A Phase II Trial of the Small Molecule Pan-Bcl-2 Family Inhibitor Obatoclax Mesylate (GX15-070) Administered by a 24-h Continuous Infusion Every 2 Weeks to Patients with Chronic Idiopathic Myelofibrosis (CIMF).
Bibliographic record
Abstract
Abstract Obatoclax is an antagonist of the BH3-binding groove of the bcl-2 family of anti apoptotic proteins. It activates apoptosis and has clinical activity in chronic lymphocytic leukemia (CLL; O’Brien et al, ASH 2005) and myelodysplastic syndromes (MDS ; Borthakur et al., ASH 2006). In both CLL and MDS, treatment with obatoclax has resulted in achievement of red blood cell transfusion independence in chronically anemic patients. CIMF is also frequently associated with chronic anemia as well as activating mutations of the JAK2 kinase. Activated JAK2 in turns activates Stat5 which leads to the transcriptional activation of bcl-xl. Currently ongoing two-stage trial was designed to detect a ≥30% response rate to obatoclax given as a flat dose of 60 mg by 24-h infusion every 2 weeks (2-week period equals one cycle) using the International Working Group Consensus Criteria. Patients were assessed for response every 2 weeks while on therapy. Of the 19 patients required for Stage 1, 17 have been enrolled and 14 currently have data available. Median age was 68 (range: 45–89) and 8 patients were male. JAK2 mutated in 3, wild type in 3, status unknown in 8. Prior CIMF directed therapy other then hydroxyurea and erythropoietin was given to 8 patients (1–3 regimens, median = 1). A total of 102 cycles have been administered with 3 patients still receiving obatoclax. The most common adverse events (AEs) were fatigue (57%), gait disturbance (43%), dyspnea (43%), nausea (36%), peripheral edema (36%), diarrhea (29%), chest pain (29%), chills (29%), weight loss (29%), dizziness (29%), headache (29%), cough (29%), hyperhydrosis (29%), somnolence (21%) and euphoria (21%). All were of Grades 1–2 with the exception of 3 Grade 3 AEs of peripheral edema, 2 of dyspnea, 2 of fatigue and one each of diarrhea and chest pain. Two patients died of disease related complications shortly after having received their first cycle of obatoclax. The plasma concentrations of obatoclax appeared to have reached a steady state before end of infusion. The mean ±SD plasma levels at 0, 3, and 23 hr time-points after infusion started were 0, 6.45±2.64, and 4.33±0.83 ng/mL, respectively. Two patients amongst the 8 previously treated experienced a Clinical Improvement Response persisting 6 months with increases in hemoglobin and red blood cell transfusion independence, while continuing to receive chronic recombinant erythropoietin therapy to which they had not previously responded. While still responding, one was referred for an unrelated donor allogeneic stem cell transplant while the other progressed after 6 months. Of the 6 previously untreated patients 3 are still receiving therapy with stable disease. Conclusions: Obatoclax shows activity in CIMF. Enrollment is now focusing on patients without prior CIMF-directed therapies in order to better estimate the therapeutic potential of bcl-2 family inhibition in this disease.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| 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".