ALBERT

Description: Phosphoinositide-3 kinases (PI3Ks) are key cellular signaling proteins that act as a central node, relaying signals from cell surface receptors to downstream mediators such as AKT. The PI3K-δ and PI3K-γ isoforms are preferentially expressed in normal and malignant leukocytes where they play critical roles in cell differentiation, migration, and proliferation. IPI-145 is a potent, oral PI3K-δ,γ inhibitor that has shown clinical activity in the Phase 1 trial (IPI-145-02) in patients with advanced hematologic malignancies (ClinicalTrials.gov NCT01476657). Cytokines, chemokines, and matrix metalloproteinases (MMPs) play key roles in the homing, migration and activation of normal immune cells, and can have similar effects on malignant leukocytes. To further explore the biological effects of IPI-145, a panel of cytokines, chemokines, and MMPs were evaluated at several time points in the serum of patients enrolled in the IPI-145-02 trial. Serum was collected from consenting subjects at baseline, Cycle 1 Day 8 (C1D8), and Cycle 2 Day 1 (C2D1). Serum was frozen and stored at -80°C prior to analysis. Serum proteins were analyzed using Luminex xMAP(®) technology in which analytes are captured on uniquely labeled fluorescent beads, and the amount of analyte is quantified using an LED CCD camera contained in Millipore's MagPix(®) instrument. Multiplex panels of cytokines, chemokines and MMPs covering 72 analytes were evaluated in 30 chronic lymphocytic leukemia (CLL) and 19 indolent non-Hodgkin lymphoma (iNHL) subjects. Each sample was tested in duplicate, and duplicate measurements were averaged. Measurements were excluded from further analysis if duplicate readings exhibited a coefficient of variation of greater than 20% or if all values for a specific analyte and subject were below the limit of detection. Each analyte was evaluated for evidence of a consistent change (reduction or increase) in serum levels at C1D8 and/or C2D1 compared to baseline. When data were compared between CLL subjects treated with IPI-145 at 25 mg twice daily (BID) and those treated at 75 mg BID, no clear differences in serum analyte levels were observed, although the population subgroups were relatively small. For the purposes of this analysis, all doses were pooled together (n=1 at 8 mg BID, 2 at 15 mg BID, 15 at 25 mg BID, and 13 at 75 mg BID). Likewise, the iNHL dose groups were also pooled (n=1 at 15 mg BID, 12 at 25 mg BID, 1 at 50 mg BID, and 5 at 75 mg BID). In CLL subjects, 9 of 72 analytes decreased after IPI-145 treatment compared to baseline, whereas none increased significantly. Analytes that decreased after IPI-145 treatment include CXCL13, CCL3, CCL4, IL-10, TNFα, IL-12p40, MMP-9, CCL17 and CCL22. Median serum levels of these analytes decreased by C1D8, ranging from 16% to 59% of baseline. In iNHL subjects, median serum levels of 7 analytes decreased by C1D8 (ranging from 32% to 70% of baseline), whereas none increased significantly. Of the 7 analytes that decreased in iNHL subjects, 5 also decreased in CLL subjects (CXCL13, MMP-9, TNFα, CCL17 and CCL22) and 2 were distinct (CCL1 and MMP-12). Interestingly, many of the analytes that decreased with IPI-145 treatment are involved in the communication between malignant B-cells and the microenvironment. CCL3, CCL4, CCL17 and CCL22 are expressed by malignant B-cells and may play a role in recruiting T-cells to interact with the malignant B-cells. CXCL13 is secreted by stromal