Safety and Efficacy of Subcutaneous-Administered Omacetaxine Mepesuccinate in Chronic Myeloid Leukemia (CML) Patients Who Are Resistant or Intolerant to Two or More Tyrosine Kinase Inhibitors – Results of A Multicenter Phase 2/3 Study.
Bibliographic record
Abstract
Abstract Abstract 861 Background: Omacetaxine is a first-in-class cetaxine with clinical activity against Ph+ CML and a mechanism of action independent of tyrosine kinase inhibition. The development of TKI resistance and intolerance is an emerging problem and patients (Pts) who have failed multiple TKIs may benefit from an alternative therapy for CML. Study Goals: To evaluate the safety and efficacy of SC omacetaxine in CML Pts who are resistant and/or intolerant to two or more TKIs. Methods: Eligible Pts included adult CML Pts in chronic, accelerated, or blast disease phase (CP, AP, BP) with resistance and/or intolerance to at least two TKIs. Bcr-Abl mutational analysis was performed at one of 2 central reference laboratories and Pts harboring the T315I Bcr-Abl mutation were enrolled in a separate clinical trial. 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, 99 Pts have enrolled, with data available for analysis on 65 Pts (30 CP, 20 AP and 15 BP). The median age was 57 yrs (23-78) with 52% male and a median disease duration of 77 mo (1-197). Nearly all (64/65, 99%) Pts failed prior IM therapy and 57% failed 3 or more prior TKIs. Baseline mutations were identified in 21 (32%) Pts with 10 non-P Loop, 7 P Loop and 4 compound mutations. Baseline clonal evolution was evident in 5 (17%) CP, 8 (40%) AP, and 13 (87%) BP Pts. Six CP Pts entered the study in CHR. The median follow-up for all Pts is 4.0 mo (0.3 to 14.7). Efficacy: In CP Pts, CHR was achieved in 18 Pts and maintained for more than 8 weeks in the 6 Pts enrolled with baseline CHR, for an overall CHR rate of 80%; median duration 4.7+ mo (1.4 to 13). Major cytogenetic response (MCyR) was achieved in 6 (20%) CP Pts (1 complete, 5 partial); median duration 1.6+ mo (0.0 to 2.9). Major molecular response was achieved in 10% of CP Pts. In AP Pts, overall hematologic response was achieved in 15 (75%) Pts; 12 CHR and 3 return to chronic phase (RCP); median duration 2.5+ mo (1.8 to 10.5). One (5%) AP Pt achieved a complete CyR, identified immediately prior to data cut-off and ongoing. In BP Pts, overall hematologic response was achieved in 8 (53.3%); 6 CHR and 2 RCP. Three Pts (2 CP, 1 AP) received bone marrow/stem cell transplants after achieving major cytogenetic response, a therapeutic option not available to them at study enrollment. No deaths occurred in CP Pts. The median overall survival for AP Pts has not been reached and 13 Pts were alive at the time of data cut-off. Median overall survival was 14.5 mo for BP Pts. Median time to progression was 11.1, 5.7, and 2.6 mo for CP, AP, and BP Pts, respectively. Safety: Grade 3/4 related events occurred in 47/65 (72%) of Pts. The most commonly reported events (>15%) were thrombocytopenia (43%), neutropenia (29%), and anemia (22%). Non-hematologic toxicities were generally grade 1/2 with the most frequently reported; diarrhea (32%), nausea (26%), pyrexia (23%), headache (20%), fatigue (19%), vomiting (17%), and asthenia (17%). Grade 3/4 non-hematologic toxicities were uncommon with no events occurring in >5% of Pts and fatigue (3%) the most common event. Treatment delays occurred in approximately 50% of the Pts with median duration of approximately 9 days for all disease phases and cycles (CP=7, AP=11, and BP=12 days). The primary causes of delay were thrombocytopenia, neutropenia and pancytopenia. Deaths occurred in 6 (9.2%) Pts, including 2 (10%) AP pts and 4 (26.7%) BP Pts. Of the deaths, one occurrence in an AP Pt was considered to be possibly related to omacetaxine treatment (febrile neutropenia). Conclusions: Omacetaxine administered by SC injection produced hematologic and cytogenetic responses with a safety profile primarily consisting of hematologic toxicities. This study demonstrated that omacetaxine may be a potential treatment option for CML Pts who have failed multiple TKIs. Disclosures: Cortes-Franco: ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Raghunadharao:ChemGenex: Research Funding. Parikh:ChemGenex: Research Funding. Wetzler:ChemGenex: Membership on an entity's Board of Directors or advisory committees, 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. Kantarjian:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Craig:ChemGenex: Employment. Benichou:ChemGenex: Employment. Humphriss:ChemGenex: Employment. Nicolini:ChemGenex: 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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 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 | 0.000 |
| 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".