ACTR-50. MARIZOMIB (MRZ) WITH BEVACIZUMAB (BEV) IN WHO GRADE IV MALIGNANT GLIOMA (G4 MG): FULL ENROLLMENT RESULTS FROM THE PHASE 1, MULTICENTER, OPEN-LABEL STUDY
Bibliographic record
Abstract
MRZ is an irreversible, brain-penetrant, pan-proteasome inhibitor (PI) with anti-MG efficacy preclinically in vitro and in vivo. The safety, pharmocokinetics, and activity of MRZ+BEV is evaluated in BEV-naïve G4 MG patients (pts) in first or second relapse (no prior anti-angiogenic or PI therapy), in a 3+3 dose-escalation (MRZ 0.55 (6 pts), 0.7 (3 pts), and 0.8 mg/m2 (3 pts)) followed by dose-expansion (0.8 mg/m2, 24 pts). Treatments administered IV, 28-day cycles: MRZ (10 min) days 1, 8, & 15; BEV (10 mg/kg) days 1 & 15. Tumor response assessed every other cycle by RANO criteria; MRZ and BEV pharmacokinetics, and proteasome inhibition in circulating blood cells also evaluated. Data reported as of 17 May 2016; median age 55 yrs (range 27–76 yrs), 64% male, Karnofsky score ≥70. Duration of dosing 0.5–11.6 months to date; treatment ongoing in 16 pts. Study treatment-related Grade ≥3 AEs: fatigue, headache, hypertension, hallucination, confusional state, ataxia; one Grade 4 SAE (appendicitis perforated, not related to study treatment), one Grade 5 SAE (intracranial hemorrhage, BEV-related). One pt (cohort 1) had DLT (fatigue); no other DLTs occurred. N=36 for the intent-to-treat population; 30 pts efficacy evaluable by RANO criteria. Overall response (≥ partial response, PR) 39% (14/36, including 5 with complete target lesion response and 2 unconfirmed PRs); 11 stable disease, 5 progressive disease. PFS 6-months is 39%; median OS not yet reached. MGMT status known for 15 of 36 pts; 14 unmethylated (uMGMT), 1 methylated. Seven of 14 uMGMT pts achieved ≥PR; 49% PFS 6-months in uMGMT subgroup. Preliminary activity in uMGMT subgroup suggests therapeutic advantage provided by brain-penetrant PI in comparison with BEV single agent (Taal et al., 2014). MRZ+BEV combination is well tolerated with promising early signs of efficacy in recurrent G4 MG pts.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| 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".