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The two major subtypes of diffuse large B cell lymphoma (DLBCL)—activated B cell–like (ABC) and germinal center B cell–like (GCB)—arise by distinct mechanisms, with ABC selectively acquiring mutations that target the B cell receptor (BCR), fostering chronic active BCR signaling(1). The ABC subtype has a ∼40% cure rate with currently available therapies, which is worse than the rate for GCB DLBCL, and highlights the need for ABC subtype-specific treatment strategies(2). We hypothesized that ABC, but not GCB, DLBCL tumors would respond to ibrutinib, an inhibitor of BCR signaling. In a phase 1/2 clinical trial that involved 80 subjects with relapsed or refractory DLBCL, ibrutinib produced complete or partial responses in 37% (14/38) of those with ABC DLBCL, but in only 5% (1/20) of subjects with GCB DLBCL (P = 0.0106). ABC tumors with BCR mutations responded to ibrutinib frequently (5/9; 55.5%), especially those with concomitant myeloid differentiation primary response 88 (MYD88) mutations (4/5; 80%), a result that is consistent with in vitro cooperation between the BCR and MYD88 pathways. However, the highest number of responses occurred in ABC tumors that lacked BCR mutations (9/29; 31%), suggesting that oncogenic BCR signaling in ABC does not require BCR mutations and might be initiated by non-genetic mechanisms. These results support the selective development of ibrutinib for the treatment of ABC DLBCL.

7056 Background: Ibrutinib is a first-in-class selective small molecular inhibitor of Bruton’s tyrosine kinase (BTK) under development for the treatment of B-cell malignancies. Because of covalent binding to cys-481 of BTK, ibrutinib has a sustained pharmacodynamic (PD) effect. The aim of this study was to determine the PK of ibrutinib in patients (pts) with CLL. Methods: A Phase 1b/2 study (PCYC-1102-CA) of an oral dosing of single agent ibrutinib was conducted in pts with treatment-naïve (TN) or relapsed/refractory (R/R) CLL. Pts were enrolled into one of the following groups: R/R pts at 420 mg/day (n=27), TN pts at 420 mg/day (n=26), R/R pts at 840 mg/day (n=34), R/R high-risk pts at 420 mg/day (n=24), TN pts at 840 mg/day (n=5), and R/R pts at 420 mg/day for food-effect evaluation (n=16). One cycle was 28 days. Blood samples for PK assessment were obtained during the first cycle. PK parameters were calculated using non-compartmental analyses. Results: A total of 132 pts (98 males and 34 females) with CLL were treated across the 6 groups. Median ages for Groups 1 through 6 were 64, 71, 64, 68, 71, and 62 years, respectively. Ibrutinib exhibited rapid absorption (median Tmax of 2 h) and a mean elimination plasma half-life of approximately 6-9 hours. The AUCtau increased approximately proportional to doses from 420 to 840 mg/day. No accumulation of ibrutinib was apparent on Day 8. Ibrutinib exposure in males and females was similar. At 420 mg/day, pts ≥ 65 years old had AUC values that were ~30% higher than those of pts < 65 years. In R/R pts, there were no substantive differences in systemic exposure to ibrutinib between the del 17p positive and del 17p negative pts. An increase in ibrutinib exposure (

Abstract 4039 Introduction: Bruton tyrosine kinase (Btk) is essential in the development and function of B cells through normal B cell receptor signaling, and it is down-regulated in non-malignant plasma cells. This is not the case in malignant plasma cells of patients with MM where robust Btk gene expression is usual. In addition, Btk is expressed and functional in osteoclasts and their precursors, which play a pathogenic role in MM-related bone disease, as well as growth and survival of MM in the microenvironment. Researchers in our group (Tai, Chang et al, Blood, 2012) recently demonstrated that the Btk inhibitor ibrutinib (PCI-32765) inhibited the interaction of MM cells with stromal cells, and inhibited the growth in vitro of MM colony forming cells from patient explants. Ibrutinib suppressed in vitro osteoclast differentiation and production of multiple cytokines and chemokines including CCL3, CCL4, IL-8, and TGF-β. Ibrutinib furthermore decreased MM progression and accompanying bone destruction in an in vivo SCID-Hu myeloma model. Based on these observations, we initiated a clinical trial of ibrutinib in patients with relapsed (R) and relapsed/refractory (R/R) MM. This report of early marker changes is based upon 7 patients who have