SAKK 35/15: A PHASE I TRIAL OF OBINUTUZUMAB IN COMBINATION WITH VENETOCLAX IN PREVIOUSLY UNTREATED FOLLICULAR LYMPHOMA PATIENTS

Introduction: The anti-CD20 monoclonal antibody obinutuzumab and the bcl-2 inhibitor venetoclax are both active in different lymphoma subtypes. 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) and aims to determine the recommended phase II dose (RP2D), toxicity profile and preliminary activity of obinutuzumab in combination with 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 are being evaluated in a 3+3 design with an expansion cohort at the RP2D. DL1 consists of venetoclax 600mg once daily (OD) and DL2 of venetoclax 800mg OD, continuously for six 28-day (d) cycles, starting on cycle 1 d 2. In both DLs pts receive 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= 2:10:13 pts, FLIPI score low:intermediate:high=5:10:10 pts, reason for start of systemic therapy B symptoms:bulky disease:clinical progression:symptomatic disease=10:10:13:19 pts. Among 22 pts completing cycle 1, only one patient treated at DL2 had a dose limiting toxicity consisting of grade (G) 4 thrombocytopenia after the first obinutuzumab infusion. Three pts have not completed cycle 1 yet. Thus far, adverse events (AE) of G ≥3, of at least possible attribution to study treatment, were neutropenia (2 pts, both G4), thrombocytopenia (2 pts, 1 G3 and 1 G4), and one pt each for anemia (G3), febrile neutropenia (G3), fatigue (G3), AST increase (G3), ALT increase (G3), lymphopenia (G3) and pneumonitis (G3). AEs were all manageable and no toxic deaths were seen. The median relative dose intensity (proportion of administered doses relative to planned doses) was 100% for both drugs. Eleven pts are currently receiving combination therapy and 10 are on maintenance, while 4 pts discontinued treatment, 3 for progressive disease (2 under combination therapy and one during maintenance) and one for AEs (thrombocytopenia G4, ALT increase G3 and pneumonitis G3). Eleven pts are evaluable for response at 6 months, 10 were evaluated by PET-CT and one by CT only. Five achieved CR (45%; 95% CI, 17-77%), 4 PR (36%; 95% CI, 11-69%) and 2 pts had progressive disease, for an overall response rate (ORR) at 6 months of 82% (95% CI, 48-98%). Conclusions: This is the first study to assess obinutuzumab plus venetoclax in untreated advanced FL in need of systemic therapy. The two drugs could be safely combined and may represent a valuable chemotherapy-free regimen. The RP2D is venetoclax 800mg OD continuously for 6 cycles starting on d 2 of cycle 1 in combination 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. Preliminary data show promising activity and updated results will be presented. Keywords: follicular lymphoma (FL); obinutuzumab; venetoclax. Disclosures: Stathis, A: Research Funding: Roche; Other Remuneration: Travel support Abbvie. Mey, U: Consultant Advisory Role: Roche; Honoraria: Roche. Schmidt, C: Research Funding: Roche. Hess, D: Stock Ownership: Roche. Moccia, A: Consultant Advisory Role: Roche. Unterhalt, M: Research Funding: Roche. Rossi, D: Honoraria: Roche. Zucca, E: Consultant Advisory Role: Roche; Research Funding: Roche. Hiddemann, W: Honoraria: Roche; Research Funding: Roche.