BID) at cycle 1 were 200 (2 pt)/400 (5)/600 (2)/800 (1); corresponding cycle 1 day 1RAF STC I (%) were 5, 53/94, 100, 95, 16, 65/25, 41/71, respectively (R 2 = 0.13 p = 0.72) Most frequent Gr 3 non-hematologic possibly related adverse events in 30 cycles: hand-foot (2 pt), hypertension, abdominal pain, diarrhea, vomiting, lipase, ileal perforation (1 each). Disease control rate (9 evaluable pt): 78% (95% CI: 52–100%) (1PR, 6 SD). Conclusions: This approach appears feasible/safe. Large interpatient S dose differences are needed to achieve RAF SCT I/toxicity balance. No S dose-RAF SCT I relation is shown. Disease control rate is promising. No significant financial relationships to disclose.
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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 | 0.002 | 0.005 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.001 | 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".