DOSE ESCALATION STUDY OF CRENOLANIB IN COMBINATION WITH HIGH DOSE CYTARABINE/IDARUBICIN SALVAGE CHEMOTHERAPY IN MULTIPLY RELAPSED FLT3 POSITIVE AML
(Abstract release date: 05/19/16)
EHA Library. Cortes J. 06/09/16; 132468; E919
Dr. Jorge Cortes
Contributions
Contributions
Abstract
Abstract: E919
Type: Eposter Presentation
Background
FLT3 inhibitors usually provide transient clinical benefit to patients with FLT3-mutated AML. FLT3 inhibitor-based combination therapy has been suggested to enhance such benefit. Crenolanib is a novel, type I, oral pan-FLT3 inhibitor with high single-agent activity against multiply relapsed FLT3-ITD and tyrosine kinase domain (TKD) mutant AML. We here report interim data from a Phase I trial to evaluate the safety and efficacy of salvage therapy with high dose cytarabine/idarubicin followed by crenolanib in multiply relapsed FLT3+ve AML.
Aims
Dose escalation study to determine the maximum tolerated dose (MTD) of crenolanib when combined with high dose cytarabine + idarubicin.
Methods
Pts >18y with refractory/relapsed FLT3 ITD and/or TKD+ve AML are eligible. Pts receive salvage therapy with high dose cytarabine (1.5 g/m2/day over 3 hours for 4d or for 3d if >60y) along with idarubicin (12 mg/m2 for 3d). Daily crenolanib starts from d5 and is continued until 72hrs prior to next chemotherapy regimen. The starting dose cohort of crenolanib is 60 mg TID and is then escalated in subsequent cohorts to 80 mg TID and 100 mg TID. Pts may receive consolidation with cytarabine (750mg/m2 for 3d) and idarubicin (8 mg/m2 for 2d) followed by daily crenolanib. Crenolanib may be administered for maintenance for up to 365 days.
Results
To date, 11 pts (10 males, 1 female) have been enrolled with a median age of 43 (range 19-70). Pts were heavily pre-treated with a median of 3 prior systemic treatments (range: 1-9). 8/11 pts had received prior investigation agents including 6 with prior FLT3 inhibitors. Three pts had undergone allogeneic SCT.
Besides FLT3, multiple other leukemia associated mutations were present at baseline: NPM1 (40%), DNMT3A (40%), WT1 (30%), TET2 (30%), NRAS/KRAS (30%), IDH2 (20%), NOTCH1 (20%), MLL (20%), RUNX1 (10%), ASXL1 (10%) and EZH2 (10%).All 3 pts treated with cytarabine/idarubicin followed by crenolanib 60 mg TID tolerated the regimen well with no DLTs. Two achieved a CR (including one who became FLT3 negative after reinduction). Both these patients have undergone an allo SCT. 5 pts received cytarabine/idarubicin followed by crenolanib 80 mg TID. One of the three evaluable pts in this cohort achieved a CRi and has undergone SCT. The patient with ETP-ALL had no response. No pt required dose reduction in the 80mg TID cohort. All 3 pts in crenolanib 100mg TID cohort have now completed cytarabine/idarubicin salvage and are receiving crenolanib (but are too early for assessment of response).
Conclusion
Crenolanib can be safely administered with HiDAC/idarubicin salvage chemotherapy in multiply relapsed AML. 3 patients have achieved a CR/CRi which allowed them to be bridged to an allo SCT. Accrual to this trial will continue at the crenolanib 100 mg TID dose.
Session topic: E-poster
Keyword(s): Flt3 inhibitor, Relapsed acute myeloid leukemia, Salvage chemotherapy, Tyrosine kinase inhibitor
Type: Eposter Presentation
Background
FLT3 inhibitors usually provide transient clinical benefit to patients with FLT3-mutated AML. FLT3 inhibitor-based combination therapy has been suggested to enhance such benefit. Crenolanib is a novel, type I, oral pan-FLT3 inhibitor with high single-agent activity against multiply relapsed FLT3-ITD and tyrosine kinase domain (TKD) mutant AML. We here report interim data from a Phase I trial to evaluate the safety and efficacy of salvage therapy with high dose cytarabine/idarubicin followed by crenolanib in multiply relapsed FLT3+ve AML.
Aims
Dose escalation study to determine the maximum tolerated dose (MTD) of crenolanib when combined with high dose cytarabine + idarubicin.
