Contributions
Abstract: PB1767
Type: Publication Only
Background
Aggressive non Hodgkin lymphomas (aNHL) relapsing after high-dose therapy or, in not transplant-eligible patients (pts), after 1st line chemotherapy, represent an unmet clinical need. Therefore, we developed a salvage combination regimen based on pixantrone, an azaanthracenadione recently approved in Europe for pts with multiply relapsed or refractory aNHL, etoposide, bendamustine and, in CD20+ tumors, rituximab (PREBEN/PEBEN). A preliminary pre-trial experience on heavily pretreated aNHL pts showed good feasibility and efficacy and was previously reported. On this background, the Nordic Lymphoma Group launched an open label phase 1b/2 study (EudraCTno.201500075839) testing the feasibility and efficacy of the P[R]EBEN regimen in relapsed aNHL of B-or T-cell phenotype.
Aims
Here, we present the final results of the dose finding phase 1 part of the P[R]EBEN study.
Methods
According to predefined criteria, pts were subdivided in ‘fit’ and ‘frail’. 'Fit’ pts entered the phase 1 part of the study at baseline dose level. This consisted of 4 to 6 cycles of Pixantrone 50 mg/m2 i.v. day 1+8, Etoposide 100 mg i.v. day 1, Bendamustine 90 mg i.v. day 1 with or without the addition of Rituximab 375 mg/m2 i.v. day 1. ‘Frail’ pts entered directly the phase 2 part of the study at the same baseline dose level. Dose escalation was only applied to ‘fit’ pts and done according to a Bayesian model. Maximum tolerated dose (MTD) was based on the occurrence, within the first two cycles of therapy, of at least two DLT events (uncomplicated Grade 4 neutropenia lasting more than 5 days in patients without marrow involvement; grade 3-4 febrile neutropenia, or neutropenic infection; grade 4 thrombocytopenia; grade 3 drug-related non-hematopoietic toxicity with the exception of nausea, vomiting and alopecia). Primary end-points were identification of the MTD in phase 1 and overall response rate (ORR) in phase2. MTD was defined as the Response evaluation was performed by PET/CT after cycle 2 and at the end of therapy (EOT).
Results
In total, five pts were treated in the phase 1 part of the study. They had a median age of 60 years (range 39-68 years). Four of the pts (3 males and 1 female) had diffuse large cell B-cell lymphoma (DLBCL) and one (male) peripheral T-cell lymphoma (PTCL). All had relapsed disease after autologous transplant. The median time from last treatment to relapse was 20 months (range 8-86 months). All the chemotherapy courses were administered in an out-patient setting. No toxic deaths occurred. A total of 6 SAEs were reported among 4 pts: one grade 1 (transitory asymptomatic troponin T increase after cycle 3), one grade 2 (respiratory tract infection with non-neutropenic fever at cycle 6), three grade 3 (1 non-neutropenic fever at cycle 4, 1 neutropenic fever with anemia at cycle 4, 1 pneumonia/sinusitis at cycle 2), and one grade 4 (sepsis at cycle 3). All SAEs resolved without premature treatment interruption. No overt cardiac toxicity was recorded. Two DLT-defining events occurred within cycle 2 at baseline level, fulfilling MTD criteria. The two DLT defining events were: (i) neutropenic infection and (ii) post-therapeutic neutropenia (<0.5 mia/l) of >5 days in a pt without marrow involvement. PK measurements for pixantrone are ongoing. ORR was 60% after 2 cycles (1CR, 2 PRs) and at EOT (1 PR converted to CR: 2CR, 1PR).
Conclusion
The MTD of the PREBEN regimen was Pixantrone 50 mg/m2 i.v. day 1+8, Etoposide 100 mg i.v. day 1, Bendamustine 90 mg i.v. day 1 and Rituximab 375 mg/m2 i.v. day 1. The schedule was feasible and the preliminary efficacy data are promising.
