An international, biomarker-directed, randomized, phase II trial of AZD1775 plus paclitaxel and carboplatin (P/C) for the treatment of women with platinum-sensitive, <i>TP53</i>-mutant ovarian cancer.
Bibliographic record
Abstract
5506 Background: Data suggest synthetic lethality when TP53-deficient cells are exposed to genotoxic drugs plus the Wee1 inhibitor AZD1775 (MK-1775). AZD1775 plus C was well tolerated in patients (pts) with advanced solid tumors (NCT00648648). This current two-part study (NCT01357161) evaluated the efficacy of AZD1775 plus P/C compared with P/C alone in women with TP53-mutant OC. Methods: After confirming a dose of AZD1775 (225 mg bid; capsules) in 15 pts in part 1, pts in part 2 received AZD1775 or placebo bid for 2.5 days plus P (175 mg/m2; IV) and C (AUC5; IV) on day 1 per 21-day treatment cycle, until progression or the completion of six cycles. Primary objectives: PFS (enhanced [volumetric] RECIST v1.1, criterion for superiority = P< 0.1), safety and tolerability (CTCAE v4.0). Secondary objectives: PFS (RECIST v1.1), ORR (enhanced RECIST v1.1, CA-125 levels) and OS. Results: 121 pts with confirmed TP53 mutations were randomized, 59 and 62 to AZD1775/P/C and P/C, respectively. PFS by independent central review (~57% maturity) was greater with AZD1775/P/C compared with P/C alone (enhanced RECIST: HR 0.63, 80% CI 0.45, 0.89, 95% CI 0.38, 1.06, P= 0.080, median 34.14 vs 31.86 weeks; RECIST: HR 0.55, 80% CI 0.39, 0.79, 95% CI 0.32, 0.95, P= 0.030, median 42.86 vs 34.86 weeks). ORRs were 81.4% vs 75.8% (difference 5.6%, 95% CI for difference –9.4, 20.2, P= 0.459) with AZD1775/P/C vs P/C, respectively. Best response rates based on CA-125 criteria were 81.35% vs 74.19% with AZD1775/P/C vs P/C, respectively. OS data are immature. Most common adverse events (AEs) were nausea (78.0% vs 60.0% for AZD1775/P/C vs P/C, respectively), diarrhea (74.6% vs 36.7%), alopecia (54.2% vs 66.7%) and fatigue (54.2% vs 55.0%). 85 pts had grade ≥ 3 AEs (78.0% vs 65.0% for AZD1775/P/C vs P/C, respectively), 36 pts had serious AEs (40.7% vs 20.0%) and 25 pts had AEs resulting in discontinuation (20.3% vs 21.7%). Conclusions: AZD1775/P/C was associated with a significant increase in PFS when compared with P/C alone, met the preset primary and secondary PFS efficacy bar for clinical importance, and showed acceptable tolerability in women with TP53-mutant OC. Clinical trial information: NCT01357161.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.005 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".