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Jorge E Cortes - One of the best experts on this subject based on the ideXlab platform.
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clinical outcomes in patients with flt3 itd mutated relapsed refractory acute myeloid leukemia undergoing hematopoietic stem cell transplant after Quizartinib or salvage chemotherapy in the quantum r trial
Biology of Blood and Marrow Transplantation, 2020Co-Authors: Siddhartha Ganguly, Mark J Levis, Jorge E Cortes, Alwin Kramer, Giovanni Martinelli, Alexander E. Perl, Nigel H. Russell, Meena Arunachalam, Cedric Dos Santos, Guy GammonAbstract:ABSTRACT Despite the substantial clinical activity of fms-related tyrosine kinase 3 (FLT3) inhibitors in relapsed or refractory (R/R) FLT3-ITD‒positive acute myeloid leukemia (AML), durable remissions and prolonged survival in this population require allogeneic hematopoietic stem cell transplant (allo-HSCT). Quizartinib, a once-daily, oral, highly potent and selective FLT3 inhibitor, significantly prolonged overall survival (OS) and improved clinical benefit compared with salvage chemotherapy (median OS, 6.2 vs 4.7 months; hazard ratio [HR], 0.76 [95% CI, 0.58-0.98]; P = 0.018; composite complete remission [CRc] rate, 48% vs 27%; median duration of CRc, 2.8 vs 1.2 months; mortality rates, 0.8% vs 14% [by day 30], 7% vs 24% [by day 60]) in patients with R/R FLT3-ITD AML in the phase 3 QuANTUM-R trial. In this post hoc analysis, we described the characteristics of and clinical outcomes in patients who underwent an on-study HSCT in QuANTUM-R per investigator discretion and institutional practices. Of 367 randomized patients, 78 (32%) in the Quizartinib arm and 14 (11%) in the salvage chemotherapy arm underwent an on-study allo-HSCT without any intervening therapy for AML after Quizartinib or study-specified salvage chemotherapy. Pooled data of patients from both treatment arms showed a longer median OS in transplanted patients vs those treated without a transplant (12.2 vs 4.4 months; HR, 0.315 [95% CI, 0.233-0.427]). Pooled data also showed a longer median OS in patients with a last recorded response of CRc before allo-HSCT vs patients without a CRc (20.1 vs 8.8 months; HR, 0.506 [95% CI, 0.296-0.864]). By treatment arm, the median OS was 25.1 months with Quizartinib and 20.1 months with salvage chemotherapy in patients with a last recorded response of CRc prior to allo-HSCT. Forty-eight patients in the Quizartinib arm continued Quizartinib treatment after allo-HSCT. In the 31 patients with a last recorded response of CRc prior to allo-HSCT who continued Quizartinib after allo-HSCT, median OS was 27.1 months. Continuation of Quizartinib after allo-HSCT was tolerable and no new safety signals were identified. These results suggest that post-transplant survival following salvage chemotherapy and Quizartinib treatment are similar. However, Quizartinib response occurs more frequently than with salvage chemotherapy, potentially allowing more patients to undergo transplant and achieve durable clinical benefit. Additionally, post-HSCT Quizartinib was found to be tolerable and may be associated with prolonged survival in some patients, highlighting its potential value in the management of patients with FLT3-ITD R/R AML.
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abstract 784 effect of co mutations and flt3 itd variant allele frequency vaf on response to Quizartinib or salvage chemotherapy sc in relapsed refractory r r acute myeloid leukemia aml
Cancer Research, 2020Co-Authors: Alexander E. Perl, Jorge E Cortes, Siddhartha Ganguly, Samer K Khaled, Alwin Kramer, Giovanni Martinelli, Nigel H. Russell, Kazunobu Kato, Ken C Chang, Yuhu YanAbstract:Introduction: We evaluated the impact of baseline (BL) co-mutations and FLT3-ITD VAF on overall survival (OS) and response (composite complete remission [CRc]) to Quizartinib and SC in the phase III QuANTUM-R trial. Methods: We analyzed 37 recurrently mutated genes in AML in BL samples from 304 patients (pts) (83% of ITT population) with R/R FLT3-ITD-positive AML using next-generation sequencing and a customized Archer® Core Myeloid panel. Positive mutation status was defined as ≥1 mutation detected in the gene region using a VAF cutoff of 2.7%. FLT3-ITD VAF was measured by the Navigate BioPharma FLT3 Mutation Assay (polymerase chain reaction-based, VAF cutoff of 3%). Low and high FLT3-ITD VAF were defined as ≤25% and >25%, respectively. Results: In addition to FLT3-ITD, the prevalence of key BL co-mutations were 59.9% for DNMT3Amut and 55.3% for NPM1mut. Pts with DNMT3Amut treated with Quizartinib had significantly longer OS vs SC (6.3 and 5.4 mos, respectively; hazard ratio [HR], 0.652), p Conclusions: Key co-mutations identified here potentially affect treatment response and OS with Quizartinib vs SC. Our results suggest that molecular subsets of R/R AML pts may particularly derive clinical benefit from Quizartinib. Citation Format: Alexander E. Perl, Jorge E. Cortes, Siddhartha Ganguly, Samer K. Khaled, Alwin Kramer, Giovanni Martinelli, Nigel H. Russell, Ken C. Chang, Kazunobu Kato, Yuhu Yan, Li-An Xu, Sergey Korkhov, Tobias Gunnel, Hiroyuki Sumi, Arnaud Lesegretain, Flora Berisha, Derek Mires, Aziz Benzohra, Takeshi Isoyama, Cedric Dos Santos, Mark J. Levis. Effect of co-mutations and FLT3-ITD variant allele frequency (VAF) on response to Quizartinib or salvage chemotherapy (SC) in relapsed/refractory (R/R) acute myeloid leukemia (AML) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 784.
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population pharmacokinetic analysis of Quizartinib in healthy volunteers and patients with relapsed refractory acute myeloid leukemia
The Journal of Clinical Pharmacology, 2020Co-Authors: Dongwoo Kang, Elizabeth Ludwig, David Jaworowicz, Hannah Huang, Jill Fiedlerkelly, Jorge E Cortes, Siddhartha Ganguly, Samer K Khaled, Alwin Kramer, Mark J LevisAbstract:Quizartinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown robust clinical activity in patients with FLT3-internal tandem duplication-mutated relapsed/refractory acute myeloid leukemia (AML). This analysis evaluated the population pharmacokinetics (PK) of Quizartinib and its active metabolite, AC886, in a pooled analysis of data from 649 healthy volunteers or patients with AML from 8 clinical trials including the phase 3 QuANTUM-R study. Quizartinib was given as a single dose or multiple once-daily doses of 20, 30, 60, or 90 mg. Nonlinear mixed-effects modeling was performed using observed concentrations of Quizartinib and AC886. Strong CYP3A inhibitor use resulted in an 82% increase in the area under the curve (AUC) and a 72% increase in the maximum concentration (Cmax ) of Quizartinib. Albumin level, age, and body surface area were statistically significant covariates on Quizartinib PK. However, their individual effects on Quizartinib AUC and Cmax were <20%. For AC886, strong CYP3A inhibitor use, body surface area and black/African American race were significant covariates. Except for strong CYP3A inhibitor use, the effects on the overall exposure (AUC of Quizartinib + AC886) were <20%. The population PK model provided an adequate description of the observed concentrations of Quizartinib and AC886 in both healthy volunteers and patients with AML. Only concomitant use of strong CYP3A inhibitors had a clinically meaningful effect on Quizartinib PK exposure.
