OPTIMIZATION OF RADOTINIB DOSES BASED ON DOSE-EFFICACY AS WELL AS DOSE-SAFETY RELATIONSHIP ANALYSES FOR NEWLY DIAGNOSED PATIENTS WITH CHRONIC PHASE CHRONIC MYELOID LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Noh H. 06/09/16; 134721; PB1821
Ms. Hayeon Noh
Contributions
Contributions
Abstract
Abstract: PB1821
Type: Publication Only
Background
Radotinib is a selective second generation BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia (CML). In the previous dose-safety relationship analyses (Leuk Lymphoma. DOI 10.3109/10428194.2015.1113278), a positive association was found between the radotinib dose adjusted for the patient’s body weight (Dose/BW) and the risk of dose-limiting toxicity (DLT). Hence, a weight-based dosing method was suggested to improve the safety outcomes of radotinib.
Aims
To explore an optimal radotinib dosing regimen for the treatment of chronic phase (CP) CML based on the dose-efficacy as well as dose-safety relationship analyses of Phase 3 study data
Methods
The Phase 3 data were derived from a total of 160 newly diagnosed patients with CP CML treated with radotinib 300 mg BID or 400 mg BID (fixed dose regardless of BW). A logistic regression analysis was conducted to assess the impact of Dose/BW of radotinib on the achievement of major molecular response (MMR) (dose-efficacy relationship) or occurrence of DLT (dose-safety relationship) within 48 weeks of treatment. Subsequently, an optimal Dose/BW cut-off was selected based on chi-square tests and Kaplan-Meier analyses with log-rank test.
Results
Efficacy. A statistically significant inverse relationship was found between Dose/BW and the probability of achieving MMR when gender was controlled for (p = 0.033). A significantly higher rate of MMR was achieved in patients who received <6.5 mg/kg than ≥6.5 mg/kg (56% vs. 34%; chi-square test, p = 0.045). Safety. A statistically significant positive relationship was found between Dose/BW and the probability of DLT occurrence (p = 0.003). Among various Dose/BW cut-offs, the greatest difference in the rate of DLT occurrence was observed between patients who received <6.5 mg/kg and ≥6.5 mg/kg (57% vs. 91%; chi-square test, p <0.001) with the median time to first DLT being 194 days and 83 days, respectively (log-rank test, p <0.001). Therefore, Dose/BW of 6.5 mg/kg BID appears to be a threshold dose of radotinib below which the efficacy is improved as well as the risk of toxicity is reduced.
Conclusion
The results indicate the need for dose adjustment of radotinib according to the patients’ individual BW. Based on the proposed cut-off of Dose/BW 6.5 mg/kg BID, the radotinib doses for patients weighing ≤60 kg and >60 kg are suggested to be 300 mg BID and 400 mg BID, respectively. A randomized well-controlled clinical trial would be needed to confirm the efficacy and safety of this weight-based dosing strategy.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, Tyrosine kinase inhibitor
Type: Publication Only
Background
Radotinib is a selective second generation BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia (CML). In the previous dose-safety relationship analyses (Leuk Lymphoma. DOI 10.3109/10428194.2015.1113278), a positive association was found between the radotinib dose adjusted for the patient’s body weight (Dose/BW) and the risk of dose-limiting toxicity (DLT). Hence, a weight-based dosing method was suggested to improve the safety outcomes of radotinib.
Aims
To explore an optimal radotinib dosing regimen for the treatment of chronic phase (CP) CML based on the dose-efficacy as well as dose-safety relationship analyses of Phase 3 study data
Methods
The Phase 3 data were derived from a total of 160 newly diagnosed patients with CP CML treated with radotinib 300 mg BID or 400 mg BID (fixed dose regardless of BW). A logistic regression analysis was conducted to assess the impact of Dose/BW of radotinib on the achievement of major molecular response (MMR) (dose-efficacy relationship) or occurrence of DLT (dose-safety relationship) within 48 weeks of treatment. Subsequently, an optimal Dose/BW cut-off was selected based on chi-square tests and Kaplan-Meier analyses with log-rank test.
Results
Efficacy. A statistically significant inverse relationship was found between Dose/BW and the probability of achieving MMR when gender was controlled for (p = 0.033). A significantly higher rate of MMR was achieved in patients who received <6.5 mg/kg than ≥6.5 mg/kg (56% vs. 34%; chi-square test, p = 0.045). Safety. A statistically significant positive relationship was found between Dose/BW and the probability of DLT occurrence (p = 0.003). Among various Dose/BW cut-offs, the greatest difference in the rate of DLT occurrence was observed between patients who received <6.5 mg/kg and ≥6.5 mg/kg (57% vs. 91%; chi-square test, p <0.001) with the median time to first DLT being 194 days and 83 days, respectively (log-rank test, p <0.001). Therefore, Dose/BW of 6.5 mg/kg BID appears to be a threshold dose of radotinib below which the efficacy is improved as well as the risk of toxicity is reduced.
