PRE-DOSING WITH UNLABELLED ANTIBODY SIGNIFICANTLY INCREASES THE PHARMACOKINETIC EXPOSURE BUT PROTECTS AGAINST MYELOSUPPRESSION OF 177LU-LILOTOMAB IN NON-HODGKIN B-CELL LYMPHOMA PATIENTS
(Abstract release date: 05/19/16)
EHA Library. Kolstad A. 06/09/16; 132714; E1165
Disclosure(s): The following are employees of Nordic nanovector and own stock in Nordic Nanovector.
Jostein Dahle; Laurie Baylor Curtis; Åse Østengen; Helen Heyerdahl; Simon Turner; Roy Hartvig Larsen;
Mr. Arne Kolstad
Contributions
Contributions
Abstract
Abstract: E1165
Type: Eposter Presentation
Background
177Lu-lilotomab (177Lu-DOTA-HH1; BetalutinTM) is a novel CD37-binding murine IgG1 antibody (HH1) labelled with the beta-emitter lutetium-177, in a ready-to-use formulation currently in Phase 1/2 clinical development for the treatment of non-Hodgkin`s lymphoma (NHL). Pre-dosing with unlabelled antibody is routinely given with radio-immunotherapies for NHL.
Aims
This pharmacokinetic (PK) sub-study in NHL patients (pts) was designed to determine the PK profile of 177Lu-lilotomab and to compare the PK profile with and without pre-dosing with unlabelled HH1.
Methods
Pts with relapsed incurable indolent NHL and with platelet counts ≥ 150 x109/L were eligible for inclusion in the study. Pts received rituximab (375 mg/m2) on day 1 and 8 to deplete normal B cells. On day 29 pre-dosing with 50 mg HH1 was administered before the single dose of 177Lu-lilotomab in 9 pts. The remaining 4 pts received 177Lu-lilotomab without HH1 pre-dosing. Activity of 177Lu-lilotomab administered after the pre-dose of HH1 were 10, 15 and 20 MBq/kg vs 10 and 15 MBq/kg without HH1. PK samples were collected at 0 and 5 minutes, then after 1, 2, and 20 hours and further 2, 3, 4, 7, 14 and 21 days post-177Lu-lilotomab administration. Urine samples were also collected. Response was assessed by FDG PET/CT scans.
Results
A total of 13 pts, 12 with follicular lymphoma and 1 with mantle cell lymphoma, were enrolled into this sub-study and either received pre-dosing with HH1 (n=9) or without HH1 (n=4). The number of prior therapies ranged from 1 to 7, median body weight was 91.5kg (range: 67-118kg). A total of 153 blood samples were collected.As expected, the median AUC0-∞ increased with increasing activity of 177Lu-lilotomab irrespective of pre-dosing (range: 3830.7 to 15226.48 h*kBq/mL). There was an increase in median activity-adjusted AUC0-∞ (675.51 vs 421.11 h*kBq/mL/(MBq/kg); p<0.001) in pts with pre-dosing compared to no HH1 pre-dosing and a decrease in the volume of distribution Vz (10.48L vs 17.56L) and clearance rate Cl (126 v 227 mL/h). The median activity-adjusted Cmax (6.6 vs 6.9 kBq/mL/(MBq/kg)) and T1/2 (53.3 vs 51.6 h) were similar with and without HH1 pre-dosing.The most common toxicities observed were haematological which were all reversible and manageable. With HH1 pre-dosing all Grade 4 thrombocytopenia and neutropenia were reported by pts with a 177Lu-lilotomab AUC0-∞ >13415 h*kBq/mL (n=3), compared with > 6147 h*kBq/mL (n=2) without pre-dosing. In addition grade 3 thrombocytopenia was reported by one pt with an AUC of 11730 h*kBq/mL with pre-dosing compared to one pt with an AUC of 4913 h*kBq/mL without HH1.The overall tumor response rate observed in the 12 evaluable pts in the PK sub-study was 67% (one pt had a transformed lesion at 3 months and is excluded from the efficacy analysis). Five pts with pre-dosing achieved CR or PR and had an AUC of >6976 h*kBq/mL. Without HH1 pre-dosing a PR was observed in 3 pts, with AUCs of 3830, 4913 and 6195 h*kBq/mL.