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Quizartinib in flt3 itd mutated relapsed refractory acute myeloid leukemia quantum r trial results
Annals of Oncology, 2019Co-Authors: Jorge E Cortes, Siddhartha Ganguly, Samer K Khaled, Alwin Kramer, Giovanni Martinelli, Alexander E. Perl, Nigel H. Russell, Hervé Dombret, Donna E. Hogge, Brian A. JonasAbstract:Abstract Background FLT3-ITD mutations occur in about 25% of patients (pts) with acute myeloid leukemia (AML) and are associated with poor outcomes. Pts with relapsed/refractory (R/R) FLT3-ITD AML have worse prognosis and high unmet medical need. Quizartinib (Q) is a potent and selective FLT3i with promising activity and a manageable safety profile. QuANTUM-R was a global, phase 3, randomized trial of Q vs chemotherapy (SC) in pts with R/R FLT3-ITD AML (NCT02039726). Methods Pts with R/R FLT3-ITD AML w/wo hematopoietic stem cell transplant (HSCT) were randomized to receive Q or a preselected investigator choice SC: low-dose cytarabine; mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and G-CSF with idarubicin (FLAG-IDA). Prior midostaurin was allowed. Pts receiving HSCT after Q could resume Q after HSCT. Primary and secondary endpoints were overall survival (OS) and event-free survival (EFS), respectively. Exploratory endpoints included response rate, time to and duration of response, and transplant rate. Results 367 pts were randomized; 245 to Q and 122 to SC. Median follow-up was 23.5 mo. OS hazard ratio (HR) of Q relative to SC was 0.76 (95% CI, 0.58-0.98; P=.0177). Median OS was 6.2 (95% CI, 5.3-7.2) vs 4.7 (95% CI, 4.0-5.5) mo in Q and SC arms, respectively. EFS HR was 0.90 (95% CI, 0.70-1.16; P=.1071); median EFS was 1.4 (95% CI, 0.0-1.9) vs 0.9 (95% CI, 0.4-1.3) mo, respectively. Sensitivity analyses and OS subgroup analyses supported Q vs SC. Composite complete response (CRc) was 48% and 27% in Q and SC arms, respectively. Transplant rate was 32% (Q) and 12% (SC). Median time to first CRc was 4.9 wk for Q. The most common grade ≥ 3 TEAEs in both arms were infections and those associated with cytopenia. Conclusion OS benefit was observed with single-agent Q vs SC in pts with R/R FLT3-ITD AML with a favorable Q safety profile, providing evidence of meaningful clinical benefit in pts with limited treatment options.
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Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial
Lancet Oncology, 2019Co-Authors: Jorge E Cortes, Siddhartha Ganguly, Samer K Khaled, Alwin Kramer, Giovanni Martinelli, Alexander E. Perl, Nigel H. Russell, Hervé Dombret, Donna E. Hogge, Brian A. JonasAbstract:Summary Background Patients with relapsed or refractory FLT3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia have a poor prognosis, including high frequency of relapse, poorer response to salvage therapy, and shorter overall survival than those with FLT3 wild-type disease. We aimed to assess whether single-agent Quizartinib, an oral, highly potent and selective type II FLT3 inhibitor, improves overall survival versus salvage chemotherapy. Methods QuANTUM-R is a randomised, controlled, phase 3 trial done at 152 hospitals and cancer centres in 19 countries. Eligible patients aged 18 years or older with ECOG performance status 0–2 with relapsed or refractory (duration of first composite complete remission ≤6 months) FLT3-ITD acute myeloid leukaemia after standard therapy with or without allogeneic haemopoietic stem-cell transplantation were randomly assigned (2:1; permuted block size of 6; stratified by response to previous therapy and choice of chemotherapy via a phone-based and web-based interactive response system) to Quizartinib (60 mg [30 mg lead-in] orally once daily) or investigator's choice of preselected chemotherapy: subcutaneous low-dose cytarabine (subcutaneous injection of cytarabine 20 mg twice daily on days 1–10 of 28-day cycles); intravenous infusions of mitoxantrone (8 mg/m2 per day), etoposide (100 mg/m2 per day), and cytarabine (1000 mg/m2 per day on days 1–5 of up to two 28-day cycles); or intravenous granulocyte colony-stimulating factor (300 μg/m2 per day or 5 μg/kg per day subcutaneously on days 1–5), fludarabine (intravenous infusion 30 mg/m2 per day on days 2–6), cytarabine (intravenous infusion 2000 mg/m2 per day on days 2–6), and idarubicin (intravenous infusion 10 mg/m2 per day on days 2–4 in up to two 28-day cycles). Patients proceeding to haemopoietic stem-cell transplantation after Quizartinib could resume Quizartinib after haemopoietic stem-cell transplantation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02039726, and follow-up is ongoing. Findings Between May 7, 2014, and Sept 13, 2017, 367 patients were enrolled, of whom 245 were randomly allocated to Quizartinib and 122 to chemotherapy. Four patients in the Quizartinib group and 28 in the chemotherapy group were not treated. Median follow-up was 23·5 months (IQR 15·4–32·3). Overall survival was longer for Quizartinib than for chemotherapy (hazard ratio 0·76 [95% CI 0·58–0·98; p=0·02]). Median overall survival was 6·2 months (5·3–7·2) in the Quizartinib group and 4·7 months (4·0–5·5) in the chemotherapy group. The most common non-haematological grade 3–5 treatment-emergent adverse events (within ≤30 days of last dose or >30 days if suspected to be a treatment-related event) for Quizartinib (241 patients) and chemotherapy (94 patients) were sepsis or septic shock (46 patients [19%] for Quizartinib vs 18 [19%] for chemotherapy), pneumonia (29 [12%] vs eight [9%]), and hypokalaemia (28 [12%] vs eight [9%]). The most frequent treatment-related serious adverse events were febrile neutropenia (18 patients [7%]), sepsis or septic shock (11 [5%]), QT prolongation (five [2%]), and nausea (five [2%]) in the Quizartinib group, and febrile neutropenia (five [5%]), sepsis or septic shock (four [4%]), pneumonia (two [2%]), and pyrexia (two [2%]) in the chemotherapy group. Grade 3 QT prolongation in the Quizartinib group was uncommon (eight [3%] by central reading, ten [4%] by investigator report); no grade 4 events occurred. There were 80 (33%) treatment-emergent deaths in the Quizartinib group (31 [13%] of which were due to adverse events) and 16 (17%) in the chemotherapy group (nine [10%] of which were due to adverse events). Interpretation Treatment with Quizartinib had a survival benefit versus salvage chemotherapy and had a manageable safety profile in patients with rapidly proliferative disease and very poor prognosis. Quizartinib could be considered a new standard of care. Given that there are only a few available treatment options, this study highlights the value of targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor. Funding Daiichi Sankyo.
Alexander E. Perl - One of the best experts on this subject based on the ideXlab platform.
