Phase I Study Demonstrates Activity and Tolerability of Diphtheria Toxin Interleukin-3 Fusion Protein in Patients with AML and MDS.
Bibliographic record
Abstract
Abstract Interleukin-3 receptor (IL-3R) proteins are over-expressed on blasts and cancer stem cells of multiple hematologic malignancies. The recombinant diphtheria toxin fusion protein, DT388IL3, specifically targets IL-3R and is composed of the catalytic and translocation domains of diphtheria toxin (DT388) fused to human interleukin-3 (IL3). DT388IL3 demonstrated selective toxicity to acute myeloid leukemia (AML) stem cells both in vitro and in vivo, and was prepared for a Phase I clinical study in AML and myelodysplasia (MDS) patients. FDA approval (BB IND#11314) and IRB approvals were obtained. 80 AML and MDS patients were screened and 38 AML and 3 MDS patients were treated. The median age of treated patients was 62 years (range, 25–81 years). There were 22 males and 19 females. AML disease was de novo in 5, 1st relapse in 12, 2nd relapse in 8, and refractory in 12. MDS disease was high-grade in one and intermediate-grade in 2. Five AML patients had a history of MDS, and one had a history of secondary AML. One patient each had previously received an autologous or allogeneic stem cell transplant. AML cytogenetics was unfavorable in 15, intermediate in 21, and not done in 2. Seven patients were treated with 4 ug/kg, eight patients with 5.3 ug/kg, thirteen patients with 7.1 ug/kg, seven with 9.4 ug/kg, and six with 12.5 ug/kg DT388IL3 for up to six treatments (one cycle). Of note, patients have not yet received a second cycle. Drug-related toxicities were mild to moderate and transient including fever, chills, hypotension, transaminasemia, hypoxemia, and hypoalbuminemia. Pretreatment anti-DT antibody levels ranged from 0 – 9.6ug/mL (mean = 2.3ug/mL); day 15 post-treatment antibody levels were 0 – 600ug/mL (mean = 92ug/mL); day 30 antibody levels were 1.1 – 306ug/mL (mean = 82ug/mL). Day 1 Cmax ranged from 0 – 350 ng/mL and correlated with dose; Day 12 Cmax ranged from 0 – 179 ng/mL and correlated with Day 12 anti-DT antibody levels. Development of anti-DT antibody levels at Day 15 and 30 did not interfere with response. Consistent with an absence of toxicity to normal hematopoietic progenitors, responses occurred in the absence of prolonged myelosuppression. Among 38 evaluable AML patients, we have observed one CR of 8 months duration, 2 partial remissions (PRs) lasting one and three months, and 3 minimal responses with clearance of peripheral blasts and marrow blast cytoreductions of 89%, 90%, and 90% lasting one to two months. In one evaluable MDS patient, we achieved a PR lasting four months with improvement in hematologic parameters and conversion to transfusion independence. Patient accrual is proceeding with correlative IL3R content of blasts and cancer stem cells. These results of activity and tolerability are encouraging and suggest that DT388IL3 may achieve a role in the management of patients with myeloid malignancies.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".