Conclusion
Pre-dosing with unlabelled antibody (HH1) increases the activity-adjusted AUC and decreases the volume of distribution and clearance rate of 177Lu-lilotomab in NHL pts. Despite the increase in AUC resulting from pre-dosing with HH1 the incidence of haematological AEs was reduced compared with no HH1 pre-dosing, suggesting a protective effect of HH1 against the myelosuppression of 177Lu-lilotomab. Further optimisation of the pre-dosing of 177Lu-lilotomab may lead to greater increases in AUC, and/or improvement in the side-effect profile.
Session topic: E-poster
Keyword(s): Clinical trial, Non-Hodgkin's lymphoma, Pharmacokinetic, Radioimmunotherapy
Type: Eposter Presentation
Background
177Lu-lilotomab (177Lu-DOTA-HH1; BetalutinTM) is a novel CD37-binding murine IgG1 antibody (HH1) labelled with the beta-emitter lutetium-177, in a ready-to-use formulation currently in Phase 1/2 clinical development for the treatment of non-Hodgkin`s lymphoma (NHL). Pre-dosing with unlabelled antibody is routinely given with radio-immunotherapies for NHL.
Aims
This pharmacokinetic (PK) sub-study in NHL patients (pts) was designed to determine the PK profile of 177Lu-lilotomab and to compare the PK profile with and without pre-dosing with unlabelled HH1.
Methods
Pts with relapsed incurable indolent NHL and with platelet counts ≥ 150 x109/L were eligible for inclusion in the study. Pts received rituximab (375 mg/m2) on day 1 and 8 to deplete normal B cells. On day 29 pre-dosing with 50 mg HH1 was administered before the single dose of 177Lu-lilotomab in 9 pts. The remaining 4 pts received 177Lu-lilotomab without HH1 pre-dosing. Activity of 177Lu-lilotomab administered after the pre-dose of HH1 were 10, 15 and 20 MBq/kg vs 10 and 15 MBq/kg without HH1. PK samples were collected at 0 and 5 minutes, then after 1, 2, and 20 hours and further 2, 3, 4, 7, 14 and 21 days post-177Lu-lilotomab administration. Urine samples were also collected. Response was assessed by FDG PET/CT scans.
Results
A total of 13 pts, 12 with follicular lymphoma and 1 with mantle cell lymphoma, were enrolled into this sub-study and either received pre-dosing with HH1 (n=9) or without HH1 (n=4). The number of prior therapies ranged from 1 to 7, median body weight was 91.5kg (range: 67-118kg). A total of 153 blood samples were collected.As expected, the median AUC0-∞ increased with increasing activity of 177Lu-lilotomab irrespective of pre-dosing (range: 3830.7 to 15226.48 h*kBq/mL). There was an increase in median activity-adjusted AUC0-∞ (675.51 vs 421.11 h*kBq/mL/(MBq/kg); p<0.001) in pts with pre-dosing compared to no HH1 pre-dosing and a decrease in the volume of distribution Vz (10.48L vs 17.56L) and clearance rate Cl (126 v 227 mL/h). The median activity-adjusted Cmax (6.6 vs 6.9 kBq/mL/(MBq/kg)) and T1/2 (53.3 vs 51.6 h) were similar with and without HH1 pre-dosing.The most common toxicities observed were haematological which were all reversible and manageable. With HH1 pre-dosing all Grade 4 thrombocytopenia and neutropenia were reported by pts with a 177Lu-lilotomab AUC0-∞ >13415 h*kBq/mL (n=3), compared with > 6147 h*kBq/mL (n=2) without pre-dosing. In addition grade 3 thrombocytopenia was reported by one pt with an AUC of 11730 h*kBq/mL with pre-dosing compared to one pt with an AUC of 4913 h*kBq/mL without HH1.The overall tumor response rate observed in the 12 evaluable pts in the PK sub-study was 67% (one pt had a transformed lesion at 3 months and is excluded from the efficacy analysis). Five pts with pre-dosing achieved CR or PR and had an AUC of >6976 h*kBq/mL. Without HH1 pre-dosing a PR was observed in 3 pts, with AUCs of 3830, 4913 and 6195 h*kBq/mL.
Conclusion
Pre-dosing with unlabelled antibody (HH1) increases the activity-adjusted AUC and decreases the volume of distribution and clearance rate of 177Lu-lilotomab in NHL pts. Despite the increase in AUC resulting from pre-dosing with HH1 the incidence of haematological AEs was reduced compared with no HH1 pre-dosing, suggesting a protective effect of HH1 against the myelosuppression of 177Lu-lilotomab. Further optimisation of the pre-dosing of 177Lu-lilotomab may lead to greater increases in AUC, and/or improvement in the side-effect profile.
