Résumé
Background. Mantle Cell Lymphoma (MCL) drug resistance are highly dependent on B-cell-receptor signaling, Bcl-2 and the microenvironment. Ibrutinib inhibits both tumor cell proliferation and binding to the microenvironment. Venetoclax is a Bcl-2 inhibitor and Bcl-2 family members like Mcl-1 and Bcl-xL confers resistance to Venetoclax and are upregulated by the tumor microenvironment but downregulated by Ibrutinib (Touzeau, 2011, Chiron, 2015). Ibrutinib plus venetoclax has recently demonstrated high efficacy in relapsed/refractory (R/R) MCL (Tam et al NEJM 2018). Preclinical investigations show that microenvironment-dependent long-term expansion and drug resistance to venetoclax are counteracted by obinutuzumab (type II glycoengineered humanized anti-CD20 antibody) and obinutuzumab/venetoclax/ibrutinib is highly active against primary MCL cells. (Chiron Blood 2016). All together these findings gave the rational to investigate Obinutuzumab/Ibrutinib (step A) and Obinutuzumab/Venetoclax/Ibrutinib (step B) combinations. The OAsIs trial (NCT02558816) has been designed to assess the safety, tolerability and efficacy of these two combos in R/R MCL. DLTs were assessed during the first 2 months (step A) and 3 months (step B) of treatment.
Methods: Oasis is a multicenter, non-randomized, phase I study. Step A evaluates the safety of obinutuzumab (1000mg IV C1D1, 8,15, C2-6 D1 and every 2 months until C24) plus Ibrutinib (560mg/d until progression) (n=9). Step B primary objective is to determine the MTD of obinutuzumab/venetoclax/ibrutinib. Venetoclax is administered from C2 (C2W1 100mg/d, C2W2 200mg/d, C2W3 400mg/d and C2W4-C6: 400, 600 or 800mg/d). A continual reassessment method is used to allocate venetoclax doses (3 patients-pts- per dose-level). Enrolment in step A and B for R/R MCL started in November 2015 and October 2016, respectively.
Results. Step A (Obinutuzumab/Ibrutinib) (n=9). Median age at inclusion was 64y (range 58-82) and median lines of treatment prior to inclusion is 1 (1-4), including ASCT in 7 patients and allo-SCT in one case. Median time from diagnosis to C1D1 is 46.5m (18.4-103). Two pts presented with blastoid variant. One of nine step A patients presented TP53 mutation. Median time from diagnosis to C1D1 is 46.5m (18.5-103). During the first 3 months of treatment, there was no clinically relevant non-hematological grade 3-4 AEs. Eight grade 3-4 hematological AEs were reported in 4 pts (lymphopenia 4 ; neutropenia 4 ; thrombocytopenia 1). One patient progressed at end of C2 and died few weeks later while 7 (87%) were in CR according to Lugano criteria at end of C6. MRD status was assessed by ASO qPCR targeted to clonal immunoglobulin rearrangements in 6 /9 step A pts (one progressed before C6, data missing = 2). Of these, 4 were MRD negative in both blood and bone marrow after C6 (one remained MRD pos with no clinical relapse and underwent allo-SCT, one was not evaluated in BM). At the 12 months time point, the 3 evaluated pts remained MRD negative. With a median follow-up of 23,5m (8,9-31.6), 8 pts are alive (6 completed the 2y treatment program and are in CR).
Step B (Obinutuzumab/ Ibrutinib/Venetoclax; Ven 400mg (n=3); at Ven=600mg (n=3) and Ven=800mg (n=6)). Median age at inclusion is 64.5y (range 45-74). Median lines of treatment prior inclusion is 2 (1-3), including ASCT in 8 patients. Five pts presented with blastoid MCL. TP53 status was assessed in 3/10 pts (2 ongoing). Of these 10, 3 presented TP53 mutations. Median time from diagnosis to C1D1 is 50.2m (12.8-123). The median follow-up for living pts (n=8) is 6.5m (2.5-15). During the first three months of treatment, there was no clinically relevant non-hematological grade 3-4 AEs. Twenty-nine grade 3-4 hematological AEs were reported in 7 pts (febrile neutropenia 1, neutropenia 4 ; thombopenia 4, anemia 2 and lymphopenia 3). At end of C2 , 3 achieved CR, 5 PR and 4 pts had PD. Among 9 pts assessed after C6, 5 patients were in CR (MRD analysis ongoing)
Conclusion. No DLT has been reported in both step A and B. Both combinations are well tolerated and provide high disease control including CR at the molecular level. Oasis step C (obinutuzumab/venetoclax/ibrutinib) for untreated MCL pts is now open for inclusion since July 2018.