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clinical outcomes in patients with flt3 itd mutated relapsed refractory acute myeloid leukemia undergoing hematopoietic stem cell transplant after Quizartinib or salvage chemotherapy in the quantum r trial
Biology of Blood and Marrow Transplantation, 2020Co-Authors: Siddhartha Ganguly, Mark J Levis, Jorge E Cortes, Alwin Kramer, Giovanni Martinelli, Alexander E. Perl, Nigel H. Russell, Meena Arunachalam, Cedric Dos Santos, Guy GammonAbstract:ABSTRACT Despite the substantial clinical activity of fms-related tyrosine kinase 3 (FLT3) inhibitors in relapsed or refractory (R/R) FLT3-ITD‒positive acute myeloid leukemia (AML), durable remissions and prolonged survival in this population require allogeneic hematopoietic stem cell transplant (allo-HSCT). Quizartinib, a once-daily, oral, highly potent and selective FLT3 inhibitor, significantly prolonged overall survival (OS) and improved clinical benefit compared with salvage chemotherapy (median OS, 6.2 vs 4.7 months; hazard ratio [HR], 0.76 [95% CI, 0.58-0.98]; P = 0.018; composite complete remission [CRc] rate, 48% vs 27%; median duration of CRc, 2.8 vs 1.2 months; mortality rates, 0.8% vs 14% [by day 30], 7% vs 24% [by day 60]) in patients with R/R FLT3-ITD AML in the phase 3 QuANTUM-R trial. In this post hoc analysis, we described the characteristics of and clinical outcomes in patients who underwent an on-study HSCT in QuANTUM-R per investigator discretion and institutional practices. Of 367 randomized patients, 78 (32%) in the Quizartinib arm and 14 (11%) in the salvage chemotherapy arm underwent an on-study allo-HSCT without any intervening therapy for AML after Quizartinib or study-specified salvage chemotherapy. Pooled data of patients from both treatment arms showed a longer median OS in transplanted patients vs those treated without a transplant (12.2 vs 4.4 months; HR, 0.315 [95% CI, 0.233-0.427]). Pooled data also showed a longer median OS in patients with a last recorded response of CRc before allo-HSCT vs patients without a CRc (20.1 vs 8.8 months; HR, 0.506 [95% CI, 0.296-0.864]). By treatment arm, the median OS was 25.1 months with Quizartinib and 20.1 months with salvage chemotherapy in patients with a last recorded response of CRc prior to allo-HSCT. Forty-eight patients in the Quizartinib arm continued Quizartinib treatment after allo-HSCT. In the 31 patients with a last recorded response of CRc prior to allo-HSCT who continued Quizartinib after allo-HSCT, median OS was 27.1 months. Continuation of Quizartinib after allo-HSCT was tolerable and no new safety signals were identified. These results suggest that post-transplant survival following salvage chemotherapy and Quizartinib treatment are similar. However, Quizartinib response occurs more frequently than with salvage chemotherapy, potentially allowing more patients to undergo transplant and achieve durable clinical benefit. Additionally, post-HSCT Quizartinib was found to be tolerable and may be associated with prolonged survival in some patients, highlighting its potential value in the management of patients with FLT3-ITD R/R AML.
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abstract 784 effect of co mutations and flt3 itd variant allele frequency vaf on response to Quizartinib or salvage chemotherapy sc in relapsed refractory r r acute myeloid leukemia aml
Cancer Research, 2020Co-Authors: Alexander E. Perl, Jorge E Cortes, Siddhartha Ganguly, Samer K Khaled, Alwin Kramer, Giovanni Martinelli, Nigel H. Russell, Kazunobu Kato, Ken C Chang, Yuhu YanAbstract:Introduction: We evaluated the impact of baseline (BL) co-mutations and FLT3-ITD VAF on overall survival (OS) and response (composite complete remission [CRc]) to Quizartinib and SC in the phase III QuANTUM-R trial. Methods: We analyzed 37 recurrently mutated genes in AML in BL samples from 304 patients (pts) (83% of ITT population) with R/R FLT3-ITD-positive AML using next-generation sequencing and a customized Archer® Core Myeloid panel. Positive mutation status was defined as ≥1 mutation detected in the gene region using a VAF cutoff of 2.7%. FLT3-ITD VAF was measured by the Navigate BioPharma FLT3 Mutation Assay (polymerase chain reaction-based, VAF cutoff of 3%). Low and high FLT3-ITD VAF were defined as ≤25% and >25%, respectively. Results: In addition to FLT3-ITD, the prevalence of key BL co-mutations were 59.9% for DNMT3Amut and 55.3% for NPM1mut. Pts with DNMT3Amut treated with Quizartinib had significantly longer OS vs SC (6.3 and 5.4 mos, respectively; hazard ratio [HR], 0.652), p Conclusions: Key co-mutations identified here potentially affect treatment response and OS with Quizartinib vs SC. Our results suggest that molecular subsets of R/R AML pts may particularly derive clinical benefit from Quizartinib. Citation Format: Alexander E. Perl, Jorge E. Cortes, Siddhartha Ganguly, Samer K. Khaled, Alwin Kramer, Giovanni Martinelli, Nigel H. Russell, Ken C. Chang, Kazunobu Kato, Yuhu Yan, Li-An Xu, Sergey Korkhov, Tobias Gunnel, Hiroyuki Sumi, Arnaud Lesegretain, Flora Berisha, Derek Mires, Aziz Benzohra, Takeshi Isoyama, Cedric Dos Santos, Mark J. Levis. Effect of co-mutations and FLT3-ITD variant allele frequency (VAF) on response to Quizartinib or salvage chemotherapy (SC) in relapsed/refractory (R/R) acute myeloid leukemia (AML) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 784.
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Quizartinib in flt3 itd mutated relapsed refractory acute myeloid leukemia quantum r trial results
Annals of Oncology, 2019Co-Authors: Jorge E Cortes, Siddhartha Ganguly, Samer K Khaled, Alwin Kramer, Giovanni Martinelli, Alexander E. Perl, Nigel H. Russell, Hervé Dombret, Donna E. Hogge, Brian A. JonasAbstract:Abstract Background FLT3-ITD mutations occur in about 25% of patients (pts) with acute myeloid leukemia (AML) and are associated with poor outcomes. Pts with relapsed/refractory (R/R) FLT3-ITD AML have worse prognosis and high unmet medical need. Quizartinib (Q) is a potent and selective FLT3i with promising activity and a manageable safety profile. QuANTUM-R was a global, phase 3, randomized trial of Q vs chemotherapy (SC) in pts with R/R FLT3-ITD AML (NCT02039726). Methods Pts with R/R FLT3-ITD AML w/wo hematopoietic stem cell transplant (HSCT) were randomized to receive Q or a preselected investigator choice SC: low-dose cytarabine; mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and G-CSF with idarubicin (FLAG-IDA). Prior midostaurin was allowed. Pts receiving HSCT after Q could resume Q after HSCT. Primary and secondary endpoints were overall survival (OS) and event-free survival (EFS), respectively. Exploratory endpoints included response rate, time to and duration of response, and transplant rate. Results 367 pts were randomized; 245 to Q and 122 to SC. Median follow-up was 23.5 mo. OS hazard ratio (HR) of Q relative to SC was 0.76 (95% CI, 0.58-0.98; P=.0177). Median OS was 6.2 (95% CI, 5.3-7.2) vs 4.7 (95% CI, 4.0-5.5) mo in Q and SC arms, respectively. EFS HR was 0.90 (95% CI, 0.70-1.16; P=.1071); median EFS was 1.4 (95% CI, 0.0-1.9) vs 0.9 (95% CI, 0.4-1.3) mo, respectively. Sensitivity analyses and OS subgroup analyses supported Q vs SC. Composite complete response (CRc) was 48% and 27% in Q and SC arms, respectively. Transplant rate was 32% (Q) and 12% (SC). Median time to first CRc was 4.9 wk for Q. The most common grade ≥ 3 TEAEs in both arms were infections and those associated with cytopenia. Conclusion OS benefit was observed with single-agent Q vs SC in pts with R/R FLT3-ITD AML with a favorable Q safety profile, providing evidence of meaningful clinical benefit in pts with limited treatment options.
