SAKK 35/15: A PHASE I TRIAL OF OBINUTUZUMAB IN COMBINATION WITH VENETOCLAX INPREVIOUSLY UNTREATED FOLLICULAR LYMPHOMA PATIENTS.
Author(s): ,
Anastasios Stathis
Affiliations:
Oncology Institute of Southern Switzerland,Bellinzona,Switzerland
,
Ulrich Mey
Affiliations:
Oncology and Hematology, Kantonsspital Graubuenden,Chur,Switzerland
,
Sämi Schär
Affiliations:
Coordinating Center, SAKK,Bern ,Switzerland
,
Felicitas Hitz
Affiliations:
Oncology/Hematology,Kantosspital,St. Gallen,Switzerland
,
Christiane Pott
Affiliations:
Medizinischen Klinik II Hämatologie und Internistische Onkologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel ,Kiel,Germany
,
Nicolas Mach
Affiliations:
Service d'Oncologie, Département d'Oncologie, Hôpitaux Universitaires de Genève,Genève,Switzerland
,
Fatime Krasniqi
Affiliations:
Medical Oncology, University Hospital of Basel,Basel,Switzerland
,
Urban Novak
Affiliations:
Department of Medical Oncology, Inselspital / Bern University Hospital,Bern,Switzerland
,
Christian Schmidt
Affiliations:
Department of Medicine III, University of Munich,Munich,Germany
,
Karin Hohloch
Affiliations:
Oncology and Hematology, Kantonsspital Graubuenden ,Chur,Switzerland
,
Dirk Lars Kienle
Affiliations:
Oncology and Hematology, Kantonsspital Graubuenden,Chur,Switzerland
,
Dagmar Hess
Affiliations:
Oncology/Hematology,Kantosspital,St. Gallen,Switzerland
,
Alden Moccia
Affiliations:
Oncology Institute of Southern Switzerland,Bellinzona,Switzerland
,
Michael Unterhalt
Affiliations:
Department of Medicine III, University of Munich,Munich,Germany
,
Katrin Eckhardt
Affiliations:
Coordinating Center, SAKK,Bern,Switzerland
,
Stefanie Hayoz
Affiliations:
Coordinating Center, SAKK,Bern,Switzerland
,
Davide Rossi
Affiliations:
Laboratory of Experimental Hematology, Institute of Oncology Research,Bellinzona,Switzerland
,
Stefan Dirnhofer
Affiliations:
Pathologie, Universitätsspital Basel,Basel,Switzerland
,
Luca Ceriani
Affiliations:
Nuclear Medicine and PET-CT centre, Imaging Institute of Southern Switzerland,Bellinzona,Switzerland
,
Francesco Bertoni
Affiliations:
Institute of Oncology Research, Faculty of Biomedical Sciences, USI,Bellinzona,Switzerland
,
Christian Buske
Affiliations:
CCC Ulm, University Hospital Ulm,Ulm,Germany
,
Emanuele Zucca
Affiliations:
Oncology Institute of Southern Switzerland,Bellinzona,Switzerland
Wolfgang Hiddemann
Affiliations:
Department of Medicine III, University of Munich,Munich,Germany
EHA Library. Stathis A. 06/12/20; 293662; EP1173
Dr. Anastasios Stathis
Dr. Anastasios Stathis
Contributions
Abstract

Abstract: EP1173

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background
SAKK 35/15 is an open label phase I trial, which is being conducted by the Swiss Group for Clinical Cancer Research (SAKK) and the German Low Grade Lymphoma Study Group (GLSG)/German Lymphoma Alliance (GLA).

Aims
To determine the recommended phase II dose (RP2D), toxicity profile and preliminary activity of the anti-CD20 monoclonal antibody obinutuzumab in combination with the bcl-2 inhibitor venetoclax in previously untreated advanced stage follicular lymphoma (FL) patients (pts).

Methods
Pts with grade 1 to 3A FL, untreated and in need of systemic therapy were eligible. Two dose levels were evaluated in a 3+3 design with an expansion cohort at the RP2D. DL1 consisted of venetoclax 600mg once daily (OD) and DL2 of venetoclax 800mg OD, continuously for six 28-day (d) cycles. In both DLs pts received obinutuzumab 1000mg on d 1,8,15 of cycle 1 and on d 1 of cycles 2-6. Following cycle 6, pts on partial or complete remission (PR or CR) continue maintenance treatment with single agent obinutuzumab 1000mg every two months for up to 2 years.

