MASITINIB FOR THE TREATMENT OF SEVERELY SYMPTOMATIC INDOLENT AND SMOLDERING SYSTEMIC MASTOCYTOSIS: A RANDOMIZED, PLACEBO-CONTROLLED, INTERNATIONAL, PHASE 3 STUDY
(Abstract release date: 05/19/16)
EHA Library. Hermine O. 06/12/16; 135322; S828
Prof. Olivier Hermine
Contributions
Contributions
Abstract
Abstract: S828
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:00 - 08:15
Location: Room H5
Background
Indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM) are life-long conditions associated with a significant reduction in quality-of-life. Masitinib (AB1010) is a selective oral tyrosine kinase inhibitor targeting wild-type KIT (WT-KIT), LYN and FYN. Masitinib does not inhibit KIT-D816V mutated mast cells (MC) but does target normal MCs. This is in part via dual inhibition of LYN and FYN modulating MC degranulation in a KIT-independent manner, and secondly by greatly reducing the normal MC burden through inhibition of WT-KIT.
Aims
To assess the efficacy and safety of masitinib (6 mg/kg/day over 24-weeks with a possible extension period) against placebo in severely symptomatic ISM/ISM patients (pt) who were unresponsive to optimized symptomatic treatments.
Methods
Severely symptomatic ISM/SSM pts were defined as having at least one baseline symptom among: pruritus score ≥9, number of flushes/week ≥8, Hamilton rating scale for depression score ≥19, or Fatigue Impact Scale (FIS) total score ≥75. Treatment-effect was tested using repeated measures methodology for rare diseases via the generalized estimating equation (GEE) model in a modified intention-to-treat (mITT) population. Response was defined as a ≥75% improvement from baseline for any one of the aforementioned severe symptoms. Primary endpoint (4R75%) was cumulative response (timeframe W8-W24) in at least one severe baseline symptom. Long-term analysis was performed over the timeframe of W8-W96. Secondary endpoints included outcomes related to safety, patient-reported symptomatic endpoints and objective endpoints representative of MC activity or burden.
Results
A total of 135 pts were enrolled. Masitinib showed a significant improvement over placebo in its primary endpoint, 18.7% vs 7.4%, respectively, odds ratio of 3.6 (95%CI 1.2-10.8, P=0.008). Masitinib sustained a significant 4R75% response over the long-term with odds ratio of 3.5 (95%CI 1.3-9.7, P=0.016). This result was corroborated by statistically significant outcomes in various sensitivity and secondary analyses. For example, at W24 the mean change of tryptase level relative to baseline in pts with baseline tryptase level >20µg/L was a decrease of 18.0% in the masitinib arm vs an increase of 2.2% in the placebo arm, i.e. an absolute difference of 20.2% (P<0.001). The response of urticaria pigmentosa to masitinib was also statistically significant when compared with placebo (P=0.02), an observation supported by abolition of Darier’s sign (P=0.02). Toxicities were predominantly gastrointestinal or skin events, consistent with masitinib’s known safety adverse events (AE) profile and typically manageable via dose reduction. Severe AE reported with a >4% difference between treatment-arms were diarrhea (9.8%), rash (5.7%), and asthenia (4.1%). The most frequent serious AEs in the masitinib arm were diarrhea (4.3%) and urticaria (2.9%). There were no deaths or life-threatening AEs in the masitinib arm. Long-term safety assessment revealed comparable incidence of AEs between treatment-arms.
Conclusion
Masitinib generated a significant therapeutic benefit across a diverse range of symptoms in pts with severely symptomatic ISM/SSM who were unresponsive to optimized symptomatic treatments. Moreover, the response criterion of ≥75% improvement in at least one severe baseline symptom constitutes a clinically meaningful effect. Data from the study’s extension period showed that masitinib was capable of maintaining remission of symptoms for over 2 years. This is an important observation given that ISM and SSM are a life-long conditions requiring chronic management. Masitinib was associated with increased frequency of AEs during the first 6 months of treatment, although no toxicities were life-threatening, and over the long-term the incidence of AEs was similar between masitinib and placebo.In summary, masitinib has shown a positive benefit/risk ratio and may be an important future treatment option for severely symptomatic ISM/SSM pts.