completed 3 cycles of treatment. Methods: Patients with progressive disease (PD) after at least 2 prior lines of therapy received a fixed dose of oral ibrutinib 420 mg orally once daily, with a cycle defined as 28 days. Dexamethasone 40 mg weekly could be added if no response or PD was observed by cycle 2. Blood levels of cytokines, chemokines and bone markers (bone-specific alkaline phosphatase (bAP), sclerostin and RANKL) were assessed centrally at Days 1, 2, 8, and 15 of Cycle 1, Cycle 2 Day 1 and every 2 cycles thereafter, by single or multiplexed immunoassays. Serum cross-linked C-terminal peptide of collagen I (sCTx) was determined by a central lab at the start of Cycles 1 and 2 and every other cycle thereafter. Responses were assessed following the International Myeloma Working Group criteria (modified to include minimal response). Results: Thirteen patients [M/F: 8/5; median age 62, range 49–74 years] were enrolled between March 21 and June 6, 2012. All patients had received prior treatment with lenalidomide, bortezomib, alkylators and dexamethasone. 7 were refractory to their last treatment. At the time of data cut off, 7 of the 13 patients enrolled had completed 3 cycles of therapy and were the ones used for analysis. Over the course of three cycles, several markers relevant to bone metabolism exhibited gradual decreases. At Cy4D1 plasma RANKL, sclerostin, and bAP exhibited (median) decreases of 47%, 39%, and 36%, respectively. Relative changes in sCTx were more variable at Cy2D1, but there appeared to be a trend towards subject-by-subject decreases at C4D1 (Fig. 1). Factors promoting growth and angiogenesis (e.g. VEGF, EGF, and FGF) and cytokines and chemokines (CCL3, CCL4, TNFα, Groα and MDC) with roles in MM micro-environmental interactions exhibited similar reductions (Fig. 2). Among these the most dramatic and consistent changes were in CCL3 and CCL4, chemokines enhancing adhesive interactions contributing to osteolysis in MM, which showed median decreases of 43% and 77% at Cy4D1, respectively. Ibrutinib has been uniformly well tolerated and the safety experience to date has been similar to that noted in other studies of ibrutinib in lymphoma and CLL. Conclusions: Early reductions in blood levels of cytokines, chemokines, markers of bone metabolism, and pro-angiogenic and growth factors, were observed among MM patients treated with ibrutinib, which were consistent with pre-clinical studies. Among markers related to bone metabolism, it appeared that changes in regulatory molecules (sclerostin, RANKL) were more marked and perhaps preceded changes in markers of osteoclast (sCTx) or osteoblast (bAP) activity. Elucidation of these patterns and their significance will require longer follow-up of a larger number of patients. These results indicate that ibrutinib can exert significant biologic effects on the microenvironment in MM. Clinical correlations will be forthcoming based upon maturing results over the next several months. Disclosures: Vij: Millennium: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Onyx: Honoraria, Research Funding. Chang:Pharmacyclics, Inc.: Employment, Equity Ownership. Huff:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Chang:Pharmacyclics, Inc.: Employment, Equity Ownership. Moussa:Pharmacyclics, Inc.: Employment, Equity Ownership. Buggy:Pharmacyclics: Employment, Equity Ownership. Elias:Pharmacyclics, Inc.: Employment, Equity Ownership. Richardson:Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

686 Background DLBCL has two molecular subtypes, termed activated B cell-like (ABC) and germinal center B cell-like (GCB), with ABC DLBCL being less curable with current therapy. The survival of ABC but not GCB DLBCL cell lines is sustained by “chronic active” B cell receptor (BCR) signaling. Gain-of-function mutations affecting the BCR subunit CD79B occur in 21% of ABC but only 5% of GCB DLBCL tumors. ABC DLBCL cell lines also depend upon a second pathway for survival that is coordinated by MYD88, an adapter for Toll-like receptors. A constitutively active MYD88 mutant (L265P) is frequent in ABC DLBCL tumors (29%) but rare in GCB DLBCL. CD79B and MYD88 L265P mutations often coexist in ABC DLBCL tumors, suggesting oncogenic collaboration, but can also occur alone. Here, we present interim results of a phase 2 study in relapsed/refractory DLBCL of ibrutinib, a first in class inhibitor of BTK, a kinase in the BCR pathway. We tested the hypothesis