Session topic: 21. Aggressive Non-Hodgkin lymphoma - Clinical
Keyword(s): Experimental Therapeutics, Phase I/II, Relapsed lymphoma
Abstract: PB1767
Type: Publication Only
Background
Aggressive non Hodgkin lymphomas (aNHL) relapsing after high-dose therapy or, in not transplant-eligible patients (pts), after 1st line chemotherapy, represent an unmet clinical need. Therefore, we developed a salvage combination regimen based on pixantrone, an azaanthracenadione recently approved in Europe for pts with multiply relapsed or refractory aNHL, etoposide, bendamustine and, in CD20+ tumors, rituximab (PREBEN/PEBEN). A preliminary pre-trial experience on heavily pretreated aNHL pts showed good feasibility and efficacy and was previously reported. On this background, the Nordic Lymphoma Group launched an open label phase 1b/2 study (EudraCTno.201500075839) testing the feasibility and efficacy of the P[R]EBEN regimen in relapsed aNHL of B-or T-cell phenotype.
Aims
Here, we present the final results of the dose finding phase 1 part of the P[R]EBEN study.
Methods
According to predefined criteria, pts were subdivided in ‘fit’ and ‘frail’. 'Fit’ pts entered the phase 1 part of the study at baseline dose level. This consisted of 4 to 6 cycles of Pixantrone 50 mg/m2 i.v. day 1+8, Etoposide 100 mg i.v. day 1, Bendamustine 90 mg i.v. day 1 with or without the addition of Rituximab 375 mg/m2 i.v. day 1. ‘Frail’ pts entered directly the phase 2 part of the study at the same baseline dose level. Dose escalation was only applied to ‘fit’ pts and done according to a Bayesian model. Maximum tolerated dose (MTD) was based on the occurrence, within the first two cycles of therapy, of at least two DLT events (uncomplicated Grade 4 neutropenia lasting more than 5 days in patients without marrow involvement; grade 3-4 febrile neutropenia, or neutropenic infection; grade 4 thrombocytopenia; grade 3 drug-related non-hematopoietic toxicity with the exception of nausea, vomiting and alopecia). Primary end-points were identification of the MTD in phase 1 and overall response rate (ORR) in phase2. MTD was defined as the Response evaluation was performed by PET/CT after cycle 2 and at the end of therapy (EOT).
Results
In total, five pts were treated in the phase 1 part of the study. They had a median age of 60 years (range 39-68 years). Four of the pts (3 males and 1 female) had diffuse large cell B-cell lymphoma (DLBCL) and one (male) peripheral T-cell lymphoma (PTCL). All had relapsed disease after autologous transplant. The median time from last treatment to relapse was 20 months (range 8-86 months). All the chemotherapy courses were administered in an out-patient setting. No toxic deaths occurred. A total of 6 SAEs were reported among 4 pts: one grade 1 (transitory asymptomatic troponin T increase after cycle 3), one grade 2 (respiratory tract infection with non-neutropenic fever at cycle 6), three grade 3 (1 non-neutropenic fever at cycle 4, 1 neutropenic fever with anemia at cycle 4, 1 pneumonia/sinusitis at cycle 2), and one grade 4 (sepsis at cycle 3). All SAEs resolved without premature treatment interruption. No overt cardiac toxicity was recorded. Two DLT-defining events occurred within cycle 2 at baseline level, fulfilling MTD criteria. The two DLT defining events were: (i) neutropenic infection and (ii) post-therapeutic neutropenia (<0.5 mia/l) of >5 days in a pt without marrow involvement. PK measurements for pixantrone are ongoing. ORR was 60% after 2 cycles (1CR, 2 PRs) and at EOT (1 PR converted to CR: 2CR, 1PR).
Conclusion
The MTD of the PREBEN regimen was Pixantrone 50 mg/m2 i.v. day 1+8, Etoposide 100 mg i.v. day 1, Bendamustine 90 mg i.v. day 1 and Rituximab 375 mg/m2 i.v. day 1. The schedule was feasible and the preliminary efficacy data are promising.
Session topic: 21. Aggressive Non-Hodgkin lymphoma - Clinical
Keyword(s): Experimental Therapeutics, Phase I/II, Relapsed lymphoma