Session topic: Non-malignant hematopoietic disorders
Keyword(s): Mast cell disease, Mastocytosis, Phase III, Treatment
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:00 - 08:15
Location: Room H5
Background
Indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM) are life-long conditions associated with a significant reduction in quality-of-life. Masitinib (AB1010) is a selective oral tyrosine kinase inhibitor targeting wild-type KIT (WT-KIT), LYN and FYN. Masitinib does not inhibit KIT-D816V mutated mast cells (MC) but does target normal MCs. This is in part via dual inhibition of LYN and FYN modulating MC degranulation in a KIT-independent manner, and secondly by greatly reducing the normal MC burden through inhibition of WT-KIT.
Aims
To assess the efficacy and safety of masitinib (6 mg/kg/day over 24-weeks with a possible extension period) against placebo in severely symptomatic ISM/ISM patients (pt) who were unresponsive to optimized symptomatic treatments.
Methods
Severely symptomatic ISM/SSM pts were defined as having at least one baseline symptom among: pruritus score ≥9, number of flushes/week ≥8, Hamilton rating scale for depression score ≥19, or Fatigue Impact Scale (FIS) total score ≥75. Treatment-effect was tested using repeated measures methodology for rare diseases via the generalized estimating equation (GEE) model in a modified intention-to-treat (mITT) population. Response was defined as a ≥75% improvement from baseline for any one of the aforementioned severe symptoms. Primary endpoint (4R75%) was cumulative response (timeframe W8-W24) in at least one severe baseline symptom. Long-term analysis was performed over the timeframe of W8-W96. Secondary endpoints included outcomes related to safety, patient-reported symptomatic endpoints and objective endpoints representative of MC activity or burden.
Results
A total of 135 pts were enrolled. Masitinib showed a significant improvement over placebo in its primary endpoint, 18.7% vs 7.4%, respectively, odds ratio of 3.6 (95%CI 1.2-10.8, P=0.008). Masitinib sustained a significant 4R75% response over the long-term with odds ratio of 3.5 (95%CI 1.3-9.7, P=0.016). This result was corroborated by statistically significant outcomes in various sensitivity and secondary analyses. For example, at W24 the mean change of tryptase level relative to baseline in pts with baseline tryptase level >20µg/L was a decrease of 18.0% in the masitinib arm vs an increase of 2.2% in the placebo arm, i.e. an absolute difference of 20.2% (P<0.001). The response of urticaria pigmentosa to masitinib was also statistically significant when compared with placebo (P=0.02), an observation supported by abolition of Darier’s sign (P=0.02). Toxicities were predominantly gastrointestinal or skin events, consistent with masitinib’s known safety adverse events (AE) profile and typically manageable via dose reduction. Severe AE reported with a >4% difference between treatment-arms were diarrhea (9.8%), rash (5.7%), and asthenia (4.1%). The most frequent serious AEs in the masitinib arm were diarrhea (4.3%) and urticaria (2.9%). There were no deaths or life-threatening AEs in the masitinib arm. Long-term safety assessment revealed comparable incidence of AEs between treatment-arms.
Conclusion
Masitinib generated a significant therapeutic benefit across a diverse range of symptoms in pts with severely symptomatic ISM/SSM who were unresponsive to optimized symptomatic treatments. Moreover, the response criterion of ≥75% improvement in at least one severe baseline symptom constitutes a clinically meaningful effect. Data from the study’s extension period showed that masitinib was capable of maintaining remission of symptoms for over 2 years. This is an important observation given that ISM and SSM are a life-long conditions requiring chronic management. Masitinib was associated with increased frequency of AEs during the first 6 months of treatment, although no toxicities were life-threatening, and over the long-term the incidence of AEs was similar between masitinib and placebo.In summary, masitinib has shown a positive benefit/risk ratio and may be an important future treatment option for severely symptomatic ISM/SSM pts.