Session topic: E-poster
Keyword(s): Clinical trial, Non-Hodgkin's lymphoma, Pharmacokinetic, Radioimmunotherapy
Abstract: E1165
Type: Eposter Presentation
Background
177Lu-lilotomab (177Lu-DOTA-HH1; BetalutinTM) is a novel CD37-binding murine IgG1 antibody (HH1) labelled with the beta-emitter lutetium-177, in a ready-to-use formulation currently in Phase 1/2 clinical development for the treatment of non-Hodgkin`s lymphoma (NHL). Pre-dosing with unlabelled antibody is routinely given with radio-immunotherapies for NHL.
Aims
This pharmacokinetic (PK) sub-study in NHL patients (pts) was designed to determine the PK profile of 177Lu-lilotomab and to compare the PK profile with and without pre-dosing with unlabelled HH1.
Methods
Pts with relapsed incurable indolent NHL and with platelet counts ≥ 150 x109/L were eligible for inclusion in the study. Pts received rituximab (375 mg/m2) on day 1 and 8 to deplete normal B cells. On day 29 pre-dosing with 50 mg HH1 was administered before the single dose of 177Lu-lilotomab in 9 pts. The remaining 4 pts received 177Lu-lilotomab without HH1 pre-dosing. Activity of 177Lu-lilotomab administered after the pre-dose of HH1 were 10, 15 and 20 MBq/kg vs 10 and 15 MBq/kg without HH1. PK samples were collected at 0 and 5 minutes, then after 1, 2, and 20 hours and further 2, 3, 4, 7, 14 and 21 days post-177Lu-lilotomab administration. Urine samples were also collected. Response was assessed by FDG PET/CT scans.
Results
A total of 13 pts, 12 with follicular lymphoma and 1 with mantle cell lymphoma, were enrolled into this sub-study and either received pre-dosing with HH1 (n=9) or without HH1 (n=4). The number of prior therapies ranged from 1 to 7, median body weight was 91.5kg (range: 67-118kg). A total of 153 blood samples were collected.As expected, the median AUC0-∞ increased with increasing activity of 177Lu-lilotomab irrespective of pre-dosing (range: 3830.7 to 15226.48 h*kBq/mL). There was an increase in median activity-adjusted AUC0-∞ (675.51 vs 421.11 h*kBq/mL/(MBq/kg); p<0.001) in pts with pre-dosing compared to no HH1 pre-dosing and a decrease in the volume of distribution Vz (10.48L vs 17.56L) and clearance rate Cl (126 v 227 mL/h). The median activity-adjusted Cmax (6.6 vs 6.9 kBq/mL/(MBq/kg)) and T1/2 (53.3 vs 51.6 h) were similar with and without HH1 pre-dosing.The most common toxicities observed were haematological which were all reversible and manageable. With HH1 pre-dosing all Grade 4 thrombocytopenia and neutropenia were reported by pts with a 177Lu-lilotomab AUC0-∞ >13415 h*kBq/mL (n=3), compared with > 6147 h*kBq/mL (n=2) without pre-dosing. In addition grade 3 thrombocytopenia was reported by one pt with an AUC of 11730 h*kBq/mL with pre-dosing compared to one pt with an AUC of 4913 h*kBq/mL without HH1.The overall tumor response rate observed in the 12 evaluable pts in the PK sub-study was 67% (one pt had a transformed lesion at 3 months and is excluded from the efficacy analysis). Five pts with pre-dosing achieved CR or PR and had an AUC of >6976 h*kBq/mL. Without HH1 pre-dosing a PR was observed in 3 pts, with AUCs of 3830, 4913 and 6195 h*kBq/mL.
Conclusion
Pre-dosing with unlabelled antibody (HH1) increases the activity-adjusted AUC and decreases the volume of distribution and clearance rate of 177Lu-lilotomab in NHL pts. Despite the increase in AUC resulting from pre-dosing with HH1 the incidence of haematological AEs was reduced compared with no HH1 pre-dosing, suggesting a protective effect of HH1 against the myelosuppression of 177Lu-lilotomab. Further optimisation of the pre-dosing of 177Lu-lilotomab may lead to greater increases in AUC, and/or improvement in the side-effect profile.