Methods
Pts >18y with refractory/relapsed FLT3 ITD and/or TKD+ve AML are eligible. Pts receive salvage therapy with high dose cytarabine (1.5 g/m2/day over 3 hours for 4d or for 3d if >60y) along with idarubicin (12 mg/m2 for 3d). Daily crenolanib starts from d5 and is continued until 72hrs prior to next chemotherapy regimen. The starting dose cohort of crenolanib is 60 mg TID and is then escalated in subsequent cohorts to 80 mg TID and 100 mg TID. Pts may receive consolidation with cytarabine (750mg/m2 for 3d) and idarubicin (8 mg/m2 for 2d) followed by daily crenolanib. Crenolanib may be administered for maintenance for up to 365 days.
Results
To date, 11 pts (10 males, 1 female) have been enrolled with a median age of 43 (range 19-70). Pts were heavily pre-treated with a median of 3 prior systemic treatments (range: 1-9). 8/11 pts had received prior investigation agents including 6 with prior FLT3 inhibitors. Three pts had undergone allogeneic SCT.
| Age | Sex | FLT3 Status | Prior chemo regimens | Prior Investigational agents | Crenolanib dose | Response |
| 43 | F | ITD | 2 | sorafenib | 60 mg | CRi |
| 67 | M | D835 | 1 | 60 mg | CR | |
| 21 | M | ITD | 4+SCT | sorafenib, E6201 | 60 mg | No Response |
| 31 | M | ITD+ D835 | 1 | 80 mg | ETP-ALL | |
| 51 | M | ITD | 8 | AG221, BGB324 | 80 mg | NE |
| 30 | M | D835 | 9+SCT | sorafenib, AG221, E6201 | 80 mg | NE |
| 58 | M | ITD+ D835 | 3 | quizartinib | 80 mg | CRi |
| 57 | M | ITD+ D835 | 2 | sorafenib | 80 mg | No Response |
| 70 | M | D835 | 3 | AMG330 | 100 mg | pending |
| 19 | M | D835 | 3+2 SCT | 100 mg | pending | |
| 24 | M | ITD+ D835 | 3 | quizartinib | 100 mg | pending |
Conclusion
Crenolanib can be safely administered with HiDAC/idarubicin salvage chemotherapy in multiply relapsed AML. 3 patients have achieved a CR/CRi which allowed them to be bridged to an allo SCT. Accrual to this trial will continue at the crenolanib 100 mg TID dose.
Session topic: E-poster
Keyword(s): Flt3 inhibitor, Relapsed acute myeloid leukemia, Salvage chemotherapy, Tyrosine kinase inhibitor
Abstract: E919
Type: Eposter Presentation
Background
FLT3 inhibitors usually provide transient clinical benefit to patients with FLT3-mutated AML. FLT3 inhibitor-based combination therapy has been suggested to enhance such benefit. Crenolanib is a novel, type I, oral pan-FLT3 inhibitor with high single-agent activity against multiply relapsed FLT3-ITD and tyrosine kinase domain (TKD) mutant AML. We here report interim data from a Phase I trial to evaluate the safety and efficacy of salvage therapy with high dose cytarabine/idarubicin followed by crenolanib in multiply relapsed FLT3+ve AML.
Aims
Dose escalation study to determine the maximum tolerated dose (MTD) of crenolanib when combined with high dose cytarabine + idarubicin.
Methods
Pts >18y with refractory/relapsed FLT3 ITD and/or TKD+ve AML are eligible. Pts receive salvage therapy with high dose cytarabine (1.5 g/m2/day over 3 hours for 4d or for 3d if >60y) along with idarubicin (12 mg/m2 for 3d). Daily crenolanib starts from d5 and is continued until 72hrs prior to next chemotherapy regimen. The starting dose cohort of crenolanib is 60 mg TID and is then escalated in subsequent cohorts to 80 mg TID and 100 mg TID. Pts may receive consolidation with cytarabine (750mg/m2 for 3d) and idarubicin (8 mg/m2 for 2d) followed by daily crenolanib. Crenolanib may be administered for maintenance for up to 365 days.
Results
To date, 11 pts (10 males, 1 female) have been enrolled with a median age of 43 (range 19-70). Pts were heavily pre-treated with a median of 3 prior systemic treatments (range: 1-9). 8/11 pts had received prior investigation agents including 6 with prior FLT3 inhibitors. Three pts had undergone allogeneic SCT.
