Abstract CT019: Biological mechanisms underlying objective responses in recurrent GBM patients treated with sequential bortezomib and temozolomide: An interim analysis of NCT03643549 Phase IB/II trial
Bibliographic record
Abstract
Abstract Background: Glioblastoma (GBM) has dismal prognosis, where median survival is approximately 12 months for patients harboring unmethylated O6−methylguanine DNA methyltransferase (MGMT) promoter (uMGMT) due to temozolomide (TMZ) chemotherapy resistance. In preclinical studies, we showed that sequential administration of bortezomib (BTZ) prior to TMZ depleted MGMT protein, abrogated autophagic flux and sensitized uMGMT GBM cells to TMZ. Thus, a phase I/II was launched to investigate clinical benefit. An interim analysis based on Simon´s MinMax design (where at least 2 patients should show clinical benefit amongst the first 15 evaluable patients) would allow the study to continue to full recruitment. Clinical benefit, was defined by progression free survival and or objective radiological complete (CR), partial (PR) responses or stable disease (SD) based on RANO criteria at 6 months and 1-year follow-up. This study aimed to identify the biological mechanisms underlying the objective responses in the initial 15 recurrent GBM patients treated in this trial. Methods: Adult recurrent GBM patients with uMGMT promoter, progressing ≥12 weeks after radiotherapy, Karnofsky performance status (KPS) ≥70 and with measurable lesions were enrolled. They received BTZ 1.3mg/m2 IV on days 1,4,7, during each 4-week cycle starting on day 3 with per oral TMZ at 200mg/m2 5 days/week. The sample size was powered for n=63 patients. Quantitative LC-MS/MS was used to identify novel biomarkers that correlate with objective treatment responses by determining proteomic changes in plasma collected on days 1,4,7,11,15 and 22 during first cycle of treatment. Targeted sequencing of 360 cancer genes and whole exome sequencing (WES) of tumor DNA were conducted to identify associated molecular genetic changes. Results: The 15 patients had median age 52 yrs (range 25-62 yrs), 10 male and 5 female treated at Haukeland University Hospital in Norway. Median KPS was 90 (70-100) and median NANO score was 1 (0-7). 27% (n=4/15) of patients obtained objective radiological responses, where 2/4 (50%) obtained PR and 2/4 (50%) had SD. LC-MS/MS revealed significantly increased (p<0.05) levels of proteins important for regulation of cell death and apoptosis (ADAMTS13, HPR, HBD, CLU and APOE) in objective responders compared to the rest of the patients. Sequential BTZ+ TMZ therapy was safe, tolerated and platelet nadirs consistently normalized by day 22 of each cycle. Proteins associated with platelet activation, aggregation and degranulation (ACTN1, ITGB3, PLEK, PPBP, THBS1, TF, TAGLN2, TLN1, PFN1, VCL and FERMT3) were significantly upregulated (1.6-4.8 fold, p<0.05) on day 15 and 22 compared to baseline in patient plasma. Preliminary analysis of sequencing data identified EGFR gain-of-function mutation in 3 of the 4 responder patients; potentially distinguishing this as a molecular biomarker for the objective treatment responders. Conclusion: Sequential BTZ+TMZ therapy is safe and effective as indicated by objective radiological response. Activation of tumor cell death and apoptosis pathways was observed specifically in objective responders. The interim criteria were fulfilled as 4 amongst the first 15 patients showed clinical benefit. The study is currently recruiting. Citation Format: Mohummad Aminur Rahman, Dorota Goplen, Andreas Waha, Leif Oltedal, Judit Haasz, Surendra Kumar, Even Birkeland, Hrvoje Miletic, Frode Selheim, Martha Chekenya. Biological mechanisms underlying objective responses in recurrent GBM patients treated with sequential bortezomib and temozolomide: An interim analysis of NCT03643549 Phase IB/II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT019.
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 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 | 0.005 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| 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 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".