Session topic: Non-malignant hematopoietic disorders
Keyword(s): Mast cell disease, Mastocytosis, Phase III, Treatment
Abstract: S828
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:00 - 08:15
Location: Room H5
Background
Indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM) are life-long conditions associated with a significant reduction in quality-of-life. Masitinib (AB1010) is a selective oral tyrosine kinase inhibitor targeting wild-type KIT (WT-KIT), LYN and FYN. Masitinib does not inhibit KIT-D816V mutated mast cells (MC) but does target normal MCs. This is in part via dual inhibition of LYN and FYN modulating MC degranulation in a KIT-independent manner, and secondly by greatly reducing the normal MC burden through inhibition of WT-KIT.
Aims
To assess the efficacy and safety of masitinib (6 mg/kg/day over 24-weeks with a possible extension period) against placebo in severely symptomatic ISM/ISM patients (pt) who were unresponsive to optimized symptomatic treatments.
Methods
Severely symptomatic ISM/SSM pts were defined as having at least one baseline symptom among: pruritus score ≥9, number of flushes/week ≥8, Hamilton rating scale for depression score ≥19, or Fatigue Impact Scale (FIS) total score ≥75. Treatment-effect was tested using repeated measures methodology for rare diseases via the generalized estimating equation (GEE) model in a modified intention-to-treat (mITT) population. Response was defined as a ≥75% improvement from baseline for any one of the aforementioned severe symptoms. Primary endpoint (4R75%) was cumulative response (timeframe W8-W24) in at least one severe baseline symptom. Long-term analysis was performed over the timeframe of W8-W96. Secondary endpoints included outcomes related to safety, patient-reported symptomatic endpoints and objective endpoints representative of MC activity or burden.
Results
A total of 135 pts were enrolled. Masitinib showed a significant improvement over placebo in its primary endpoint, 18.7% vs 7.4%, respectively, odds ratio of 3.6 (95%CI 1.2-10.8, P=0.008). Masitinib sustained a significant 4R75% response over the long-term with odds ratio of 3.5 (95%CI 1.3-9.7, P=0.016). This result was corroborated by statistically significant outcomes in various sensitivity and secondary analyses. For example, at W24 the mean change of tryptase level relative to baseline in pts with baseline tryptase level >20µg/L was a decrease of 18.0% in the masitinib arm vs an increase of 2.2% in the placebo arm, i.e. an absolute difference of 20.2% (P<0.001). The response of urticaria pigmentosa to masitinib was also statistically significant when compared with placebo (P=0.02), an observation supported by abolition of Darier’s sign (P=0.02). Toxicities were predominantly gastrointestinal or skin events, consistent with masitinib’s known safety adverse events (AE) profile and typically manageable via dose reduction. Severe AE reported with a >4% difference between treatment-arms were diarrhea (9.8%), rash (5.7%), and asthenia (4.1%). The most frequent serious AEs in the masitinib arm were diarrhea (4.3%) and urticaria (2.9%). There were no deaths or life-threatening AEs in the masitinib arm. Long-term safety assessment revealed comparable incidence of AEs between treatment-arms.
Conclusion
Masitinib generated a significant therapeutic benefit across a diverse range of symptoms in pts with severely symptomatic ISM/SSM who were unresponsive to optimized symptomatic treatments. Moreover, the response criterion of ≥75% improvement in at least one severe baseline symptom constitutes a clinically meaningful effect. Data from the study’s extension period showed that masitinib was capable of maintaining remission of symptoms for over 2 years. This is an important observation given that ISM and SSM are a life-long conditions requiring chronic management. Masitinib was associated with increased frequency of AEs during the first 6 months of treatment, although no toxicities were life-threatening, and over the long-term the incidence of AEs was similar between masitinib and placebo.In summary, masitinib has shown a positive benefit/risk ratio and may be an important future treatment option for severely symptomatic ISM/SSM pts.