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Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial
Lancet Oncology, 2019Co-Authors: Jorge E Cortes, Siddhartha Ganguly, Samer K Khaled, Alwin Kramer, Giovanni Martinelli, Alexander E. Perl, Nigel H. Russell, Hervé Dombret, Donna E. Hogge, Brian A. JonasAbstract:Summary Background Patients with relapsed or refractory FLT3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia have a poor prognosis, including high frequency of relapse, poorer response to salvage therapy, and shorter overall survival than those with FLT3 wild-type disease. We aimed to assess whether single-agent Quizartinib, an oral, highly potent and selective type II FLT3 inhibitor, improves overall survival versus salvage chemotherapy. Methods QuANTUM-R is a randomised, controlled, phase 3 trial done at 152 hospitals and cancer centres in 19 countries. Eligible patients aged 18 years or older with ECOG performance status 0–2 with relapsed or refractory (duration of first composite complete remission ≤6 months) FLT3-ITD acute myeloid leukaemia after standard therapy with or without allogeneic haemopoietic stem-cell transplantation were randomly assigned (2:1; permuted block size of 6; stratified by response to previous therapy and choice of chemotherapy via a phone-based and web-based interactive response system) to Quizartinib (60 mg [30 mg lead-in] orally once daily) or investigator's choice of preselected chemotherapy: subcutaneous low-dose cytarabine (subcutaneous injection of cytarabine 20 mg twice daily on days 1–10 of 28-day cycles); intravenous infusions of mitoxantrone (8 mg/m2 per day), etoposide (100 mg/m2 per day), and cytarabine (1000 mg/m2 per day on days 1–5 of up to two 28-day cycles); or intravenous granulocyte colony-stimulating factor (300 μg/m2 per day or 5 μg/kg per day subcutaneously on days 1–5), fludarabine (intravenous infusion 30 mg/m2 per day on days 2–6), cytarabine (intravenous infusion 2000 mg/m2 per day on days 2–6), and idarubicin (intravenous infusion 10 mg/m2 per day on days 2–4 in up to two 28-day cycles). Patients proceeding to haemopoietic stem-cell transplantation after Quizartinib could resume Quizartinib after haemopoietic stem-cell transplantation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02039726, and follow-up is ongoing. Findings Between May 7, 2014, and Sept 13, 2017, 367 patients were enrolled, of whom 245 were randomly allocated to Quizartinib and 122 to chemotherapy. Four patients in the Quizartinib group and 28 in the chemotherapy group were not treated. Median follow-up was 23·5 months (IQR 15·4–32·3). Overall survival was longer for Quizartinib than for chemotherapy (hazard ratio 0·76 [95% CI 0·58–0·98; p=0·02]). Median overall survival was 6·2 months (5·3–7·2) in the Quizartinib group and 4·7 months (4·0–5·5) in the chemotherapy group. The most common non-haematological grade 3–5 treatment-emergent adverse events (within ≤30 days of last dose or >30 days if suspected to be a treatment-related event) for Quizartinib (241 patients) and chemotherapy (94 patients) were sepsis or septic shock (46 patients [19%] for Quizartinib vs 18 [19%] for chemotherapy), pneumonia (29 [12%] vs eight [9%]), and hypokalaemia (28 [12%] vs eight [9%]). The most frequent treatment-related serious adverse events were febrile neutropenia (18 patients [7%]), sepsis or septic shock (11 [5%]), QT prolongation (five [2%]), and nausea (five [2%]) in the Quizartinib group, and febrile neutropenia (five [5%]), sepsis or septic shock (four [4%]), pneumonia (two [2%]), and pyrexia (two [2%]) in the chemotherapy group. Grade 3 QT prolongation in the Quizartinib group was uncommon (eight [3%] by central reading, ten [4%] by investigator report); no grade 4 events occurred. There were 80 (33%) treatment-emergent deaths in the Quizartinib group (31 [13%] of which were due to adverse events) and 16 (17%) in the chemotherapy group (nine [10%] of which were due to adverse events). Interpretation Treatment with Quizartinib had a survival benefit versus salvage chemotherapy and had a manageable safety profile in patients with rapidly proliferative disease and very poor prognosis. Quizartinib could be considered a new standard of care. Given that there are only a few available treatment options, this study highlights the value of targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor. Funding Daiichi Sankyo.
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Quizartinib an flt3 inhibitor as monotherapy in patients with relapsed or refractory acute myeloid leukaemia an open label multicentre single arm phase 2 trial
Lancet Oncology, 2018Co-Authors: Jorge E Cortes, Giovanni Martinelli, Alexander E. Perl, Hervé Dombret, Hagop M. Kantarjian, Hartmut Döhner, Philippe Rousselot, Bjorn Steffen, Tibor Kovacsovics, Elihu H. EsteyAbstract:Summary Background Old age and FMS-like tyrosine kinase 3 internal tandem duplication ( FLT3 -ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent Quizartinib in patients with relapsed or refractory acute myeloid leukaemia. Methods We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3 -ITD allelic frequency of more than 10% were considered as FLT3 -ITD positive, whereas all other patients were considered as FLT3 -ITD negative. Patients received Quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of Quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed. Findings Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3 -ITD-positive patients and 16 (36%) of 44 FLT3 -ITD-negative patients achieved composite complete remission, with three (3%) FLT3 -ITD-positive patients and two (5%) FLT3 -ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3 -ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3 -ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [ Interpretation Single-agent Quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3 -ITD mutations. These findings confirm that targeting the FLT3 -ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine Quizartinib at lower starting doses. Funding Ambit Biosciences/Daiichi Sankyo.
Giovanni Martinelli - One of the best experts on this subject based on the ideXlab platform.
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clinical outcomes in patients with flt3 itd mutated relapsed refractory acute myeloid leukemia undergoing hematopoietic stem cell transplant after Quizartinib or salvage chemotherapy in the quantum r trial
Biology of Blood and Marrow Transplantation, 2020Co-Authors: Siddhartha Ganguly, Mark J Levis, Jorge E Cortes, Alwin Kramer, Giovanni Martinelli, Alexander E. Perl, Nigel H. Russell, Meena Arunachalam, Cedric Dos Santos, Guy GammonAbstract:ABSTRACT Despite the substantial clinical activity of fms-related tyrosine kinase 3 (FLT3) inhibitors in relapsed or refractory (R/R) FLT3-ITD‒positive acute myeloid leukemia (AML), durable remissions and prolonged survival in this population require allogeneic hematopoietic stem cell transplant (allo-HSCT). Quizartinib, a once-daily, oral, highly potent and selective FLT3 inhibitor, significantly prolonged overall survival (OS) and improved clinical benefit compared with salvage chemotherapy (median OS, 6.2 vs 4.7 months; hazard ratio [HR], 0.76 [95% CI, 0.58-0.98]; P = 0.018; composite complete remission [CRc] rate, 48% vs 27%; median duration of CRc, 2.8 vs 1.2 months; mortality rates, 0.8% vs 14% [by day 30], 7% vs 24% [by day 60]) in patients with R/R FLT3-ITD AML in the phase 3 QuANTUM-R trial. In this post hoc analysis, we described the characteristics of and clinical outcomes in patients who underwent an on-study HSCT in QuANTUM-R per investigator discretion and institutional practices. Of 367 randomized patients, 78 (32%) in the Quizartinib arm and 14 (11%) in the salvage chemotherapy arm underwent an on-study allo-HSCT without any intervening therapy for AML after Quizartinib or study-specified salvage chemotherapy. Pooled data of patients from both treatment arms showed a longer median OS in transplanted patients vs those treated without a transplant (12.2 vs 4.4 months; HR, 0.315 [95% CI, 0.233-0.427]). Pooled data also showed a longer median OS in patients with a last recorded response of CRc before allo-HSCT vs patients without a CRc (20.1 vs 8.8 months; HR, 0.506 [95% CI, 0.296-0.864]). By treatment arm, the median OS was 25.1 months with Quizartinib and 20.1 months with salvage chemotherapy in patients with a last recorded response of CRc prior to allo-HSCT. Forty-eight patients in the Quizartinib arm continued Quizartinib treatment after allo-HSCT. In the 31 patients with a last recorded response of CRc prior to allo-HSCT who continued Quizartinib after allo-HSCT, median OS was 27.1 months. Continuation of Quizartinib after allo-HSCT was tolerable and no new safety signals were identified. These results suggest that post-transplant survival following salvage chemotherapy and Quizartinib treatment are similar. However, Quizartinib response occurs more frequently than with salvage chemotherapy, potentially allowing more patients to undergo transplant and achieve durable clinical benefit. Additionally, post-HSCT Quizartinib was found to be tolerable and may be associated with prolonged survival in some patients, highlighting its potential value in the management of patients with FLT3-ITD R/R AML.
