A phase I study of the pan-Bcl2 family inhibitor GX15–070, administered as a 3-hour weekly infusion in patients with refractory solid tumors or lymphomas
Bibliographic record
Abstract
3081 Background: GX15–070 is an antagonist of the BH3-binding groove of the bcl-2 family of anti apoptotic proteins. GX15–070 activates apoptosis in vitro and exhibits clinical activity in chronic lymphocytic leukemia (O’Brien et al, ASH 2005) with a recommended phase II dose of 28 mg/m 2 every 3 weeks with DLT of grade 3 infusional CNS toxicities. Methods: In a standard titration design, 4 cohorts of 3 patients (pt) were treated with 5mg/m 2 - 14 mg/m 2 IV infused over 3 hours, weekly. Each cycle of therapy consisted of 4 weekly infusions. Pharmacokinetics (PK) and pharmacodynamic (PD) response based on plasma oligonucleosomal DNA levels were evaluated. Results: N=15 pts were treated. Median age was 58 (range 24–71). Median number of prior regimens was 4 (range 1–11). A total of 105 infusions (26 cycles) was administered. GX15–070 underwent first order elimination kinetics with a short initial distribution phase (α t 1/2 =0.6 h), followed by a longer elimination γphase (t 1/2 =43.8 h). At the 14 mg/m 2 dose level, median C max and AUC values were 98 ng/ml and 276 ng.hr/ml, respectively. The coefficient of variation was low at 38%. Adverse events have mostly been observed during or shortly after the infusion and have been transient. The most common pertain to the central nervous and gastro-intestinal system (drowsiness, euphoria, ataxia, and abdominal pain). Most toxicities were mild to moderate, with the exception of grade 3 pain experienced by 2/2 pts with Hodgkin’s disease, that resolved rapidly but resulted in treatment discontinuation in 1 patient. One episode of Grade 3 infusional CNS toxicity was reported at 14 mg/m 2 requiring the inclusion of 6 patients with no further DLT. No neutropenia, thrombocytopenia or lymphopenia have been reported. The MTD has not been reached. Mean increase in plasma oligonucleosomal DNA was 36 fold (range 0–182 fold) over baseline. Best response to treatment to date : SD ≥ 8 weeks (4); PD (5); too early (6). Conclusion: Weekly GX15–070 as been well tolerated at doses showing biological activity. Dose escalation will be pursued up to 28 mg/m 2 weekly. No significant financial relationships to disclose.
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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 | 0.003 | 0.005 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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".