cells and recruits malignant B-cells to the lymph nodes. In addition, IL-10 is produced by many normal immune cell types as well as by neoplastic B-cells. IL-10 is known to be an autocrine growth factor for B-cell lymphoma cell lines. These pharmacodynamic data provide further evidence for biological activity of IPI-145 in patients with CLL and iNHL and suggest both similarities and differences in how these two malignancies respond to IPI-145. The association of many of these pharmacodynamic factors with the tumor microenvironment suggests a mechanistic basis for the clinical observation of lymphocytosis and nodal reduction with IPI-145 treatment of CLL subjects. Cytokine, chemokine and MMP levels from patients in IPI-145-02 are being evaluated further for associations with multiple clinical parameters to determine if there is evidence for biomarkers predictive of efficacy and tolerability. Disclosures: Douglas: Infinity Pharmaceuticals, Inc.: Employment. Allison:Infinity Pharmaceuticals, Inc.: Employment. Ted:Infinity Pharmaceuticals, Inc.: Employment. Allen:Infinity Pharmaceuticals, Inc.: Employment. Kahl:Infinity Pharmaceuticals, Inc.: Consultancy, Research Funding. Horwitz:Celgene, Allos, Seattle Genetics, Bristol-Myers Squibb, Genzyme, Kyowa, Janssen, Johnson & Johnson, Millenium: Consultancy; Celgene, Allos, Seattle Genetics, Kyowa, Infinty, Millenium: Research Funding. Flinn:Infinity Pharmaceuticals, Inc.: Consultancy, Research Funding. Kelly:Infinity Pharmaceuticals, Inc.: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment.

Description: Introduction: Duvelisib (IPI-145) belongs to an emerging class of therapeutic small molecule kinase inhibitors that target B-cell receptor (BCR) signaling pathways important in various lymphoproliferative disorders. Duvelisib, a novel oral inhibitor of PI3K-δ,γ, has shown clinical activity across a range of hematologic malignancies in an ongoing Phase 1 study. Some patients (pts) treated with ibrutinib (IBR), a BCR inhibitor that targets Bruton’s tyrosine kinase (BTK), have had disease progression and various mechanisms of IBR resistance have been characterized. Since the mechanism of action of duvelisib differs from IBR, duvelisib was evaluated in a subset of pts previously treated with IBR enrolled in an ongoing Phase I study. Methods: The study was designed to evaluate the safety, maximum tolerated dose, pharmacokinetics, and activity of orally administered duvelisib twice daily in 28-day cycles. Pts with relapsed/refractory (R/R) hematologic malignancies were enrolled, including pts previously treated with IBR with R/R chronic lymphocytic leukemia (CLL) and aggressive B-cell NHL (aNHL including DLBCL and Richter’s transformation [RT]). Pharmacodynamic studies in CLL pts with measurable disease in the peripheral blood (PB) included flow cytometry to evaluate whether duvelisib inhibits the phosphorylation of AKT (pAKT) at S473 and the CLL cell proliferation index via measurement of Ki67. DNA sequencing on malignant PB cells was performed to determine the mutation status of BTK and other genes involved in hematologic malignancies. Clinical responses were based on IWCLL (2008) criteria and revised IWG (2007) criteria as applicable. Results: Twelve pts previously treated with IBR were enrolled (R/R CLL, n=6; aNHL, n=6 [DLBCL=2; RT=4]) and received IPI-145 at 25 mg BID (n=2) or 75 mg BID (n=10). The median age in R/R CLL pts was 58 years (y) (42-76), 67% were male, 100% had ≥3 prior systemic therapies, the median time from prior therapy to first dose of duvelisib was 0.34 months (mo) (0.0-1.6), and 67% started duvelisib within 2 wks of last dose of IBR. The median age in R/R aNHL pts was 62 y (36-81), 67% were male, 50% had ≥3 prior systemic therapies, a median time from last prior therapy to first dose of duvelisib of 0.74 months (0.2-3.7), and 50% started duvelisib within 3 weeks of last dose of IBR. With a median of 4.1 treatment cycles (range 3.0-9.2) in the R/R CLL pts and 2.5 treatment cycles (range 1.8-5.4) in R/R aNHL pts, the safety profile in these pts previously treated with IBR appears consistent with all pts (n=206) with advanced hematologic malignancies receiving duvelisib. The best response observed in R/R CLL pts includes 1 partial response (PR) and 5 stable disease (SD). Of these 6 pts, 2 pts (1 PR, 1 SD) remain on duvelisib for 8 and 9 months, respectively, and 4 pts have discontinued treatment (progressive disease [PD], n=3; physician decision, n=1). The best response observed in R/R aNHL pts included 2 PRs, 1 SD, 2 PD, and 1 not evaluated [NE]. Three pts remain on duvelisib (1 PR, 1 SD, 1 NE) for 3-5 mo and 3 pts have discontinued treatment (progressive disease, n=2; AE, n=1). The median baseline proliferative index (Ki67) in R/R CLL pts previously treated with IBR (n=5) was substantially higher (22.2% vs 3.8%) than in non-IBR exposed R/R CLL pts (n=23). Across both R/R CLL populations, Ki67 was reduced with duvelisib treatment by Cycle 2 Day 1 (at steady state); however, the effect was more pronounced in non-IBR treated pts. Despite this apparent difference in baseline proliferative index, the IBR previously treated pts with measureable disease in PB (R/R CLL=5), including 3 pts with a known IBR-resistance mutation in BTK (2 with C481S, 1 with C481F) demonstrated reductions of pAKT that were observed within 1 hour of duvelisib treatment and sustained through 24 hours postdose. This pAKT pharmacodynamic response was consistent with results in R/R CLL pts not previously treated with IBR (n=35). Conclusions: Pharmacodynamic data demonstrates duvelisib inhibits pAKT in R/R CLL pts, including those with an IBR-resistance mutation in BTK, and is consistent with duvelisib having a non-overlapping MOA with IBR. Baseline Ki67 data suggest a more aggressive clinical phenotype in R/R CLL pts who progress on IBR compared to those without previous IBR treatment. Early evidence of clinical activity and a tolerable safety profile suggest additional studies of duvelisib in pts who have progressed on IBR are warranted. Disclosures Porcu: Actelion (e), Cutaneous Lymphoma Foundation (h), United States Cutaneous Lymphoma Consortium (h), Infinity (d), Celgene (d), : Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: IPI-145. Flinn:Infinity Pharmaceuticals: Consultancy. Kahl:Infinity Pharmaceuticals: Consultancy, Research Funding. Horwitz:Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, SpectrumConsulting: Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Millennium, seattle genetics: Consultancy, Honoraria, Research Funding. Oki:Infinity Pharmaceuticals: Research Funding. Byrd:Pharmacyclics, Genentech: Research Funding. Sweeney:Infinity Pharmaceuticals: Employment. Allen:Infinity Pharmaceuticals: Employment. Faia:Infinity Pharmaceuticals, Inc.: Employment. Ni:Infinity Pharmaceuticals: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Kelly:Infinity Pharmaceuticals: Employment.

