Phase 1 study of a focal adhesion kinase (FAK) inhibitor PF-00562271 in patients (pts) with advanced solid tumors
Bibliographic record
Abstract
3527 Background: PF-00562271 is a potent ATP-competitive inhibitor of FAK and, to a lesser extent, Pyk2. FAK transduces signaling from integrins and growth factors to modulate multiple properties important in neoplasia, including tumor cell invasion, proliferation and survival. Structure-activity relationships and preclinical antitumor activity are reported (W.G. Roberts et al, Proc AACR, 2007). Methods: Phase 1 dose-escalation study of PF-00562271 given as twice daily oral doses in 21 day cycles. Endpoints included safety, tolerability, PK, PD (serial tumor biopsies) and antitumor activity. PD was also evaluated by tumor glucose metabolism using FDG-PET. Dose escalation was performed in sequential cohorts of 3–6 pts. Results: 32 pts received 5 mg up to 105 mg BID with demographics M:F = 10:22; median age 60 (range 38–80). Primary tumor sites: colorectal (10), breast (4), neuroendocrine (2), lung (2), gastric (2), SCC (2), ovary (2), others (8). A total of 136 cycles have been administered, median = 3.2, range = 1–10+. Adverse events (AEs) possibly related to PF-00562271 in over 10% of pts included nausea, vomiting, fatigue, anorexia, abdominal pain, diarrhea, headache, sensory neuropathy, rash, constipation, dizziness. AEs were generally CTC grades 1–2 and reversible. Cmax and AUC increased dose-dependently, and AUC accumulated over 6-fold by day 14. Doses over 15 mg BID produced steady-state plasma concentrations, exceeding target efficacious levels predicted from preclinical models. On day 14, PET scans in one pt demonstrated significant (46%) decline in SUV of metastatic ovarian carcinoma, associated with improved tumor-related symptoms. Nine pts tolerated over 3 cycles and another 4 pts continued treatment over 6 cycles with stable disease. At 105 mg BID, dose- limiting toxicities included nausea, vomiting, diarrhea. Conclusions: At the doses evaluated, PF-00562271 is tolerable with extended BID oral administration and exhibits favorable PK and PD. Additional dose and schedule evaluations continue, and updated clinical and biomarker results will be presented. 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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| 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".