Phase I study of the PI3K/mTOR inhibitor gedatolisib (PF-05212384) in combination with docetaxel, cisplatin, and dacomitinib.
Bibliographic record
Abstract
2566 Background: Inhibition of phosphatidylinositol-3-kinase (PI3K)-mediated signaling may overcome resistance to chemotherapy or human epidermal growth factor receptor (EGFR) inhibitors. Gedatolisib (G) is a dual inhibitor of PI3K/mammalian target of rapamycin (mTOR) in development for solid tumors. Methods: This is an ongoing study to determine the maximum tolerated dose (MTD) and safety of G in combination with: 1) docetaxel: Arm A, in castrate resistant prostate cancer, advanced breast cancer (BC), or non-small cell lung cancer (NSCLC) patients (pts); 2) cisplatin: Arm B, in urothelial transitional cell cancer (TCC), triple negative BC (TNBC), NSCLC or ovarian cancer pts; 3) the pan-EGFR TKI dacomitinib: Arm C, in refractory HER2+BC, HER2+esophagogastric cancer, head and neck cancer, or EGFR-mutated NSCLC pts. Pts received a G lead-in dose 7 days (A, B) or 14 days (C) prior to day 1, followed by weekly intravenous (IV) G plus: docetaxel or cisplatin (75 mg IV every 3 weeks); or oral dacomitinib (30–45 mg/d). Secondary objectives included pharmacokinetics (PK), clinical efficacy (partial or complete response [PR or CR]), and associated biomarkers. Results: 74 pts (median prior therapies: 2; range: 0–6) received 90–260 mg/week of G in: A, 21; B, 21; and C, 32. The top drug related adverse events: A: neutropenia, mucositis, alopecia; B: nausea, fatigue, vomiting; and C: mucositis, diarrhea, nausea, fatigue. Cycle 1 dose limiting toxicities (DLTs) were: A: grade 3 mucositis (n = 1); B: no DLT; C: grade 3 mucositis (n = 1), pneumonitis (n = 1), rash (n = 1), and grade 2 fatigue (n = 1). PK parameters for G were similar regardless of combination agent. Best overall response was A: 4/21 PRs; B: 8/21 PRs (5 TNBC, 2 NSCLC, 1 TCC), and C: 6/32, (1 CR, 5 PRs). In Arm B, 3 of the 8 PRs (2 NSCLC, 1 TCC) had prior platinum exposure. Next generation sequencing involving PI3K data from a subset of patients is under evaluation. Conclusions: G can be combined with docetaxel, cisplatin, or dacomitinib, with manageable toxicity profiles and preliminary antitumor activity, even when heavily pre-treated. Due to portfolio prioritization, dose escalation and expansion continues in Arm B, with closure of Arms A and C (MTD not reached). Clinical trial information: NCT01920061.
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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) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.002 | 0.000 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
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".