Description: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma (NHL). Despite aggressive chemoimmunotherapy, ∼40% of patients die of their disease. Molecular differences in the tumor genome are likely to be major contributors to the heterogeneity of clinical response. Several investigators have identified molecular subtypes, including a “cell-of-origin” (COO) signature with activated B-cell-like (ABC) and germinal center B-cell-like (GCB) sub-types (Alizadeh, et al. Nature 2000), and a “consensus clustering” (CC) signature with oxidative phosphorylation, B-cell receptor (BCR)/proliferation, and host response sub-types (Monti, et al. 2005). Phosphoinositide-3 kinases (PI3Ks) are key cellular signaling proteins that act as a central node, relaying signals from cell surface receptors to downstream mediators such as AKT. PI3K-δ and PI3K-γ isoforms are preferentially expressed in normal and malignant leukocytes where they are critical for cell differentiation, migration, and proliferation. IPI-145 is a potent, oral PI3K-δ,γ inhibitor that has shown clinical activity in the Phase 1 trial (IPI-145-02) in patients with advanced hematologic malignancies (ClinicalTrials.gov NCT01476657). Activation of the PI3K pathway is an important component of normal BCR signaling and has been implicated in the pathogenesis of DLBCL. To further explore the role of PI3K signaling in DLBCL, a panel of more than 10 DLBCL cell lines of varying molecular profile was treated with IPI-145. PI3K-δ and PI3K-γ were expressed at varying levels across the DLBCL cell lines, without evidence of a correlation with molecular subtype. In a cellular growth inhibition assay, 5 cell lines including 4 GCB (SU-DHL-4, SU-DHL-6, OCI-LY-8, and WSU-DLCL-2) and 1 ABC (Ri-1) subtype were sensitive to IPI-145 treatment in the micromolar (μM) range or below, and 5 cell lines (OCI-LY-3, OCI-LY-7, Pfeiffer, Toledo and U2932) were insensitive to IPI-145 (IC50 〉25μM). There was no evidence of a correlation between IPI-145 sensitivity and COO or CC molecular profile in this panel. IPI-145 sensitivity did correlate with evidence of PI3K pathway inhibition as measured by reduction in phospho (p)-AKT. To characterize the kinetics of pathway modulation, phosphorylation of AKT, PRAS40, and S6 was examined following a time-course of IPI-145 treatment in selected cell lines. P-AKT and p-PRAS40 were modulated by 30 minutes, whereas modulation of p-S6 was not detected until after 8 hours. Upon BCR stimulation via antibody-induced crosslinking, some cell lines exhibited enhanced AKT phosphorylation, which was inhibited with IPI-145. The GCB cell line OCI-LY-8 was moderately sensitive to IPI-145 without BCR crosslinking (low μM range) and exhibited enhanced sensitivity to IPI-145 with BCR crosslinking (sub-μM range). These results suggest that intact BCR pathway signaling contributes to IPI-145 sensitivity in DLBCL cell lines. Current efforts are focusing on identification of biomarkers that define IPI-145 responsive DLBCL subsets. IPI-145 activity was also explored in combination with ibrutinib, an irreversible inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK). Interestingly, in the setting of BCR crosslinking, OCI-LY-8 cells exhibited a robust increase in p-AKT which was completely inhibited by IPI-145 but only partially inhibited by ibrutinib. In other cell lines, such as SU-DHL-4, robust inhibition of p-BTK was observed with ibrutinib treatment but not with IPI-145. These findings suggest a potential mechanistic rationale for combination of PI3K-δ,γ and BTK inhibition. Supporting this hypothesis, a combination effect was observed in a cellular growth inhibition assay with IPI-145 plus ibrutinib in the SU-DHL-4 cell line and in the OCI-LY-8 cell line with BCR crosslinking. Studies are ongoing to explore this combination in additional DLBCL cell lines as well as in in vivo DLBCL models. Taken together, these findings suggest that a subset of DLBCL patients might benefit fromPI3K-δ,γ inhibition. Additional work is necessary to determine how to prospectively identify IPI-145-sensitive DLBCL. In addition, preliminary evidence suggests that there may be opportunities to improve targeted therapy options for DLBCL patients with the combination of IPI-145 and ibrutinib. Disclosures: Campbell: Infinity Pharmaceuticals, Inc.: Employment. Thompson:Infinity Pharmaceuticals, Inc.: Employment. Villegas:Infinity Pharmaceuticals, Inc.: Employment. Proctor:Infinity Pharmaceuticals, Inc.: Employment. McGovern:Infinity Pharmaceuticals, Inc.: Employment. Kutok:Infinity Pharmaceuticals, Inc.: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment.