Conclusion
The results indicate the need for dose adjustment of radotinib according to the patients’ individual BW. Based on the proposed cut-off of Dose/BW 6.5 mg/kg BID, the radotinib doses for patients weighing ≤60 kg and >60 kg are suggested to be 300 mg BID and 400 mg BID, respectively. A randomized well-controlled clinical trial would be needed to confirm the efficacy and safety of this weight-based dosing strategy.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, Tyrosine kinase inhibitor
Abstract: PB1821
Type: Publication Only
Background
Radotinib is a selective second generation BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia (CML). In the previous dose-safety relationship analyses (Leuk Lymphoma. DOI 10.3109/10428194.2015.1113278), a positive association was found between the radotinib dose adjusted for the patient’s body weight (Dose/BW) and the risk of dose-limiting toxicity (DLT). Hence, a weight-based dosing method was suggested to improve the safety outcomes of radotinib.
Aims
To explore an optimal radotinib dosing regimen for the treatment of chronic phase (CP) CML based on the dose-efficacy as well as dose-safety relationship analyses of Phase 3 study data
Methods
The Phase 3 data were derived from a total of 160 newly diagnosed patients with CP CML treated with radotinib 300 mg BID or 400 mg BID (fixed dose regardless of BW). A logistic regression analysis was conducted to assess the impact of Dose/BW of radotinib on the achievement of major molecular response (MMR) (dose-efficacy relationship) or occurrence of DLT (dose-safety relationship) within 48 weeks of treatment. Subsequently, an optimal Dose/BW cut-off was selected based on chi-square tests and Kaplan-Meier analyses with log-rank test.
Results
Efficacy. A statistically significant inverse relationship was found between Dose/BW and the probability of achieving MMR when gender was controlled for (p = 0.033). A significantly higher rate of MMR was achieved in patients who received <6.5 mg/kg than ≥6.5 mg/kg (56% vs. 34%; chi-square test, p = 0.045). Safety. A statistically significant positive relationship was found between Dose/BW and the probability of DLT occurrence (p = 0.003). Among various Dose/BW cut-offs, the greatest difference in the rate of DLT occurrence was observed between patients who received <6.5 mg/kg and ≥6.5 mg/kg (57% vs. 91%; chi-square test, p <0.001) with the median time to first DLT being 194 days and 83 days, respectively (log-rank test, p <0.001). Therefore, Dose/BW of 6.5 mg/kg BID appears to be a threshold dose of radotinib below which the efficacy is improved as well as the risk of toxicity is reduced.
Conclusion
The results indicate the need for dose adjustment of radotinib according to the patients’ individual BW. Based on the proposed cut-off of Dose/BW 6.5 mg/kg BID, the radotinib doses for patients weighing ≤60 kg and >60 kg are suggested to be 300 mg BID and 400 mg BID, respectively. A randomized well-controlled clinical trial would be needed to confirm the efficacy and safety of this weight-based dosing strategy.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, Tyrosine kinase inhibitor
Type: Publication Only
Background
Radotinib is a selective second generation BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia (CML). In the previous dose-safety relationship analyses (Leuk Lymphoma. DOI 10.3109/10428194.2015.1113278), a positive association was found between the radotinib dose adjusted for the patient’s body weight (Dose/BW) and the risk of dose-limiting toxicity (DLT). Hence, a weight-based dosing method was suggested to improve the safety outcomes of radotinib.
Aims
To explore an optimal radotinib dosing regimen for the treatment of chronic phase (CP) CML based on the dose-efficacy as well as dose-safety relationship analyses of Phase 3 study data
Methods
The Phase 3 data were derived from a total of 160 newly diagnosed patients with CP CML treated with radotinib 300 mg BID or 400 mg BID (fixed dose regardless of BW). A logistic regression analysis was conducted to assess the impact of Dose/BW of radotinib on the achievement of major molecular response (MMR) (dose-efficacy relationship) or occurrence of DLT (dose-safety relationship) within 48 weeks of treatment. Subsequently, an optimal Dose/BW cut-off was selected based on chi-square tests and Kaplan-Meier analyses with log-rank test.
Results
Efficacy. A statistically significant inverse relationship was found between Dose/BW and the probability of achieving MMR when gender was controlled for (p = 0.033). A significantly higher rate of MMR was achieved in patients who received <6.5 mg/kg than ≥6.5 mg/kg (56% vs. 34%; chi-square test, p = 0.045). Safety. A statistically significant positive relationship was found between Dose/BW and the probability of DLT occurrence (p = 0.003). Among various Dose/BW cut-offs, the greatest difference in the rate of DLT occurrence was observed between patients who received <6.5 mg/kg and ≥6.5 mg/kg (57% vs. 91%; chi-square test, p <0.001) with the median time to first DLT being 194 days and 83 days, respectively (log-rank test, p <0.001). Therefore, Dose/BW of 6.5 mg/kg BID appears to be a threshold dose of radotinib below which the efficacy is improved as well as the risk of toxicity is reduced.
Conclusion
The results indicate the need for dose adjustment of radotinib according to the patients’ individual BW. Based on the proposed cut-off of Dose/BW 6.5 mg/kg BID, the radotinib doses for patients weighing ≤60 kg and >60 kg are suggested to be 300 mg BID and 400 mg BID, respectively. A randomized well-controlled clinical trial would be needed to confirm the efficacy and safety of this weight-based dosing strategy.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, Tyrosine kinase inhibitor
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