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abstract 784 effect of co mutations and flt3 itd variant allele frequency vaf on response to Quizartinib or salvage chemotherapy sc in relapsed refractory r r acute myeloid leukemia aml
Cancer Research, 2020Co-Authors: Alexander E. Perl, Jorge E Cortes, Siddhartha Ganguly, Samer K Khaled, Alwin Kramer, Giovanni Martinelli, Nigel H. Russell, Kazunobu Kato, Ken C Chang, Yuhu YanAbstract:Introduction: We evaluated the impact of baseline (BL) co-mutations and FLT3-ITD VAF on overall survival (OS) and response (composite complete remission [CRc]) to Quizartinib and SC in the phase III QuANTUM-R trial. Methods: We analyzed 37 recurrently mutated genes in AML in BL samples from 304 patients (pts) (83% of ITT population) with R/R FLT3-ITD-positive AML using next-generation sequencing and a customized Archer® Core Myeloid panel. Positive mutation status was defined as ≥1 mutation detected in the gene region using a VAF cutoff of 2.7%. FLT3-ITD VAF was measured by the Navigate BioPharma FLT3 Mutation Assay (polymerase chain reaction-based, VAF cutoff of 3%). Low and high FLT3-ITD VAF were defined as ≤25% and >25%, respectively. Results: In addition to FLT3-ITD, the prevalence of key BL co-mutations were 59.9% for DNMT3Amut and 55.3% for NPM1mut. Pts with DNMT3Amut treated with Quizartinib had significantly longer OS vs SC (6.3 and 5.4 mos, respectively; hazard ratio [HR], 0.652), p Conclusions: Key co-mutations identified here potentially affect treatment response and OS with Quizartinib vs SC. Our results suggest that molecular subsets of R/R AML pts may particularly derive clinical benefit from Quizartinib. Citation Format: Alexander E. Perl, Jorge E. Cortes, Siddhartha Ganguly, Samer K. Khaled, Alwin Kramer, Giovanni Martinelli, Nigel H. Russell, Ken C. Chang, Kazunobu Kato, Yuhu Yan, Li-An Xu, Sergey Korkhov, Tobias Gunnel, Hiroyuki Sumi, Arnaud Lesegretain, Flora Berisha, Derek Mires, Aziz Benzohra, Takeshi Isoyama, Cedric Dos Santos, Mark J. Levis. Effect of co-mutations and FLT3-ITD variant allele frequency (VAF) on response to Quizartinib or salvage chemotherapy (SC) in relapsed/refractory (R/R) acute myeloid leukemia (AML) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 784.
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Quizartinib in flt3 itd mutated relapsed refractory acute myeloid leukemia quantum r trial results
Annals of Oncology, 2019Co-Authors: Jorge E Cortes, Siddhartha Ganguly, Samer K Khaled, Alwin Kramer, Giovanni Martinelli, Alexander E. Perl, Nigel H. Russell, Hervé Dombret, Donna E. Hogge, Brian A. JonasAbstract:Abstract Background FLT3-ITD mutations occur in about 25% of patients (pts) with acute myeloid leukemia (AML) and are associated with poor outcomes. Pts with relapsed/refractory (R/R) FLT3-ITD AML have worse prognosis and high unmet medical need. Quizartinib (Q) is a potent and selective FLT3i with promising activity and a manageable safety profile. QuANTUM-R was a global, phase 3, randomized trial of Q vs chemotherapy (SC) in pts with R/R FLT3-ITD AML (NCT02039726). Methods Pts with R/R FLT3-ITD AML w/wo hematopoietic stem cell transplant (HSCT) were randomized to receive Q or a preselected investigator choice SC: low-dose cytarabine; mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and G-CSF with idarubicin (FLAG-IDA). Prior midostaurin was allowed. Pts receiving HSCT after Q could resume Q after HSCT. Primary and secondary endpoints were overall survival (OS) and event-free survival (EFS), respectively. Exploratory endpoints included response rate, time to and duration of response, and transplant rate. Results 367 pts were randomized; 245 to Q and 122 to SC. Median follow-up was 23.5 mo. OS hazard ratio (HR) of Q relative to SC was 0.76 (95% CI, 0.58-0.98; P=.0177). Median OS was 6.2 (95% CI, 5.3-7.2) vs 4.7 (95% CI, 4.0-5.5) mo in Q and SC arms, respectively. EFS HR was 0.90 (95% CI, 0.70-1.16; P=.1071); median EFS was 1.4 (95% CI, 0.0-1.9) vs 0.9 (95% CI, 0.4-1.3) mo, respectively. Sensitivity analyses and OS subgroup analyses supported Q vs SC. Composite complete response (CRc) was 48% and 27% in Q and SC arms, respectively. Transplant rate was 32% (Q) and 12% (SC). Median time to first CRc was 4.9 wk for Q. The most common grade ≥ 3 TEAEs in both arms were infections and those associated with cytopenia. Conclusion OS benefit was observed with single-agent Q vs SC in pts with R/R FLT3-ITD AML with a favorable Q safety profile, providing evidence of meaningful clinical benefit in pts with limited treatment options.
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Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial
Lancet Oncology, 2019Co-Authors: Jorge E Cortes, Siddhartha Ganguly, Samer K Khaled, Alwin Kramer, Giovanni Martinelli, Alexander E. Perl, Nigel H. Russell, Hervé Dombret, Donna E. Hogge, Brian A. JonasAbstract:Summary Background Patients with relapsed or refractory FLT3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia have a poor prognosis, including high frequency of relapse, poorer response to salvage therapy, and shorter overall survival than those with FLT3 wild-type disease. We aimed to assess whether single-agent Quizartinib, an oral, highly potent and selective type II FLT3 inhibitor, improves overall survival versus salvage chemotherapy. Methods QuANTUM-R is a randomised, controlled, phase 3 trial done at 152 hospitals and cancer centres in 19 countries. Eligible patients aged 18 years or older with ECOG performance status 0–2 with relapsed or refractory (duration of first composite complete remission ≤6 months) FLT3-ITD acute myeloid leukaemia after standard therapy with or without allogeneic haemopoietic stem-cell transplantation were randomly assigned (2:1; permuted block size of 6; stratified by response to previous therapy and choice of chemotherapy via a phone-based and web-based interactive response system) to Quizartinib (60 mg [30 mg lead-in] orally once daily) or investigator's choice of preselected chemotherapy: subcutaneous low-dose cytarabine (subcutaneous injection of cytarabine 20 mg twice daily on days 1–10 of 28-day cycles); intravenous infusions of mitoxantrone (8 mg/m2 per day), etoposide (100 mg/m2 per day), and cytarabine (1000 mg/m2 per day on days 1–5 of up to two 28-day cycles); or intravenous granulocyte colony-stimulating factor (300 μg/m2 per day or 5 μg/kg per day subcutaneously on days 1–5), fludarabine (intravenous infusion 30 mg/m2 per day on days 2–6), cytarabine (intravenous infusion 2000 mg/m2 per day on days 2–6), and idarubicin (intravenous infusion 10 mg/m2 per day on days 2–4 in up to two 28-day cycles). Patients proceeding to haemopoietic stem-cell transplantation after Quizartinib could resume Quizartinib after haemopoietic stem-cell transplantation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02039726, and follow-up is ongoing. Findings Between May 7, 2014, and Sept 13, 2017, 367 patients were enrolled, of whom 245 were randomly allocated to Quizartinib and 122 to chemotherapy. Four patients in the Quizartinib group and 28 in the chemotherapy group were not treated. Median follow-up was 23·5 months (IQR 15·4–32·3). Overall survival was longer for Quizartinib than for chemotherapy (hazard ratio 0·76 [95% CI 0·58–0·98; p=0·02]). Median overall survival was 6·2 months (5·3–7·2) in the Quizartinib group and 4·7 months (4·0–5·5) in the chemotherapy group. The most common non-haematological grade 3–5 treatment-emergent adverse events (within ≤30 days of last dose or >30 days if suspected to be a treatment-related event) for Quizartinib (241 patients) and chemotherapy (94 patients) were sepsis or septic shock (46 patients [19%] for Quizartinib vs 18 [19%] for chemotherapy), pneumonia (29 [12%] vs eight [9%]), and hypokalaemia (28 [12%] vs eight [9%]). The most frequent treatment-related serious adverse events were febrile neutropenia (18 patients [7%]), sepsis or septic shock (11 [5%]), QT prolongation (five [2%]), and nausea (five [2%]) in the Quizartinib group, and febrile neutropenia (five [5%]), sepsis or septic shock (four [4%]), pneumonia (two [2%]), and pyrexia (two [2%]) in the chemotherapy group. Grade 3 QT prolongation in the Quizartinib group was uncommon (eight [3%] by central reading, ten [4%] by investigator report); no grade 4 events occurred. There were 80 (33%) treatment-emergent deaths in the Quizartinib group (31 [13%] of which were due to adverse events) and 16 (17%) in the chemotherapy group (nine [10%] of which were due to adverse events). Interpretation Treatment with Quizartinib had a survival benefit versus salvage chemotherapy and had a manageable safety profile in patients with rapidly proliferative disease and very poor prognosis. Quizartinib could be considered a new standard of care. Given that there are only a few available treatment options, this study highlights the value of targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor. Funding Daiichi Sankyo.
