A Multicenter, Phase II Study of Ibrutinib Plus FCR (iFCR) As Frontline Therapy for Younger CLL Patients

Introduction CR provides prolonged disease free survival for many CLL patients (pts) with mutated IGHV; however, pts with unmutated IGHV typically have less durable responses. Furthermore, complete response (CR) with bone marrow minimal residual disease negativity (BM MRD-neg) is only achieved in about 20% of pts. Given the excellent efficacy and tolerability of frontline ibrutinib across CLL risk types, we are conducting an ongoing investigator-initiated, multicenter phase II study of ibrutinib plus FCR (iFCR) as frontline treatment for young, fit CLL pts (NCT02251548). Methods The primary endpoint is the rate of CR with BM MRD-neg 2 mo. after FCR. Secondary endpoints include response rates, PFS, and safety/tolerability. Ibrutinib 420 mg daily monotherapy is given for 7 days, followed by combination with FCR for up to 6 cycles. Responders continue on ibrutinib maintenance for at least 2 years. A recent study amendment allows accrual of 50 additional pts who discontinue ibrutinib if BM MRD-neg. after 2 years of maintenance and can restart ibrutinib if they recur. Antimicrobial prophylaxis and growth factor support are mandatory. To be eligible, pts must be ≤ 65 yrs old, meet IW-CLL criteria for initial therapy, have adequate organ function, and ECOG PS ≤1. IW-CLL 2008 and CTCAE v4 criteria are used to evaluate efficacy and toxicity, with responses requiring radiographic confirmation, and evaluations after 3 cycles, 2 mo. after final FCR, and q6 mo. thereafter. MRD is assessed by 4-color flow cytometry (10-4 sensitivity) and by ClonoSEQ (Adaptive). Results As of the data cutoff of July 1, 2017, 49 pts have been accrued, including 35 pts in the original cohort and 14 pts in the new expansion cohort, in whom safety and efficacy data are not yet available. Pt characteristics for all 49 pts include: median age at enrollment 55 yrs (range 38-65), del(11q) in 12/47 tested (26%), del(17p) in 4/47 tested (9%), unmutated IGHV in 26/46 tested (57%), ZAP-70 positivity in 27/46 tested (59%), TP53 mutation without del(17p) in 3 pts (6%), and NOTCH1 mutation in 2/33 tested (6%). Baseline blood counts were as follows: WBC median 87.2, (range 2.6-776), Hgb median 12.2 (range 7.8-15.9), Plts median 134 (range 43-366). Median baseline β2M was 4.2 mg/dL (range 2.9-12.6). In the 35 pts evaluable for toxicity, gr 3/4 hematologic toxicity included: neutropenia 29% (23% gr3, 6% gr4), thrombocytopenia 26% (all gr3), and anemia 6% (all gr 3). All grade non-hematologic toxicities occurring in >15% of pts included nausea (71%), bruising (43%), rash (43%, including 34% gr1, 9% gr 2, and 1 gr 3), fatigue (37%), and gr 1 diarrhea (26%). Bleeding events included gr1 epistaxis (n=2), gr1 rectal bleeding and gr2 menorrhagia (n=1 each). SAEs included gr3 pneumonia (n=2), gr 3 febrile neutropenia, gr 3 atrial fibrillation, gr 3 transaminitis, gr 3 pneumatosis intestinalis, gr 3 Anaplasmosis infection, and gr 3 appendicitis (n=1 each). 6/35 (17%) of pts experienced ≥gr 3 infection. Number of FCR cycles administered was: 6 (n=31), 5 (n=2), 4 (n=1), 3 (n=1). One pt with febrile neutropenia had ibrutinib dose reduction, and 18% of pts had at least 1 dose reduction of chemotherapy. In the 35 pts evaluable for efficacy, the ORR is 100%, including 63% (22/35) with best response of CR/CRi. All 13 PR pts have residual lymph nodes ≤ 2.5 cm in long axis by CT imaging. The rate of CR with BM MRD-neg 2 mo. post FCR (primary endpoint) is 37% (13/35), with a best rate that increased with post-FCR ibrutinib maintenance to 57% (20/35). Best rate of BM MRD-negativity by flow irrespective of IW-CLL response is 83% (29/35), including 10/13 (77%) of pts in PR. With a median follow-up of 20 mo. (range 13-33), all pts are alive, and 86% (30/35) remain on treatment, with 2 BM MRD-neg pts electing to discontinue ibrutinib, 2 pts who discontinued ibrutinib due to toxicity (gr3 pneumatosis intestinalis and gr 3 transaminitis), and 1 pt with del(17p) who achieved MRD-pos PR and elected to pursue allogeneic stem cell transplant. Conclusions iFCR induced deep responses in a relatively high risk group of previously untreated young CLL pts, with 57% achieving CR with BM-MRD-neg and 83% achieving BM MRD-neg, significantly higher than the 20% rate seen historically with FCR alone. Low rates of hematologic and infectious toxicities may be due to mandatory growth factor and antimicrobial prophylaxis. Updated results on the ibrutinib discontinuation cohort will be presented. Disclosures Davids: Celgene: Consultancy; Genentech: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy; Merck: Consultancy; InCyte: Membership on an entity9s Board of Directors or advisory committees; Gilead: Membership on an entity9s Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Brander: Genentech: Consultancy; Teva Pharmaceuticals, Genentech, AbbVie, Pharmacyclics: Consultancy; AbbVie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Jacobson: Kite: Membership on an entity9s Board of Directors or advisory committees; Pfizer: Membership on an entity9s Board of Directors or advisory committees; Bayer: Membership on an entity9s Board of Directors or advisory committees. LaCasce: BMS: Consultancy; Forty Seven: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding. Abramson: Seattle Genetics: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; LAM Therapeutics: Research Funding. Fisher: Celgene: Membership on an entity9s Board of Directors or advisory committees; Seattle Genetics: Membership on an entity9s Board of Directors or advisory committees. Brown: Roche/Genentech: Consultancy; AbbVie: Consultancy, Honoraria; Pharmacyclics: Consultancy; Infinity Pharmaceuticals: Consultancy; Pfizer: Consultancy; Astellas Pharma: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Janssen Oncology: Honoraria; Redx: Consultancy; Gilead: Consultancy, Research Funding; Sun BioPharma: Consultancy, Research Funding; Celgene: Consultancy.