A Phase I Study of ENMD-2076 In Patients with Relapsed or Refractory Leukemia
Bibliographic record
Abstract
Abstract Abstract 3307 Background: ENMD-2076 is a novel, orally-active molecule that inhibits Aurora A kinase and FLT3, as well as multiple receptor tyrosine kinases that drive tumor vascularization, including VEGFR2 (KDR), PDGFR and FGFR. A phase I study was conducted to determine the maximum tolerated dose (MTD) and toxicities of ENMD-2076 in patients with refractory hematological malignancies. Methods. Patients (cohorts of 6 evaluable patients per dose level) received escalating doses of ENMD-2076 administered orally daily [225 mg (n=7), 375 mg (n=6), 325 mg (n=9), or 275 mg (n=5)]. Plasma levels of ENMD-2076 were measured on Days 1, 8, & 29 of cycle 1 and at the end of study. Peripheral blood and/or bone marrow were obtained at baseline for ex vivo drug sensitivity testing, and on Days 8 & 29 of cycle 1 for pharmacodynamic (PD) monitoring to assess the effects of ENMD-2076 on cell signaling pathways. The latter flow cytometry-based assay used combined pERK, pAkt, pSTAT5, and pS6 labelling, and tested the effects of acute stimulation with SCF and FLT3 ligands in the presence or absence of pathway inhibitors, including ENMD-2076. Results. Twenty-seven patients have been treated to date (26 AML; 1 CMML-2). Median age is 69 years (range, 43–84 years). Median ECOG status 1 (range, 0 to 2). Eighteen patients (89%) had received prior therapy (median, 2 regimens; range, 0 to 6 regimens); 2 had received a prior allogeneic stem cell transplant. A total of 42 cycles have been administered, with a median of 1 cycle (range, 0 to 8 cycles); 10 patients (37%) have received 2 or more cycles of therapy. The most common nonhematological toxicities of any grade, regardless of association with drug, were fatigue, diarrhea, dysphonia, dyspnea, hypertension, constipation, and abdominal pain. Two of 6 patients treated at the 375 mg/day dose level developed dose-limiting toxicities (DLT), consisting of grade 3 fatigue. The dose was therefore decreased to 325 mg/day; one patient on this dose level developed a DLT with grade 3 fatigue. However, as 2 additional patients subsequently developed grade 2 or 3 fatigue (during cycles 1 and 2, respectively), the 325 mg/day dose was not believed to be tolerable for chronic administration in this patient population. The dose was therefore decreased to 275 mg/day; 2 patients subsequently developed DLTs consisting of grade 3 typhilitis and grade 3 syncope, respectively. Overall, no patient experienced grade 4 toxicities or death from ENMD-2076. Of the 20 evaluable patients, one patient achieved a CRi (transfusion-independent with platelets <100 × 109/L), three a morphologic leukemia-free state (MLFS) with a major HI-P and/or HI-E, and 4 other patients had an 11%, 14%, 23%, and 65% reduction in marrow blast count, respectively. Ex vivo studies showed that pre-incubation with ENMD-2076 in concentrations in the range of 0.5–2 mM suppressed growth factor stimulation in the blast cells of most patients tested to date. Decreases in the stimulation of ERK, Akt, STAT5, and S6 were seen in the Day 8 & 29 samples, including a striking inhibition of cell signaling in one patient who achieved a CRi. Conclusions. Single agent ENMD-2076 has activity in a heavily pretreated group of AML patients that may correlate with inhibition of ERK, Akt, STAT5, and S6 activity. The recommended phase two dose (RPTD) is 225 mg/day. Enrollment, as well as PK and PD monitoring of this study, is ongoing. Disclosures: Off Label Use: Clinical trial investigating ENMD-2076 in patients with relapsed or refractory leukemia. Sidor:EntreMed, Inc.: Employment. Fletcher:EntreMed, Inc.: Employment. Arnott:EntreMed, Inc.: Employment. Bray:EntreMed, Inc.: Employment.
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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 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".