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Quizartinib an flt3 inhibitor as monotherapy in patients with relapsed or refractory acute myeloid leukaemia an open label multicentre single arm phase 2 trial
Lancet Oncology, 2018Co-Authors: Jorge E Cortes, Giovanni Martinelli, Alexander E. Perl, Hervé Dombret, Hagop M. Kantarjian, Hartmut Döhner, Philippe Rousselot, Bjorn Steffen, Tibor Kovacsovics, Elihu H. EsteyAbstract:Summary Background Old age and FMS-like tyrosine kinase 3 internal tandem duplication ( FLT3 -ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent Quizartinib in patients with relapsed or refractory acute myeloid leukaemia. Methods We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3 -ITD allelic frequency of more than 10% were considered as FLT3 -ITD positive, whereas all other patients were considered as FLT3 -ITD negative. Patients received Quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of Quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed. Findings Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3 -ITD-positive patients and 16 (36%) of 44 FLT3 -ITD-negative patients achieved composite complete remission, with three (3%) FLT3 -ITD-positive patients and two (5%) FLT3 -ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3 -ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3 -ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [ Interpretation Single-agent Quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3 -ITD mutations. These findings confirm that targeting the FLT3 -ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine Quizartinib at lower starting doses. Funding Ambit Biosciences/Daiichi Sankyo.
Mark J Levis - One of the best experts on this subject based on the ideXlab platform.
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a phase i ii study of the combination of Quizartinib with azacitidine or low dose cytarabine for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome
Haematologica, 2021Co-Authors: Mahesh Swaminathan, Mark J Levis, Tapan M Kadia, Hagop M. Kantarjian, Veronica A Guerra, Gautam Borthakur, Yesid Alvarado, Courtney D Dinardo, Guillermo Garciamanero, Maro OhanianAbstract:FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with poor prognosis. We hypothesized that Quizartinib, a selective and potent FLT3 inhibitor, with azacitidine (AZA) or low-dose cytarabine (LDAC) might improve the outcomes in patients with FLT3-ITD-mutated AML. In this open-label phase I/II trial, patients of any age receiving first-salvage treatment for FLT3-ITD AML or age >60 years with untreated myelodysplastic syndrome or AML were treated with Quizartinib plus AZA or LDAC. Seventy-three patients were treated (34 frontline, 39 first-salvage). Among previously untreated patients, composite response (CRc) was achieved in 13/15 (87%, 8 CR, 4 Cri, 1 CRp) treated with Quizartinib/AZA and 14/19 (74%, 1 CR, 8 CRi, 5 CRp) in Quizartinib/LDAC. The median OS was 19.2 months for Quizartinib/AZA and 8.5 months for Quizartinib/LDAC cohort; RFS was 10.5 and 6.4 months, respectively. Among previously treated patients, 16 (64%) achieved CRc in Quizartinib/AZA and 4 (29%) in Quizartinib/LDAC. The median OS for patients treated with Quizartinib/AZA and Quizartinib/LDAC was 12.8 vs. 4 months, respectively. QTc prolongation grade 3 occurred in only 1 patient in each cohort. Quizartinib-based combinations, particularly with AZA, appear effective in both frontline and first-salvage for patients with FLT3-ITD-mutated AML and are well tolerated.
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clinical outcomes in patients with flt3 itd mutated relapsed refractory acute myeloid leukemia undergoing hematopoietic stem cell transplant after Quizartinib or salvage chemotherapy in the quantum r trial
Biology of Blood and Marrow Transplantation, 2020Co-Authors: Siddhartha Ganguly, Mark J Levis, Jorge E Cortes, Alwin Kramer, Giovanni Martinelli, Alexander E. Perl, Nigel H. Russell, Meena Arunachalam, Cedric Dos Santos, Guy GammonAbstract:ABSTRACT Despite the substantial clinical activity of fms-related tyrosine kinase 3 (FLT3) inhibitors in relapsed or refractory (R/R) FLT3-ITD‒positive acute myeloid leukemia (AML), durable remissions and prolonged survival in this population require allogeneic hematopoietic stem cell transplant (allo-HSCT). Quizartinib, a once-daily, oral, highly potent and selective FLT3 inhibitor, significantly prolonged overall survival (OS) and improved clinical benefit compared with salvage chemotherapy (median OS, 6.2 vs 4.7 months; hazard ratio [HR], 0.76 [95% CI, 0.58-0.98]; P = 0.018; composite complete remission [CRc] rate, 48% vs 27%; median duration of CRc, 2.8 vs 1.2 months; mortality rates, 0.8% vs 14% [by day 30], 7% vs 24% [by day 60]) in patients with R/R FLT3-ITD AML in the phase 3 QuANTUM-R trial. In this post hoc analysis, we described the characteristics of and clinical outcomes in patients who underwent an on-study HSCT in QuANTUM-R per investigator discretion and institutional practices. Of 367 randomized patients, 78 (32%) in the Quizartinib arm and 14 (11%) in the salvage chemotherapy arm underwent an on-study allo-HSCT without any intervening therapy for AML after Quizartinib or study-specified salvage chemotherapy. Pooled data of patients from both treatment arms showed a longer median OS in transplanted patients vs those treated without a transplant (12.2 vs 4.4 months; HR, 0.315 [95% CI, 0.233-0.427]). Pooled data also showed a longer median OS in patients with a last recorded response of CRc before allo-HSCT vs patients without a CRc (20.1 vs 8.8 months; HR, 0.506 [95% CI, 0.296-0.864]). By treatment arm, the median OS was 25.1 months with Quizartinib and 20.1 months with salvage chemotherapy in patients with a last recorded response of CRc prior to allo-HSCT. Forty-eight patients in the Quizartinib arm continued Quizartinib treatment after allo-HSCT. In the 31 patients with a last recorded response of CRc prior to allo-HSCT who continued Quizartinib after allo-HSCT, median OS was 27.1 months. Continuation of Quizartinib after allo-HSCT was tolerable and no new safety signals were identified. These results suggest that post-transplant survival following salvage chemotherapy and Quizartinib treatment are similar. However, Quizartinib response occurs more frequently than with salvage chemotherapy, potentially allowing more patients to undergo transplant and achieve durable clinical benefit. Additionally, post-HSCT Quizartinib was found to be tolerable and may be associated with prolonged survival in some patients, highlighting its potential value in the management of patients with FLT3-ITD R/R AML.