Session topic: Non-malignant hematopoietic disorders
Keyword(s): Mast cell disease, Mastocytosis, Phase III, Treatment
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:00 - 08:15
Location: Room H5
Background
Indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM) are life-long conditions associated with a significant reduction in quality-of-life. Masitinib (AB1010) is a selective oral tyrosine kinase inhibitor targeting wild-type KIT (WT-KIT), LYN and FYN. Masitinib does not inhibit KIT-D816V mutated mast cells (MC) but does target normal MCs. This is in part via dual inhibition of LYN and FYN modulating MC degranulation in a KIT-independent manner, and secondly by greatly reducing the normal MC burden through inhibition of WT-KIT.
Aims
To assess the efficacy and safety of masitinib (6 mg/kg/day over 24-weeks with a possible extension period) against placebo in severely symptomatic ISM/ISM patients (pt) who were unresponsive to optimized symptomatic treatments.
Methods
Severely symptomatic ISM/SSM pts were defined as having at least one baseline symptom among: pruritus score ≥9, number of flushes/week ≥8, Hamilton rating scale for depression score ≥19, or Fatigue Impact Scale (FIS) total score ≥75. Treatment-effect was tested using repeated measures methodology for rare diseases via the generalized estimating equation (GEE) model in a modified intention-to-treat (mITT) population. Response was defined as a ≥75% improvement from baseline for any one of the aforementioned severe symptoms. Primary endpoint (4R75%) was cumulative response (timeframe W8-W24) in at least one severe baseline symptom. Long-term analysis was performed over the timeframe of W8-W96. Secondary endpoints included outcomes related to safety, patient-reported symptomatic endpoints and objective endpoints representative of MC activity or burden.
Results
A total of 135 pts were enrolled. Masitinib showed a significant improvement over placebo in its primary endpoint, 18.7% vs 7.4%, respectively, odds ratio of 3.6 (95%CI 1.2-10.8, P=0.008). Masitinib sustained a significant 4R75% response over the long-term with odds ratio of 3.5 (95%CI 1.3-9.7, P=0.016). This result was corroborated by statistically significant outcomes in various sensitivity and secondary analyses. For example, at W24 the mean change of tryptase level relative to baseline in pts with baseline tryptase level >20µg/L was a decrease of 18.0% in the masitinib arm vs an increase of 2.2% in the placebo arm, i.e. an absolute difference of 20.2% (P<0.001). The response of urticaria pigmentosa to masitinib was also statistically significant when compared with placebo (P=0.02), an observation supported by abolition of Darier’s sign (P=0.02). Toxicities were predominantly gastrointestinal or skin events, consistent with masitinib’s known safety adverse events (AE) profile and typically manageable via dose reduction. Severe AE reported with a >4% difference between treatment-arms were diarrhea (9.8%), rash (5.7%), and asthenia (4.1%). The most frequent serious AEs in the masitinib arm were diarrhea (4.3%) and urticaria (2.9%). There were no deaths or life-threatening AEs in the masitinib arm. Long-term safety assessment revealed comparable incidence of AEs between treatment-arms.
Conclusion
Masitinib generated a significant therapeutic benefit across a diverse range of symptoms in pts with severely symptomatic ISM/SSM who were unresponsive to optimized symptomatic treatments. Moreover, the response criterion of ≥75% improvement in at least one severe baseline symptom constitutes a clinically meaningful effect. Data from the study’s extension period showed that masitinib was capable of maintaining remission of symptoms for over 2 years. This is an important observation given that ISM and SSM are a life-long conditions requiring chronic management. Masitinib was associated with increased frequency of AEs during the first 6 months of treatment, although no toxicities were life-threatening, and over the long-term the incidence of AEs was similar between masitinib and placebo.In summary, masitinib has shown a positive benefit/risk ratio and may be an important future treatment option for severely symptomatic ISM/SSM pts.
Session topic: Non-malignant hematopoietic disorders
Keyword(s): Mast cell disease, Mastocytosis, Phase III, Treatment
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