Abstract CT230: Pediatric phase 1 trial of moxetumomab pasudotox: Activity in chemotherapy refractory acute lymphoblastic leukemia (ALL)
Bibliographic record
Abstract
Abstract Background: Novel therapies are needed to overcome chemotherapy resistance and reduce toxicities of treatment for childhood ALL. CD22 is an antigen expressed on B-lineage ALL blasts. Moxetumomab pasudotox (MP) is a recombinant immunoconjugate composed of an anti-CD22 immunoglobulin variable domain genetically fused to a truncated form of Pseudomonas exotoxin. Methods: This is a multicenter, open-label, phase 1, dose-escalation study of MP in pediatric patients (pts) with relapsed/refractory ALL and NHL with CD22 expression. MP is administered as a 30-min IV infusion at doses 5-50 µg/kg every other day for 6-10 doses every 21 days. Cohort A (n=7) consisted of an accelerated dose-escalation phase followed by standard 3+3 dose-escalation. To reduce the incidence of capillary leak syndrome (CLS), subsequent cohorts (B, n=23; C, n=14) received dexamethasone (2.5 mg/m2 every 12 hours) around the first 6 doses of MP in cycle 1. In Cohort C, doses were increased to 10/cycle and an expansion phase at 50 µg/kg was added. Results: 44 pts with ALL 1-23 years of age have been treated. 35/44 had treatment-refractory disease; 20/44 had relapsed after stem cell transplant (SCT). Pts received a median of 1 treatment cycle (range 1-4). The majority (55%) of treatment-related adverse events (AEs) were mild and reversible. The most common treatment-related AEs were increased AST and ALT and weight gain. There were 2 treatment-related deaths and 7 pts discontinued therapy due to a treatment-related AE. Four DLTs included CLS in 2/7 pts in Cohort A (30 µg/kg; 1 reported as pleural effusion); hypercalcemia in 1 pt treated at 40 µg/kg (Cohort B) who died of a cardiac arrhythmia during attempted venous catheter placement; and grade 4 hemolytic uremic syndrome (HUS) in 1 pt at 50 µg/kg (Cohort B). HUS was noted in 6 pts, 5 treated at the 50 µg/kg dose. Two events were grade 4 with remaining cases ≤grade 2. All but 1 patient recovered from HUS. Based on HUS, the 50 µg/kg dose was determined to exceed the maximum tolerated dose and accrual at a lower dose is ongoing. Of the 37 (84%) pts evaluable for response, objective responses were achieved in 11 (30%), including 9 (24%) complete responses (CR). Per investigator report, 4/9 CRs were minimal residual disease negative, and 3 of these pts underwent a second SCT. Hematological activity (≥50% reduction in blasts and/or improvement in neutrophil and/or platelet counts) was observed in 11 (30%) pts. Anti-drug neutralizing antibodies (≥50% neutralization) developed in 7/44 (16%) pts. Conclusions: MP is active in pediatric pts with relapsed/refractory ALL. The observed antileukemic activity and safety profile warrant further investigation; phase 2 trials are in development. Study sponsored by MedImmune, and supported in part by the Intramural Research Program of the NIH, NCI, CCR. ClinicalTrials.gov NCT00659425. Citation Format: Alan S. Wayne, Nirali N. Shah, Deepa Bhojwani, Lewis B. Silverman, James A. Whitlock, Maryalice Stetler-Stevenson, Robert J. Kreitman, Trishna Goswami, Ramy Ibrahim, Ira Pastan. Pediatric phase 1 trial of moxetumomab pasudotox: Activity in chemotherapy refractory acute lymphoblastic leukemia (ALL). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT230. doi:10.1158/1538-7445.AM2014-CT230
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 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".