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population pharmacokinetic analysis of Quizartinib in healthy volunteers and patients with relapsed refractory acute myeloid leukemia
The Journal of Clinical Pharmacology, 2020Co-Authors: Dongwoo Kang, Elizabeth Ludwig, David Jaworowicz, Hannah Huang, Jill Fiedlerkelly, Jorge E Cortes, Siddhartha Ganguly, Samer K Khaled, Alwin Kramer, Mark J LevisAbstract:Quizartinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown robust clinical activity in patients with FLT3-internal tandem duplication-mutated relapsed/refractory acute myeloid leukemia (AML). This analysis evaluated the population pharmacokinetics (PK) of Quizartinib and its active metabolite, AC886, in a pooled analysis of data from 649 healthy volunteers or patients with AML from 8 clinical trials including the phase 3 QuANTUM-R study. Quizartinib was given as a single dose or multiple once-daily doses of 20, 30, 60, or 90 mg. Nonlinear mixed-effects modeling was performed using observed concentrations of Quizartinib and AC886. Strong CYP3A inhibitor use resulted in an 82% increase in the area under the curve (AUC) and a 72% increase in the maximum concentration (Cmax ) of Quizartinib. Albumin level, age, and body surface area were statistically significant covariates on Quizartinib PK. However, their individual effects on Quizartinib AUC and Cmax were <20%. For AC886, strong CYP3A inhibitor use, body surface area and black/African American race were significant covariates. Except for strong CYP3A inhibitor use, the effects on the overall exposure (AUC of Quizartinib + AC886) were <20%. The population PK model provided an adequate description of the observed concentrations of Quizartinib and AC886 in both healthy volunteers and patients with AML. Only concomitant use of strong CYP3A inhibitors had a clinically meaningful effect on Quizartinib PK exposure.
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Quizartinib a selective flt3 inhibitor maintains antileukemic activity in preclinical models of ras mediated midostaurin resistant acute myeloid leukemia cells
Oncotarget, 2020Co-Authors: Tomoya Aikawa, Mark J Levis, Noriko Togashi, Koichi Iwanaga, Shinichi Inoue, Yumi Nishiya, Hiroyuki Okada, Takeshi IsoyamaAbstract:FLT3 internal tandem duplication (ITD) mutations are associated with poor prognosis in patients with acute myeloid leukemia (AML). In this preclinical study, we characterized the binding affinity and selectivity of Quizartinib, a small-molecule inhibitor of FLT3, and AC886, the active metabolite of Quizartinib, compared with those of other FLT3 inhibitors. Selectivity profiling against >400 kinases showed that Quizartinib and AC886 were highly selective against FLT3. Quizartinib and AC886 inhibited FLT3 signaling pathways in FLT3-ITD-mutated AML cells, leading to potent growth inhibition with IC50 values of <1 nM. When Quizartinib was administered to mice bearing FLT3-ITD mutated tumors, AC886 was rapidly detected and tumor regression was observed at doses of ≥1 mg/kg without severe body weight loss. In addition, Quizartinib inhibited the viability of midostaurin-resistant MOLM-14 cells and exerted potent antitumor activity in mouse xenograft models without severe body weight loss, while midostaurin and gilteritinib did not show significant antitumor effects. This is the first detailed characterization of Quizartinib and AC886 in comparison with other FLT3 inhibitors under the same experimental conditions. Preclinical antileukemic activity in midostaurin-resistant FLT3-ITD-mutated AML cells suggests the potential value of Quizartinib following midostaurin failure in patients with FLT3-ITD mutated AML.
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abstract 1318 preclinical characterization of Quizartinib and ac886 a metabolite of Quizartinib in aml models and anti leukemic activity of Quizartinib on midostaurin resistant aml cells
Cancer Research, 2019Co-Authors: Tomoya Aikawa, Mark J Levis, Noriko Togashi, Koichi Iwanaga, Shinichi Inoue, Yumi Nishiya, Hiroyuki Okada, Takeshi IsoyamaAbstract:FLT3 mutations have been found in about 30% of acute myeloid leukemia (AML) cases, and the most common form of FLT3 mutation is internal tandem duplication (ITD) in the juxtamembrane domain, which occurs in approximately 25% of adult AML patients and 10-15% of pediatric patients. FLT3-ITD is a driver mutation in AML and the FLT3-ITD presence is associated with poor prognosis in AML patients. Quizartinib is a second-generation small-molecule inhibitor of FLT3, and a phase 3, QuANTUM-R trial showed significantly prolonged overall survival in patients with FLT3-ITD-mutated relapsed/refractory AML. In this preclinical study, we characterized Quizartinib and AC886, a metabolite of Quizartinib, compared with other FLT3 inhibitors including midostaurin, gilteritinib, crenolanib and sorafenib, and then evaluated the anti-tumor effect of Quizartinib on midostaurin-resistant AML cells. Selectivity profiling of the FLT3 inhibitors against over 400 kinases and over 80 non-kinases showed that Quizartinib and AC886 were highly selective against FLT3. Quizartinib and AC886 clearly inhibited FLT3 signaling pathways such as STAT5, RAS/MAPK and PI3K/AKT cascades in FLT3-ITD-mutated AML cells, leading to potent growth inhibition of the AML cells with the IC50 values of Citation Format: Tomoya Aikawa, Noriko Togashi, Koichi Iwanaga, Hiroyuki Okada, Yumi Nishiya, Shinichi Inoue, Mark J. Levis, Takeshi Isoyama. Preclinical characterization of Quizartinib and AC886, a metabolite of Quizartinib, in AML models, and anti-leukemic activity of Quizartinib on midostaurin-resistant AML cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1318.
Elihu H. Estey - One of the best experts on this subject based on the ideXlab platform.
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Quizartinib an flt3 inhibitor as monotherapy in patients with relapsed or refractory acute myeloid leukaemia an open label multicentre single arm phase 2 trial
Lancet Oncology, 2018Co-Authors: Jorge E Cortes, Giovanni Martinelli, Alexander E. Perl, Hervé Dombret, Hagop M. Kantarjian, Hartmut Döhner, Philippe Rousselot, Bjorn Steffen, Tibor Kovacsovics, Elihu H. EsteyAbstract:Summary Background Old age and FMS-like tyrosine kinase 3 internal tandem duplication ( FLT3 -ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent Quizartinib in patients with relapsed or refractory acute myeloid leukaemia. Methods We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3 -ITD allelic frequency of more than 10% were considered as FLT3 -ITD positive, whereas all other patients were considered as FLT3 -ITD negative. Patients received Quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of Quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed. Findings Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3 -ITD-positive patients and 16 (36%) of 44 FLT3 -ITD-negative patients achieved composite complete remission, with three (3%) FLT3 -ITD-positive patients and two (5%) FLT3 -ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3 -ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3 -ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [ Interpretation Single-agent Quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3 -ITD mutations. These findings confirm that targeting the FLT3 -ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine Quizartinib at lower starting doses. Funding Ambit Biosciences/Daiichi Sankyo.
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Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial
The Lancet Oncology, 2018Co-Authors: Jorge Cortés, Giovanni Martinelli, Hervé Dombret, Hartmut Döhner, Philippe Rousselot, Bjorn Steffen, Tibor Kovacsovics, Alexander Perl, Hagop Kantarjian, Elihu H. EsteyAbstract:BACKGROUND: Old age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent Quizartinib in patients with relapsed or refractory acute myeloid leukaemia. METHODS: We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3-ITD allelic frequency of more than 10% were considered as FLT3-ITD positive, whereas all other patients were considered as FLT3-ITD negative. Patients received Quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of Quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed. FINDINGS: Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [<1%]) and hepatic failure (two [1%]). In total, 125 (38%) of 333 patients died within the study treatment period, including the 30-day follow-up. 18 (5%) patients died because of an adverse event considered by the investigator to be treatment related (ten [6%] of 157 patients in cohort 1 and eight [5%] of 176 in cohort 2. INTERPRETATION: Single-agent Quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations. These findings confirm that targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine Quizartinib at lower starting doses. FUNDING: Ambit Biosciences/Daiichi Sankyo.
