Exactis-03: A phase I trial of the combination of olaparib and navitoclax in women with high grade serous ovarian cancer and triple negative breast cancer.
Bibliographic record
Abstract
TPS5623 Background: Identifying new therapeutic options for patients (pts) with high grade serous ovarian cancer (HGSC) and triple negative breast cancer (TNBC) is a priority. For pts with pathogenic variants in BRCA, the PARP inhibitor (PARPi) olaparib is used to treat TNBC and as maintenance for HGSC. PARPi can induce a senescence-like phenotype in cancer cells with cell survival dependent on anti-apoptotic proteins. The intrinsic apoptotic pathway is regulated by the Bcl-2 family composed of anti-apoptotic proteins (including Bcl-2, Bcl-xL), pro-apoptotic effectors and the pro-apoptotic BH3-only proteins. Increased expression of Bcl-xL occurs in 88% of HGSC. Olaparib and navitoclax, a Bcl-2/Bcl-xL inhibitor, are synergistic in pre clinical models of HGSC and TNBC. Exactis- 03 investigates targeting, olaparib-induced sensecence as a treatment strategy for pts with HGSC and TNBC. Methods: Exactis-03 is a multi-centre phase I trial determining if olaparib can be safely combined with navitoclax in pts with TNBC who have somatic or germline mutations in BRCA1/2 or PALB2 and pts with recurrent HGSC who have progressed ≥ 6 months since their last platinum based chemotherapy. Additional eligibility criteria include : ≥3 prior lines of treatment for TNBC (no limit for HGSC); for pts with HGSC prior PARPi is allowed provided there was no progression on or ≤6 months since discontinuation of the PARPi; ECOG PS ≤2; ability to absorb study medication and pts must be willing and able to undergo study related procedures. The primary endpoint is identification of the recommended phase II dose (RP2D) of olaparib combined with navitoclax. Olaparib 200mg bid is administered alone for the first 2 weeks. Tumor biopsies will be performed at baseline and on day 7-12 (prior to navitoclax) to evaluate senescence and apoptosis biomarkers and to create 3D organoids and ex vivo microdissected tumor (MDT) models for functional assessment of drug response. Navitoclax is dose escalated with a fixed dose of olaparib in 28-day cycles with 3 pts initially treated at each dose level. If no dose limiting toxicity (DLT) is observed, the dose level will be escalated until ≥ 1/3 or ≥ 2/6 patients experience DLT. The RP2D will be defined as the dose level below the one where ≥ 1/3 or ≥ 2/6 patients experience DLT. The 2-week lead-in with olaparib alone and one full cycle of the combination (navitoclax/olaparib) must be completed before dose escalation is permitted. Blood samples are collected for pharmacokinetics and serial evaluation of plasma biomarkers. There is an optional tumor biopsy on progression. Exploratory objectives include determining levels of pro- and anti- apoptotic proteins in biopsy samples and evaluation of cell fate decision biomarkers in biopsy tissue and blood (senescence secretome). Patient-derived organoids and ex vivo MDT will be used to explore drug response and sequencing (NCT05358639). Clinical trial information: NCT05358639 .
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 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 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 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".