that ibrutinib would be more active in ABC than GCB DLBCL due to their different addiction pathways, and we assessed the association of CD79B and MYD88 mutations with response. Methods Subjects with relapsed/refractory de novo DLBCL received ibrutinib 560 mg PO QD. Gene expression profiling (GEP) of formalin-fixed paraffin-embedded biopsy tissues using Affymetrix arrays was used to identify the DLBCL subtype (ABC, GCB, unclassifiable) or were not arrayed (unknown). Sanger sequencing was used to identify CD79B and MYD88 mutations. Subjects underwent CT and PET scanning pre-treatment and every 2 cycles. The primary objective of the study was overall response rate (ORR) categorized by molecular subtype. Response was investigator determined using the revised International Working Group Criteria for NHL. Subjects Seventy subjects were enrolled; median age 63 yrs (28–92); male 71%; stage IV 63%; HI-I/HI IPI 59%; disease ≥10 cm 23%; median prior systemic therapies 3 (1–7); relapsed (27%), refractory (54%) and unknown (19%); prior stem cell transplant 23%; and median time from diagnosis 19 months. Results Safety data are available for 68 subjects who received ≥ 1 dose of ibrutinib. Ibrutinib was well tolerated, with treatment-emergent AEs consistent with data reported in other ibrutinib studies. No new safety signals were identified. Sixty subjects were evaluable per protocol for response (≥ 1 dose of ibrutinib and at least one response assessment). Four subjects in the ABC cohort were not evaluable for response (1 death at study day 12, 1 PD at study day 65, and 2 remain on study treatment but have not had their first response assessment at this analysis). One subject in the GCB cohort was not evaluable for response (death at study day 41). In the ABC subtype, per protocol ORR was 40% (10/25, 95% CI: 21–61%), CR 8% (2/25) and PR 32% (8/25). The median PFS at the time of this analysis is 5.5 months in ABC responders with 60% having not progressed (5 remain on treatment and 1 responder proceeded to transplant). Only one PR was observed in the GCB subtype and none in unclassifiable cases. Thus, ibrutinib showed preferential response activity in ABC versus GCB DLBCL (p=0.0126, Fisher's exact test). Responses occurred in ABC DLBCL tumors with CD79B mutations (60%; 3/5), but also in those with wild type CD79B (37%; 7/19), suggesting that ibrutinib sensitivity does not require a BCR mutation. All cases with both CD79B and MYD88 L265P mutations (n=4) responded, showing that the MYD88 pathway does not prevent ibrutinib activity. In comparison, tumors with only a MYD88 L265P mutation (n=4) did not respond (p=0.0286, Fisher's exact test), suggesting a MYD88-dependent but BCR-independent pathogenesis for some ABC DLBCL cases. | | ABC subtype (N=29) | GCB subtype (N=20) | Unclassifiable[1][1] (N=16) | Unknown[2][2] (N=5) | Total (N=70) | |:-------------------------- | ------------------ | ------------------ | --------------------------- | ------------------- | ------------ | | Not Evaluable for Response | 4 | 1 | 3 | 2 | 10 | | PP ORR[4][3] (CR + PR) | 10 (40%) | 1 (5.3%) | | 2 (66.7%) | 13 (21.7%) | | Complete Response (CR) | 2 (8%) | | | 1 (33.3%) | 3 (5%) | | Partial Response (PR) | 8 (32%) | 1 (5.3%) | | 1 (33.3%) | 10 (16.7%) | | PFS (months) | 2.5 | 1.28 | 0.95 | NR[3][4] | 1.64 | * [↵][5]1 GEP performed, but not assignable to ABC or GCB subtypes. * [↵][6]2 GEP not yet performed or tissue not available. * [↵][7]3 Not reached. * [↵][8]4 PP = per protocol. Efficacy Data Conclusions Ibrutinib showed a clinically meaningful response rate in relapsed/refractory ABC DLBCL, but not in other molecular subtypes. These results are consistent with an essential role of BCR signaling in ABC DLBCL and indicate that future clinical trials of ibrutinib in DLBCL should enroll patients with this subtype. Disclosures: Goy: Pharmacyclics: Research Funding. de Vos: Pharmacyclics: Research Funding. Kenkre: Pharmacyclics: Research Funding. Blum: Pharmacyclics: Research Funding. Advani: Phramacyclics, Inc: Research Funding. Kunkel: Pharmacyclics, Inc: Employment, Equity Ownership. McGreivy: Pharmacyclics, Inc.: Employment, Equity Ownership. Balasubramanian: Pharmacyclics, Inc.: Employment, Equity Ownership. Cheng: Pharmacyclics, Inc.: Employment, Equity Ownership. Moussa: Pharmacyclics, Inc.: Employment, Equity Ownership. Buggy: Pharmacyclics, Inc.: Employment, Equity Ownership. 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