Safety and Efficacy of Subcutaneous-Administered Omacetaxine Mepesuccinate in Imatinib-Resistant Chronic Myeloid Leukemia (CML) Patients Who Harbor the Bcr- Abl T315I Mutation–Results of An Ongoing Multicenter Phase 2/3 Study.
Bibliographic record
Abstract
Abstract Abstract 644 Background: Omacetaxine is a first-in-class cetaxine with clinical activity against Ph+ CML and a mechanism of action independent of tyrosine kinase inhibition. Currently available tyrosine kinase inhibitors (TKIs) have not demonstrated activity in CML patients (Pts) who harbor the Bcr-Abl T315I mutation. Study Goals: To evaluate the safety and efficacy of subcutaneously (SC) administered omacetaxine in Pts with imatinib (IM)-resistant T315I+ Ph+ CML. Methods: Eligible Pts include adult CML Pts in chronic, accelerated, or blast disease phase (CP, AP, BP) with a confirmed Bcr-Abl T315I mutation and resistance to IM therapy. Induction schedule: 1.25 mg/m2 SC omacetaxine twice daily for 14 days every 28 days until hematologic response. Maintenance dosing: 1.25 mg/m2 SC omacetaxine twice daily for 7 days every 28 days. Study Results: To date, 90 Pts have been enrolled, with data available for analysis on 66 Pts (40 CP, 16 AP and 10 BP). The median age was 58 yrs (19-83) with 70% male Pts and a median disease duration of 54 mo (5-285). All Pts failed prior IM therapy, and 79% failed two or more prior TKIs. The presence of baseline T315I mutation was confirmed in all Pts. Baseline clonal evolution was evident in 10 (25%) CP, 6 (38%) AP, and 7 (70%) BP Pts. Eight CP Pts entered the study in CHR. The median follow-up for all Pts was 6.4 mo (0.2 to 29.6). Efficacy: In CP Pts, CHR was achieved in 26 Pts and maintained in 8 Pts for an overall CHR rate of 85%; the median duration of CHR was 7.7+ mo (1.7 to 23.6). Overall cytogenetic response was 27.5% with 6 (15%) Pts achieving a major cytogenetic response (MCyR, 4 complete, 2 partial). The median duration of MCyR was 6+ mo (0.8 to 16.1). Major molecular response was achieved in 15% of Pts and a reduction of baseline T315I mutated clone occurred in 56.7% of CP Pts. In AP Pts, overall hematologic response was achieved in 6 (37.5%) Pts with 5 CHR and 1 return to chronic phase (RCP). Median duration of response was 3.9+ mo (1.7 to 14.8). One AP Pt achieved a complete cytogenetic response; duration 1.9+ mo. In BP Pts, overall hematologic response was achieved in 3 (30%) Pts with 2 CHR and 1 RCP. The median overall survival for CP Pts has not been reached and 35 (88%) Pts were alive at the time of data cut- off. The median overall survival was 18.8 mo for AP and 1.8 mo for BP Pts. Median time to progression was 11.2, 3.1, and 1.2 mo for CP, AP, and BP Pts, respectively. Safety: Grade 3/4 related events occurred in 45 of 66 (68%) Pts. The most commonly reported events were thrombocytopenia (58%), anemia (36%) and neutropenia (33%). Non-hematologic toxicities were primarily grade 1/2 with the most frequently reported events of diarrhea (44%), fatigue (35%), pyrexia (32%), nausea (26%), and asthenia (21%). Grade 3/4 non-hematologic toxicities were uncommon with no events occurring in >5% of Pts and infection (3%) the most common event. Treatment delays occurred in approximately 50% of the Pts with median duration of approximately 12 days for all disease phases and cycles (CP=12, AP=10, and BP=12 days). The primary causes of delay were thrombocytopenia, neutropenia and pancytopenia. Sixteen deaths occurred during the study (5 CP, 4 AP, and 7 BP).Three deaths (1 CP, 1 AP, and 1 BP) were considered to have a possible relationship to omacetaxine: sepsis, pancytopenia, and sudden death with unknown cause, respectively. Conclusions: Omacetaxine administered by subcutaneous injection produces durable hematologic and cytogenetic responses with a safety profile consisting mainly of hematologic toxicities. Omacetaxine may provide a treatment option for this patient population who currently has no available approved drug therapies. Disclosures: Cortes-Franco: ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Khoury:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nicolini:ChemGenex: Research Funding. Corm:ChemGenex: Research Funding. Lipton:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jones:ChemGenex: Research Funding. Hochhaus:ChemGenex: Research Funding. Craig:ChemGenex: Employment. Benichou:ChemGenex: Employment. Humphriss:ChemGenex: Employment. Kantarjian:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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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 | 0.000 |
| 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".