A randomized phase II study of bevacizumab and weekly anetumab ravtansine or weekly paclitaxel in platinum-resistant or refractory ovarian cancer NCI trial#10150.
Bibliographic record
Abstract
5514 Background: Mesothelin and its binder, antigen-CA125, are highly expressed in high grade serous and endometrioid ovarian cancers (HGOC) and, can inhibit paclitaxel-induced cell death. Anetumab ravtansine (AR) is a fully-human antibody directed at the mesothelin antigen, conjugated to a tubulin polymerization inhibitor. We assessed the safety and activity of the combination AR/bevacizumab (ARB) versus weekly paclitaxel/bevacizumab (PB) in patients (pts) with platinum resistant HGOC. Methods: An initial run-in phase I assessed the safety of ARB. After determination of the recommended phase 2 dose (RP2D), a multicenter 1:1 randomized phase 2 trial was designed to evaluate the progression free survival (PFS) in pts with platinum resistant/refractory HGOC. Pts were stratified by platinum resistant or refractory and prior bevacizumab (bev). Eligibility required measurable disease and mesothelin tested positive centrally on archival tissue by IHC. No limitation on the number of prior lines of therapy. A futility analysis was planned at 35 PFS events. The control arm was weekly intravenous paclitaxel 80mg/m2 with bev 10mg/kg every 2 weeks. A CT was performed every 8 weeks for RECIST1.1 assessment. The toxicities were reported according to CTCAE version 5.1. NCT03587311. Results: 7 pts were enrolled in the run-in phase 1 and the RP2D determined as bev (10mg/kg) biweekly with AR (2.2mg/kg) weekly on a 28 day-cycle. In the phase 2, 57 pts were enrolled, 28 pts in the ARB and 29 pts in the control group. The positivity rate for mesothelin screening was 88%. Pts were heavily pre-treated, median prior lines of 3 (range (1-9) with 24 pts received prior bev (42%) and 13 pts were platinum refractory (7 in ARB and 6 in PB). At the time of 35 PFS events, one CR and 4 PR were observed (ORR = 18%) in the ARB arm, versus no CR and 16 PR in the weekly PB (ORR = 55%). The estimated median PFS was 5.3 (95% CI: 3.7-7.4) months for ARB and 9.6 (95% CI: 7.4-17.4) months for PB (HR = 1.7(95% CI: 0.9-3.4)). The median number of cycles were 4 (1, 29) and 8 (1, 19) respectively. The most common treatment-related AEs in the ARB arm were mostly grade 1/2 increase AST (71%) and ALT (64%), thrombocytopenia (61%), fatigue (57%), and peripheral neuropathy (46%). In the PB arm, the most common treatment-related AE were anemia (66%), neutropenia (59%), epistaxis (48%), fatigue (45%) and peripheral neuropathy (45%). Conclusions: At the time of futility analysis, weekly PB had better outcome than weekly ARB leading to the study termination. Molecular and blood analyses are on-going to assess potential biomarkers of response. This study highlights the importance of randomization in assessment of novel therapies and potential for re-challenge with bevacizumab. These data show that weekly PB is an effective regimen and can be considered as the control arm in platinum resistant HGOC. Clinical trial information: NCT03587311.
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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 | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| 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 | 0.003 |
| Insufficient payload (model declined to judge) | 0.011 | 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".