7522 Background: Pts with mutated IGHV ( IGHV-M) have favorable long-term outcomes after FCR. Methods: We designed an investigator-initiated phase II trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809). The intent was to limit FC to 3 courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through addition of ibrutinib and obinutuzumab. Key eligibility included age ≥18, IGHV-M, no del17p. Pts received 3 courses of iFCG. G-CSF was not mandated. Primary endpoint: CR/CRi with bone marrow (BM) MRD-neg (4-color flow-cytometry) after 3 courses of iFCG. Pts meeting primary endpoint received ibrutinib with obinutuzumab (iG) for C3-6, then ibrutinib C7-12. Pts not achieving primary endpoint received iG (C4-12). All pts who are MRD neg at 1 year will stop all therapy, including ibrutinib. Pts MRD+ at 1 year may continue ibrutinib. Historic C3 BM MRD-neg with FCR in IGHV-M 26% (Strati, Blood 2014). Target BM MRD-neg after iFCG x3 is 45%. Sample size 45. Results: 23 pts started treatment. Median age 59 yrs (25-71). Prognostic markers [del13q (n=17), negative (n=3); trisomy 12 (n=3)]. 18 pts completed 3 courses of iFCG and had initial response assessment (the remaining 5 pts too early). All 18 pts had a response; 14/18 (78%) achieved MRD-neg in BM at 3 month with 7/18 achieving CR/CRi (all MRD neg). No pt has progressed, and all but one continue to receive treatment. Of the 23 pts, 11 pts had G3-4 neutropenia and 5 pts had G3-4 thrombocytopenia. 4 pt had neutropenic fever. 1 pt who achieved MRD-neg CR developed pulmonary MAC infection, and declined further therapy. 1 pt had atrial fibrillation. G3 ALT developed in 3 pts. FC was dose reduced in 10 pts; ibrutinib dose-reduced in 2 pts. Conclusions: iFCG achieves high rate of MRD-neg remission after 3 courses. Pt enrollment continues, and updated results will be presented at the ASCO meeting. Clinical trial information: NCT02629809. [Table: see text]