Besides FLT3, multiple other leukemia associated mutations were present at baseline: NPM1 (40%), DNMT3A (40%), WT1 (30%), TET2 (30%), NRAS/KRAS (30%), IDH2 (20%), NOTCH1 (20%), MLL (20%), RUNX1 (10%), ASXL1 (10%) and EZH2 (10%).All 3 pts treated with cytarabine/idarubicin followed by crenolanib 60 mg TID tolerated the regimen well with no DLTs. Two achieved a CR (including one who became FLT3 negative after reinduction). Both these patients have undergone an allo SCT. 5 pts received cytarabine/idarubicin followed by crenolanib 80 mg TID. One of the three evaluable pts in this cohort achieved a CRi and has undergone SCT. The patient with ETP-ALL had no response. No pt required dose reduction in the 80mg TID cohort. All 3 pts in crenolanib 100mg TID cohort have now completed cytarabine/idarubicin salvage and are receiving crenolanib (but are too early for assessment of response).
Conclusion
Crenolanib can be safely administered with HiDAC/idarubicin salvage chemotherapy in multiply relapsed AML. 3 patients have achieved a CR/CRi which allowed them to be bridged to an allo SCT. Accrual to this trial will continue at the crenolanib 100 mg TID dose.
Session topic: E-poster
Keyword(s): Flt3 inhibitor, Relapsed acute myeloid leukemia, Salvage chemotherapy, Tyrosine kinase inhibitor
Type: Eposter Presentation
Background
FLT3 inhibitors usually provide transient clinical benefit to patients with FLT3-mutated AML. FLT3 inhibitor-based combination therapy has been suggested to enhance such benefit. Crenolanib is a novel, type I, oral pan-FLT3 inhibitor with high single-agent activity against multiply relapsed FLT3-ITD and tyrosine kinase domain (TKD) mutant AML. We here report interim data from a Phase I trial to evaluate the safety and efficacy of salvage therapy with high dose cytarabine/idarubicin followed by crenolanib in multiply relapsed FLT3+ve AML.
Aims
Dose escalation study to determine the maximum tolerated dose (MTD) of crenolanib when combined with high dose cytarabine + idarubicin.
Methods
Pts >18y with refractory/relapsed FLT3 ITD and/or TKD+ve AML are eligible. Pts receive salvage therapy with high dose cytarabine (1.5 g/m2/day over 3 hours for 4d or for 3d if >60y) along with idarubicin (12 mg/m2 for 3d). Daily crenolanib starts from d5 and is continued until 72hrs prior to next chemotherapy regimen. The starting dose cohort of crenolanib is 60 mg TID and is then escalated in subsequent cohorts to 80 mg TID and 100 mg TID. Pts may receive consolidation with cytarabine (750mg/m2 for 3d) and idarubicin (8 mg/m2 for 2d) followed by daily crenolanib. Crenolanib may be administered for maintenance for up to 365 days.
Results
To date, 11 pts (10 males, 1 female) have been enrolled with a median age of 43 (range 19-70). Pts were heavily pre-treated with a median of 3 prior systemic treatments (range: 1-9). 8/11 pts had received prior investigation agents including 6 with prior FLT3 inhibitors. Three pts had undergone allogeneic SCT.
| Age | Sex | FLT3 Status | Prior chemo regimens | Prior Investigational agents | Crenolanib dose | Response |
| 43 | F | ITD | 2 | sorafenib | 60 mg | CRi |
| 67 | M | D835 | 1 | 60 mg | CR | |
| 21 | M | ITD | 4+SCT | sorafenib, E6201 | 60 mg | No Response |
| 31 | M | ITD+ D835 | 1 | 80 mg | ETP-ALL | |
| 51 | M | ITD | 8 | AG221, BGB324 | 80 mg | NE |
| 30 | M | D835 | 9+SCT | sorafenib, AG221, E6201 | 80 mg | NE |
| 58 | M | ITD+ D835 | 3 | quizartinib | 80 mg | CRi |
| 57 | M | ITD+ D835 | 2 | sorafenib | 80 mg | No Response |
| 70 | M | D835 | 3 | AMG330 | 100 mg | pending |
| 19 | M | D835 | 3+2 SCT | 100 mg | pending | |
| 24 | M | ITD+ D835 | 3 | quizartinib | 100 mg | pending |
Conclusion
Crenolanib can be safely administered with HiDAC/idarubicin salvage chemotherapy in multiply relapsed AML. 3 patients have achieved a CR/CRi which allowed them to be bridged to an allo SCT. Accrual to this trial will continue at the crenolanib 100 mg TID dose.
Session topic: E-poster
Keyword(s): Flt3 inhibitor, Relapsed acute myeloid leukemia, Salvage chemotherapy, Tyrosine kinase inhibitor
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