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the benefit of treatment with Quizartinib and subsequent bridging to hsct for flt3 itd patients with aml
Journal of Clinical Oncology, 2014Co-Authors: Mark J Levis, Neil P Shah, Guy Gammon, Giovanni Martinelli, Alexander E. Perl, Hervé Dombret, Bjoern Steffen, Philippe Rousselot, Elihu H. Estey, Denise TroneAbstract:7093^ Background: For FLT3-ITD(+) AML patients (pts) who are relapsed or refractory to chemotherapy, allogeneic HSCT offers the best prospect for long-term survival. Pts are unlikely to undergo HSCT unless their blast count can be reduced to an acceptable minimum, ideally below 5% blasts, which defines composite complete response (CRc: CR + CRp + CRi). Quizartinib is an orally active inhibitor of the FLT3 receptor tyrosine kinase being developed for the treatment of AML pts. We present a new analysis from FLT3-ITD(+) pts who were relapsed or refractory to salvage therapy or HSCT treated with Quizartinib across two Phase 2 studies in a total of 212 subjects. Methods: In Study A, pts received 90-200 mg/day Quizartinib; in Study B, pts were randomized to either 30 mg/day or 60 mg/day Quizartinib given orally during continuous 28 day cycles. Results: Median baseline blast count in Study A was 81% and 67% in Study B. Median age in Study A was 50yrs and 55yrs in Study B. In Study A, 47 of 136 (35%) proceeded to...
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effect of Quizartinib ac220 on response rates and long term survival in elderly patients with flt3 itd positive or negative relapsed refractory acute myeloid leukemia
Journal of Clinical Oncology, 2013Co-Authors: Giovanni Martinelli, Neil P Shah, Alexander E. Perl, Hervé Dombret, Bjoern Steffen, Philippe Rousselot, Elihu H. Estey, Alan Kenneth Burnett, Sabine Kayser, Guy GammonAbstract:7021 Background: Advanced age and FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib (AC220), an oral FLT3 inhibitor active against ITD mutant and wild type FLT3, has shown promising activity in Ph 1 and 2 studies. Methods: Patients (pts) in a Ph 2 open label study (N = 333) of Quizartinib monotherapy included 154 aged ≥60 y with known FLT3-ITD status and AML relapsed in <1 y or refractory to 1st line chemotherapy. Median duration of treatment was 14.2 wks (range 0.1–70.6 wks) for FLT3-ITD(+) pts and 9.5 wks (range 1.1–77.0 wks) for FLT3-ITD(-) pts. The composite complete remission (CRc) rate included complete remission (CR), complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi). Results: Of 110 FLT3-ITD(+) pts, 63 (57%) had a CRc (3 CR, 4 CRp, 56 CRi). Of 44 FLT3-ITD(-) pts, 16 (36%) had a CRc (...
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final results of a phase 2 open label monotherapy efficacy and safety study of Quizartinib ac220 in patients 60 years of age with flt3 itd positive or negative relapsed refractory acute myeloid leukemia
Blood, 2012Co-Authors: Jorge E Cortes, Giovanni Martinelli, Alexander E. Perl, Hervé Dombret, Philippe Rousselot, Elihu H. Estey, Alan Kenneth Burnett, Sabine Kayser, Bjorn Steffen, Guy GammonAbstract:Abstract 48 FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib (AC220) is an oral FLT3 receptor tyrosine kinase inhibitor that is active against both ITD mutant and wild type FLT3, and has shown promising activity in a Phase 1 study of patients (pts) with AML. This Phase 2 study was conducted to assess the efficacy and safety of Quizartinib monotherapy in FLT3-ITD positive (+) and FLT3-ITD negative (-) pts with a total of 333 pts included in two cohorts. Cohort 1 included pts aged ≥ 60 yrs with AML relapsed in <1 yr or refractory to 1st-line chemotherapy. A total of 134 pts were included in this cohort and constitute the basis for this analysis. Data through 31 January 2012 from 134 pts in this cohort were analyzed. These pts included 92 (69%) who were FLT3 ITD(+), 41 (31%) who were FLT3-ITD(-), and 1 (1%) whose FLT3-ITD status was unknown. Half the 92 FLT3-ITD(+) pts and 46% of the 41 FLT3-ITD(-) pts were male. The FLT3-ITD(+) pts had a median age of 70 yrs (range 54 to 85 yrs), and the FLT3-ITD(-) pts had a median age of 69 yrs (range 60 to 78 yrs). Pts received Quizartinib at a starting dose of 90 mg/day (females) or 135 mg/day (males and 1 female), and were treated continuously during 28-day cycles. The composite complete remission (CRc) rate included complete remission (CR), complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi). For FLT3-ITD(+) pts the CRc rate was 54% (0 CR, 3% CRp, and 51% CRi), with a median duration of response of 12.7 weeks and median overall survival of 25.3 weeks. Of those refractory to their last AML therapy, 39% achieved a CRc with Quizartinib. For FLT3-ITD(-) pts the CRc rate was 32% (2% CR, 2% CRp, and 27% CRi), with a median duration of response of 22.1 weeks and median overall survival of 19.0 weeks. Of those refractory to their last AML therapy, 44% achieved a CRc with Quizartinib. | | FLT3-ITD(+) (N = 92) | FLT3-ITD(−) (N = 41) | |:--------------------------------------------------------- | -------------------- | -------------------- | | Cumulative CRc, n (%) | 50 (54) | 13 (32) | | CRc + PR, n (%) | 66 (72) | 17 (41) | | Prior nonresponders achieving CRc to Quizartinib, n (%) | 12/31 (39) | 8/18 (44) | | Subjects discontinuing Quizartinib because of HSCT, n (%) | 9 (10) | 1 (2) | | Median CRc duration, weeks | 12.7 | 22.1 | | Median overall survival, weeks | 25.3 | 19.0 | * CRc = composite complete remission; HSCT = hematopoietic stem cell transplantation; PR = partial remission. Efficacy Results in Relapsed/Refractory AML Pts ≥ 60 Yrs The most common (≥20%) treatment-related adverse events (AEs) were nausea (40%), fatigue (31%), anemia (28%), QT interval prolongation (25%), diarrhea (23%), vomiting (23%), dysgeusia (22%), and febrile neutropenia (20%). The most common (≥10%) Grade 3 or 4 treatment-related AEs were anemia (25%), febrile neutropenia (20%), QT interval prolongation (13%), and thrombocytopenia (12%). An AE of QT interval prolongation occurred in 33/134 pts (25%) and was Grade 3 or 4 in 17 pts (13%). There was 1 occurrence of Grade 4 QT prolongation with torsade de pointes. QT interval prolongations were transient, and none were fatal. A total of 17 pts (13%) experienced a treatment-related AE resulting in discontinuation of Quizartinib. The final data from this Phase 2 study for elderly relapsed/refractory AML pts with few other available therapy options confirm the high degree of activity of Quizartinib monotherapy in FLT3-ITD(+) pts and also suggest activity in FLT3-ITD(-) pts. These data represent the highest level of single agent activity observed to date for FLT3-targeted therapy in elderly pts with relapsed/refractory FLT3-ITD(+) AML. Of clinical significance in this elderly population, a number of pts refractory to prior therapy responded to Quizartinib, with some pts (8%) able to bridge to potentially curative hematopoietic stem cell transplantation. Safety findings were manageable, and were primarily myelosuppression and QT prolongation that was mitigated with dose modifications. Results from the total study population will be presented. Further Phase 1 and 2 studies investigating lower doses of Quizartinib as monotherapy and in combination with other agents in FLT3-ITD(+) and FLT3-ITD(-) AML are being planned/ongoing. Disclosures: Cortes: Novartis: Consultancy. Perl: Ambit Biosciences: Consultancy. Dombret: Celgene: Consultancy. Steffen: Novartis: Travel/accommodations/meeting expenses Other. Rousselot: Ambit Biosciences: Consultancy. Martinelli: BMS, Novartis; Pfizer, Roche: Consultancy. Estey: Ambit Biosciences: Consultancy. Burnett: Ambit Biosciences: Consultancy. Gammon: Ambit Biosciences: Employment. Trone: Ambit Biosciences: Employment. Leo: Ambit Biosciences: Employment. Levis: Ambit Biosciences: Consultancy.
