A randomized double-blind placebo-controlled phase II trial comparing gemcitabine monotherapy to gemcitabine in combination with adavosertib in women with recurrent, platinum resistant epithelial ovarian cancer: A trial of the Princess Margaret, California, Chicago and Mayo Phase II Consortia.
Bibliographic record
Abstract
5518 Background: Platinum resistant ovarian cancer (OC) remains a therapeutic challenge. High grade serous OC (HGSOC) harbors TP53 mutations leading to increased dependency on S- and G2-phase checkpoints. Wee1 inhibition with Adavosertib (AZD 1775) (A) induces G2 checkpoint escape. Gemcitabine (G) is an antimetabolite therapy and blocks the progression of cells through the G1/S phase. We hypothesized that combining G+A would be synergistic and overcome resistance. Methods: We conducted a multicentre double-blind 2:1 randomized phase 2 trial to assess the progression free survival (PFS) in women with recurrent platinum-resistant/refractory HGSOC receiving G+A or G+placebo (P) (NCT02151292). Eligibility required measurable disease and feasibility of paired tumor biopsies; no limitation in prior lines of therapy. Non HGSOC histologic subtypes were enrolled in a separate non-randomized exploratory cohort. A/P was given orally at 175mg QD on D1-2, D8-9 and D15-16 with G 1000mg/m² IV D1, D8 and D15 in a 28-day cycle until progression or unacceptable AE. Tumor staging was scheduled every 8 weeks. TP53 mutations were analyzed on archival tissue with Sanger sequencing, TAm-Seq and IHC. TP53 mutation will be also assessed in circulating tumor DNA (ctDNA). Whole exome and RNA sequencing were performed on paired tumor tissues. Results: 124 patients (pts) with median of 3 prior lines of therapy (range 1-10) from 12 centres across Canada and US were enrolled between Sep 2014 to May 2018, with 99 pts randomized (65 in Arm G+A and 34 in G+P). 5 pts were ineligible; 64 pts have died. The median follow-up was 14.3 months. Main related AE was hematologic toxicity (Anemia G≥3: 31% in G+A vs 18% in G+P; Thrombocytopenia G≥3: 31% vs 6%; Neutropenia G≥3: 62% vs 30%). PFS was significantly improved from 3.0 to 4.6 months (HR 0.56 (95%CI: 0.35-0.90, p=0.015 Log rank). There was a significant improvement in overall survival (OS) from 7.2 to 11.5 months (HR 0.56 (95%CI: 0.34-0.92, P=0.022). Partial response by RECIST 1.1 was observed in 13 (21%) and 1 (3%) pts for Arms G+A and G+P, respectively (p=0.02). From the 25 pts in the exploratory cohort, 3 (12%) partial responses were observed. Final results will be reported at the meeting. Conclusion: Addition of adavosertib to gemcitabine in women with platinum resistant/refractory OC improved response rate, PFS and OS with manageable toxicity. Clinical trial information: NCT02151292.
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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 | 0.005 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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".