A phase I study of R04929097, an oral gamma secretase inhibitor, in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575).
Bibliographic record
Abstract
3082 Background: RO4929097 (RO) is an oral inhibitor of γ-secretase that disrupts Notch signaling. Gemcitabine (GEM) is active against many solid tumors with a favorable toxicity profile suited to combination. The primary objective of this trial is to establish the recommended phase II dose (RP2D) of RO in combination with GEM; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics (PK), biomarkers of Notch signaling and preliminary anti-tumor activity. Methods: Patients (pts) with advanced solid tumors were enrolled in escalating RO dose levels (DL) as follows: DL1 20mg, DL2 30mg; DL3 45mg and DL4 90mg using a 3+3 design. Treatment with RO was administered once daily on days (d) 1-3, 8-10, 15-17, 22-24 and GEM 1000mg/m2 on d1, 8, and 15 in 28d cycles (c). Dose limiting toxicities (DLTs) during c1 were defined as CTCAE v4 grade (g) 3 non-hematological or g4 hematological toxicities, failure to start c2 within <14 days, or failure to receive ≥75% doses of RO or d8 GEM in c1. Serial plasma samples for RO PK were collected on d1 and 10. Results: As of January 2012, 15 pts (median age 55) have been treated. DLTs were: DL1 0/3, DL2 1/7 (g3 ALT), DL3 0/3, DL4 2/2 (g3 AST/ALT and failure to receive ³75% doses); all were reversible. One death (perforated viscus) related to disease progression was observed. Most common g1/2 toxicities were nausea (9), vomiting (6), fatigue (5), hypophosphatemia (5), transaminitis (3) hypomagnasemia (2) and maculopapular rash (2). G3 hypophosphatemia (1) was observed beyond C1. RO PKs demonstrated comparable exposures at 30mg and 45mg (Table). Best response (RECIST 1.1) was stable disease > 4 months in 3 pts (pancreas, tracheal, breast CA). Conclusions: RO and GEM can be safely combined. RO levels achieved exceeded the AUC0-24 for efficacy in preclinical models using daily dosing. The maximum tolerated dose was exceeded at 90mg RO. Dose expansion at 45mg RO is ongoing to confirm the RP2D. [Table: see text]
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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) | 0.003 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.004 |
| 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".