Results
The study completed its accrual with 25 pts enrolled (3 in DL1 and 22 in DL2). Demographics: median age 55 (range 30–78), F:M = 12:13, ECOG 0:1:2 = 21:3:1 pts, stage II:III: IV= 2:9:14 pts, FLIPI score low:intermediate:high=5:8:12 pts, reason for start of systemic therapy B symptoms:bulky disease:clinical progression:symptomatic disease=10:11:13:20 occurrences. Only one patient treated at DL2 had a dose limiting toxicity consisting of grade 4 thrombocytopenia after the first obinutuzumab infusion. Adverse events (AE) of grade (G) ≥3, of at least possible attribution to study treatment, were neutropenia (7 pts, 5 G3 and 2 G4), thrombocytopenia (2 pts, 1 G3 and 1 G4), febrile neutropenia (2 pts both G3) and 1 pt each for anemia (G3), diarrhea (G3), AST increase (G3), lymphopenia (G3), upper respiratory infection (G3), bronchial infection (G3) and pneumonitis (G3). Two pts have completed trial treatment as per protocol, 15 are currently on maintenance, while 8 pts discontinued treatment (7 for progressive disease and one for AEs). Twenty-four patients are part of the full analysis set (DL1 and DL2) evaluated for response at 6 months by CT: CR 25% (95% CI, 9.8-46.7%), overall response rate (ORR) 87.5% (95% CI, 67.6-97.3%); 19 of the 24  pts were evaluated by PET/CT: CR 68.4% (95% CI, 43.4-87.4%) and ORR 84.2% (95% CI, 60.4-96.6%). One year progression-free survival (PFS) is 74.0% (95% CI, 47.6-88.5%) and 68.7% (95% CI, 30.2-88.9%) for CT and PET/CT evaluated pts respectively.

Conclusion
This is the first study to assess the combination of obinutuzumab and venetoclax in previously untreated advanced FL in need of systemic therapy. The two drugs can be safely combined and the RP2D of the combination is venetoclax 800mg OD continuously for 6 cycles with obinutuzumab 1000mg on d 1,8,15 of cycle 1 and on d 1 of cycles 2-6, followed by obinutuzumab maintenance for up to two years. Response data show promising activity that will need to be validated in phase II trial.

Session topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

Keyword(s): BCL2, Follicular lymphoma, Obinutuzumab, Phase I

Abstract: EP1173

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background
SAKK 35/15 is an open label phase I trial, which is being conducted by the Swiss Group for Clinical Cancer Research (SAKK) and the German Low Grade Lymphoma Study Group (GLSG)/German Lymphoma Alliance (GLA).

Aims
To determine the recommended phase II dose (RP2D), toxicity profile and preliminary activity of the anti-CD20 monoclonal antibody obinutuzumab in combination with the bcl-2 inhibitor venetoclax in previously untreated advanced stage follicular lymphoma (FL) patients (pts).

Methods
Pts with grade 1 to 3A FL, untreated and in need of systemic therapy were eligible. Two dose levels were evaluated in a 3+3 design with an expansion cohort at the RP2D. DL1 consisted of venetoclax 600mg once daily (OD) and DL2 of venetoclax 800mg OD, continuously for six 28-day (d) cycles. In both DLs pts received obinutuzumab 1000mg on d 1,8,15 of cycle 1 and on d 1 of cycles 2-6. Following cycle 6, pts on partial or complete remission (PR or CR) continue maintenance treatment with single agent obinutuzumab 1000mg every two months for up to 2 years.

Results
The study completed its accrual with 25 pts enrolled (3 in DL1 and 22 in DL2). Demographics: median age 55 (range 30–78), F:M = 12:13, ECOG 0:1:2 = 21:3:1 pts, stage II:III: IV= 2:9:14 pts, FLIPI score low:intermediate:high=5:8:12 pts, reason for start of systemic therapy B symptoms:bulky disease:clinical progression:symptomatic disease=10:11:13:20 occurrences. Only one patient treated at DL2 had a dose limiting toxicity consisting of grade 4 thrombocytopenia after the first obinutuzumab infusion. Adverse events (AE) of grade (G) ≥3, of at least possible attribution to study treatment, were neutropenia (7 pts, 5 G3 and 2 G4), thrombocytopenia (2 pts, 1 G3 and 1 G4), febrile neutropenia (2 pts both G3) and 1 pt each for anemia (G3), diarrhea (G3), AST increase (G3), lymphopenia (G3), upper respiratory infection (G3), bronchial infection (G3) and pneumonitis (G3). Two pts have completed trial treatment as per protocol, 15 are currently on maintenance, while 8 pts discontinued treatment (7 for progressive disease and one for AEs). Twenty-four patients are part of the full analysis set (DL1 and DL2) evaluated for response at 6 months by CT: CR 25% (95% CI, 9.8-46.7%), overall response rate (ORR) 87.5% (95% CI, 67.6-97.3%); 19 of the 24  pts were evaluated by PET/CT: CR 68.4% (95% CI, 43.4-87.4%) and ORR 84.2% (95% CI, 60.4-96.6%). One year progression-free survival (PFS) is 74.0% (95% CI, 47.6-88.5%) and 68.7% (95% CI, 30.2-88.9%) for CT and PET/CT evaluated pts respectively.

Conclusion
This is the first study to assess the combination of obinutuzumab and venetoclax in previously untreated advanced FL in need of systemic therapy. The two drugs can be safely combined and the RP2D of the combination is venetoclax 800mg OD continuously for 6 cycles with obinutuzumab 1000mg on d 1,8,15 of cycle 1 and on d 1 of cycles 2-6, followed by obinutuzumab maintenance for up to two years. Response data show promising activity that will need to be validated in phase II trial.

Session topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

Keyword(s): BCL2, Follicular lymphoma, Obinutuzumab, Phase I

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