Session topic: E-poster
Keyword(s): Clinical trial, Non-Hodgkin's lymphoma, Pharmacokinetic, Radioimmunotherapy
Type: Eposter Presentation
Background
177Lu-lilotomab (177Lu-DOTA-HH1; BetalutinTM) is a novel CD37-binding murine IgG1 antibody (HH1) labelled with the beta-emitter lutetium-177, in a ready-to-use formulation currently in Phase 1/2 clinical development for the treatment of non-Hodgkin`s lymphoma (NHL). Pre-dosing with unlabelled antibody is routinely given with radio-immunotherapies for NHL.
Aims
This pharmacokinetic (PK) sub-study in NHL patients (pts) was designed to determine the PK profile of 177Lu-lilotomab and to compare the PK profile with and without pre-dosing with unlabelled HH1.
Methods
Pts with relapsed incurable indolent NHL and with platelet counts ≥ 150 x109/L were eligible for inclusion in the study. Pts received rituximab (375 mg/m2) on day 1 and 8 to deplete normal B cells. On day 29 pre-dosing with 50 mg HH1 was administered before the single dose of 177Lu-lilotomab in 9 pts. The remaining 4 pts received 177Lu-lilotomab without HH1 pre-dosing. Activity of 177Lu-lilotomab administered after the pre-dose of HH1 were 10, 15 and 20 MBq/kg vs 10 and 15 MBq/kg without HH1. PK samples were collected at 0 and 5 minutes, then after 1, 2, and 20 hours and further 2, 3, 4, 7, 14 and 21 days post-177Lu-lilotomab administration. Urine samples were also collected. Response was assessed by FDG PET/CT scans.
Results
A total of 13 pts, 12 with follicular lymphoma and 1 with mantle cell lymphoma, were enrolled into this sub-study and either received pre-dosing with HH1 (n=9) or without HH1 (n=4). The number of prior therapies ranged from 1 to 7, median body weight was 91.5kg (range: 67-118kg). A total of 153 blood samples were collected.As expected, the median AUC0-∞ increased with increasing activity of 177Lu-lilotomab irrespective of pre-dosing (range: 3830.7 to 15226.48 h*kBq/mL). There was an increase in median activity-adjusted AUC0-∞ (675.51 vs 421.11 h*kBq/mL/(MBq/kg); p<0.001) in pts with pre-dosing compared to no HH1 pre-dosing and a decrease in the volume of distribution Vz (10.48L vs 17.56L) and clearance rate Cl (126 v 227 mL/h). The median activity-adjusted Cmax (6.6 vs 6.9 kBq/mL/(MBq/kg)) and T1/2 (53.3 vs 51.6 h) were similar with and without HH1 pre-dosing.The most common toxicities observed were haematological which were all reversible and manageable. With HH1 pre-dosing all Grade 4 thrombocytopenia and neutropenia were reported by pts with a 177Lu-lilotomab AUC0-∞ >13415 h*kBq/mL (n=3), compared with > 6147 h*kBq/mL (n=2) without pre-dosing. In addition grade 3 thrombocytopenia was reported by one pt with an AUC of 11730 h*kBq/mL with pre-dosing compared to one pt with an AUC of 4913 h*kBq/mL without HH1.The overall tumor response rate observed in the 12 evaluable pts in the PK sub-study was 67% (one pt had a transformed lesion at 3 months and is excluded from the efficacy analysis). Five pts with pre-dosing achieved CR or PR and had an AUC of >6976 h*kBq/mL. Without HH1 pre-dosing a PR was observed in 3 pts, with AUCs of 3830, 4913 and 6195 h*kBq/mL.
Conclusion
Pre-dosing with unlabelled antibody (HH1) increases the activity-adjusted AUC and decreases the volume of distribution and clearance rate of 177Lu-lilotomab in NHL pts. Despite the increase in AUC resulting from pre-dosing with HH1 the incidence of haematological AEs was reduced compared with no HH1 pre-dosing, suggesting a protective effect of HH1 against the myelosuppression of 177Lu-lilotomab. Further optimisation of the pre-dosing of 177Lu-lilotomab may lead to greater increases in AUC, and/or improvement in the side-effect profile.
Session topic: E-poster
Keyword(s): Clinical trial, Non-Hodgkin's lymphoma, Pharmacokinetic, Radioimmunotherapy
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