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Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3599-3599
Author(s):  
David Andorsky ◽  
Sarah Tomassetti ◽  
Yehuda E. Deutsch ◽  
E Randolph Broun ◽  
Ghayas C. Issa ◽  
...  

Abstract BACKGROUND: Chronic myeloid leukemia (CML) is driven by the constitutively active BCR-ABL1 tyrosine kinase. Several adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) are approved that inhibit BCR-ABL1 activity, and these have transformed CML from a fatal disease to a chronic one with near-normal life expectancy. However, many patients (pts) experience resistance to or intolerance of successive lines of TKI therapy. These pts have poor outcomes and few remaining treatment options. Moreover, pts with CML harboring the T315I mutation have limited treatment options as they are resistant to all approved TKIs except for ponatinib. Hence, there is a need for new CML therapies that are effective and well tolerated. Asciminib is an investigational agent with a novel mechanism of action. It is the first BCR-ABL1 inhibitor that inhibits BCR-ABL1 kinase activity by Specifically Targeting the ABL Myristoyl Pocket (STAMP). This contrasts with approved TKIs that target the ATP site of BCR-ABL1 to inhibit its kinase activity but are not entirely BCR-ABL1-specific and may target other kinases. In the phase III ASCEMBL trial in pts with CML in chronic phase (CP) after prior treatment with ≥2 ATP-competitive TKIs, asciminib showed superior efficacy vs bosutinib: major molecular response (MMR; BCR-ABL1 on the International Scale ≤0.1%) rate at week 24 was 25.5% vs 13.2%, respectively. In a large phase I trial, asciminib demonstrated promising efficacy and safety in pts with CML-CP without the T315I mutation previously treated with ≥2 TKIs and in those with the T315I mutation previously treated with ≥1 TKI: by 6 months, 37% and 25% of pts, respectively, achieved or maintained an MMR. Here, we describe the AIM4CML trial that was initiated to further assess the efficacy and safety of asciminib and explore a once-daily (QD) dosing regimen in pts with CML-CP (ClinicalTrials.gov, NCT04666259). DESIGN: This is a multicenter, phase IIIb, open-label, 3-cohort study of asciminib in pts with CML-CP without T315I after ≥2 prior TKIs and pts with T315I after ≥1 prior TKI (Figure 1). Adults aged ≥18 years with a diagnosis of CML-CP are eligible. Pts must have treatment failure with (as per 2020 European LeukemiaNet recommendations) or intolerance of the most recent TKI at screening. Key eligibility criteria are described in Table 1. Pts without the T315I mutation will undergo random selection to receive either asciminib 40 mg twice daily (BID; cohort A) or 80 mg QD (cohort B); those with the T315I mutation will receive asciminib 200 mg BID (cohort C). OBJECTIVES AND ENDPOINTS: The primary objective is to evaluate the safety profile of asciminib 40 mg BID and 80 mg QD in pts with CML-CP without T315I after ≥2 prior TKIs and of asciminib 200 mg BID in pts with T315I after ≥1 prior TKI. Primary endpoint analyses include incidence and severity of adverse events (AEs), serious AEs, changes in laboratory values and vital signs, and incidence of notable electrocardiogram abnormalities for 24 weeks. Primary and secondary study objectives/endpoints are summarized in Table 2. CONCLUSIONS: The AIM4CML study is currently enrolling pts across multiple sites in the United States, with an anticipated enrollment of approximately 115 heavily pretreated pts with CML-CP. Asciminib has the potential to transform the standard of care in this pt population through its novel mechanism of action as a BCR-ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP). This study is sponsored by Novartis. Figure 1 Figure 1. Disclosures Andorsky: AbbVie: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; AbbVie: Research Funding; AstraZeneca: Other: served on steering committees; Celgene/Bristol Myers Squibb: Research Funding; Epizyme: Research Funding. Tomassetti: Seagene: Research Funding; Rigel: Research Funding; Beigene: Research Funding; Natera: Research Funding; Novartis: Research Funding; Parexel: Research Funding. Deutsch: Astellas: Membership on an entity's Board of Directors or advisory committees. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Levy: Dova: Consultancy, Other: Promotional speaker; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker; Epizyme: Consultancy, Other: Promotional speaker; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Deininger: Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy. Maegawa: Novartis Pharmaceuticals Corporation: Current Employment, Current equity holder in publicly-traded company. Shrestha: Novartis: Current Employment. Mauro: Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Sun Pharma / SPARC: Research Funding.


2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S125-S125
Author(s):  
James Peterson ◽  
Carmen Deseda ◽  
Katie Julien ◽  
Betzana Zambrano ◽  
Germán Áñez ◽  
...  

Abstract Background Booster doses of meningococcal conjugate vaccines may induce long-term protection against invasive meningococcal disease. MenACYW-TT [MenQuadfi®] is a quadrivalent meningococcal conjugate vaccine, licensed for use in ages 2 years and older in USA. The vaccine is also licensed in ages 12 months and older in EU and other countries. Methods A phase IIIb study (NCT04084769) was conducted to evaluate the persistence of immune response in adults and adolescents primed 3-6 years earlier with either MenACYW-TT or MCV4-CRM (Menveo®) and, safety and immunogenicity of MenACYW-TT when administered as a booster dose with or without concomitant administration with MenB vaccines (Bexsero® and Trumenba®). Serum bactericidal assays with human complement (hSBA) and baby rabbit complement (rSBA) were used to measure antibodies against vaccine serogroups at baseline (Day 0 [D0]), D06 (in a subset) and 30 days post-vaccination (D30). Safety data were collected up to 6 months post-vaccination. Results At D0, the GMTs were higher in subjects primed with MenACYW-TT vs MCV4-CRM for serogroups C, Y and W, and were comparable for serogroup A. At D0, all hSBA GMTs were higher than those observed pre-priming dose, suggesting persistence of immunity. Sufficiency of hSBA seroresponse ( >75%) was demonstrated following administration of MenACYW-TT booster dose regardless of the priming vaccine administered 3-6 years earlier. Vaccine seroresponse in a subset of participants at D06 ranged from 77.8% (95%CI 62.9%; 88.8%) for serogroup A to 97.8% (88.5%; 99.9%) for serogroup W suggesting a quick onset of immune response post-booster. Post-vaccination (D30) hSBA GMTs were comparable for serogroups A, Y and W regardless of the nature of the priming vaccine and were higher for serogroup C in subjects primed with MenACYW-TT vaccine. The MenACYW-TT booster dose was well-tolerated and had similar safety profiles regardless of the priming vaccine. The safety profiles were comparable regardless of the MenB vaccine co-administered with MenACYW-TT vaccine. Conclusion MenACYW-TT used as priming vaccine was able to demonstrate persistence of immune response 3-6 years later. MenACYW-TT elicits robust booster responses in adults and adolescents primed with MenACYW-TT or MCV4-CRM Disclosures Betzana Zambrano, MD, Sanofi Pasteur (Employee) Germán Áñez, MD, Sanofi Pasteur (Other Financial or Material Support, Former employee) Sue Jiayuan, MSc, Sanofi Pasteur (Independent Contractor) Judy Pan, PhD, Sanofi Pasteur (Employee) Habiba Arroum, MD, Sanofi Pasteur (Employee) Kucku Varghese, PhD, Sanofi Pasteur (Employee) Emilia Jordanov, MD, Sanofi Pasteur (Employee, Shareholder) Mandeep S. Dhingra, MD, Sanofi Pasteur (Employee, Shareholder)


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