Description: The study of hematopoiesis has been greatly facilitated by transplantation of blood cell populations into recipient animals. Efficient engraftment of donor cells generally requires ablation of the host hematopoietic system. The zebrafish has recently emerged as a developmental and genetic system to study hematopoiesis. To enable the study of hematopoietic stem cell (HSC) biology, immune cell function, and leukemogenesis in zebrafish, we have developed hematopoietic cell transplantation (HCT) into adult recipient animals conditioned by γ irradiation. Dose-response experiments showed that the minimum lethal dose (MLD) of 40 Gy led to the specific ablation of hematolymphoid cells and death by 14 days after irradiation. Sublethal irradiation doses of 20 Gy predominantly ablated lymphocytes and permitted transplantation of a lethal T-cell leukemia. Finally, transplantation of hematopoietic cells carrying transgenes yielding red fluorescent erythrocytes and green fluorescent leukocytes showed that HCT is sufficient to rescue the MLD, that recipient hematolymphoid tissues were repopulated by donor-derived cells, and that donor blood cell lineages can be independently visualized in living recipients. Together, these results establish transplantation assays to test for HSC function and oncogenic transformation in zebrafish.

Description: Introduction IPI-145 is an oral, potent PI3K-δ,γ inhibitor currently in development for the treatment of hematologic (heme) malignancies. Biochemical /cellular and whole blood assays indicate that differential inhibition of the PI3K-δ and PI3K-γ isoforms is possible. An ongoing Phase 1 study (ClinicalTrials.gov NCT01476657) is evaluating patients (pts) with advanced heme malignancies and includes a subset of pts with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Preliminary results from the R/R CLL pts are reported here. Methods and Patients This Phase 1 study is designed to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and activity of orally administered IPI-145 BID in 28-day cycles. Sequential cohorts of pts with heme malignancies were enrolled in the dose escalation (DE) phase (completed), with 75 mg BID identified as the MTD. Two expansion cohorts (ECs) with R/R CLL pts are ongoing and examine 75 mg BID (MTD) and 25 mg BID; the latter dose was selected based on PK/PD showing complete suppression of PI3K-δ (〉IC90) and inhibition of PI3K-γ (≥ IC50) at steady state. Of note, CLL pts with pancytopenia and/or prior exposure to PI3K- or BTK-inhibitors are allowed in these ECs. An EC of high-risk, treatment-naïve CLL pts is also ongoing at 25 mg BID. CLL responses are evaluated based on modified IWCLL (2008) criteria. Results As of July 2013, 155 pts have enrolled, including 44 pts with R/R CLL. Within the R/R CLL pts, 77% were male and 23% female, with a median (range) age of 67 years (51-82), and 93% with a baseline ECOG ≤1. Thirty-three (75%) R/R CLL pts had ≥3 prior systemic therapies and 62% were 50% reduction in adenopathy by CT assessment) occurred in 79% of pts after 2 treatment cycles. Best overall response (based on investigator assessment per IWCLL) in evaluable pts to date (median [range] number of cycles 5.1 [1-21.1]) is 52%, with 1 CR, 15 PR, 14 SD and 1 PD. The ORR for the 19 evaluable pts treated at ≤25 mg BID is 53% (10/19; including 1 CR) and 7 of the 8 SD pts achieving nodal response. Resolution of lymphocytosis may lead to an increase in best ORR for SD pts who remain on study. R/R pts with high-risk disease (TP53 mut/17pdel) had similar ORR. Conclusions IPI-145, an oral, potent PI3K-δ,γ inhibitor, appears well tolerated and has shown promising clinical activity in pts with R/R CLL across the range of doses examined. The PK/PD and clinical activity suggest that 25 mg BID is a biologically active dose in R/R CLL, and this dose has been selected for an upcoming randomized Phase 3 trial in R/R CLL. Updated data from treatment-naïve CLL pts who received IPI-145 at 25 mg BID and R/R CLL pts who received IPI-145 at 25 mg and 75 mg BID will be presented. Disclosures: Flinn: Infinity Pharmaceuticals, Inc.: Consultancy, Research Funding. Patel:Lilly, Medivation: Honoraria, Research Funding, Speakers Bureau; Infinity Pharmaceuticals, Inc.: Research Funding. Kahl:Infinity Pharmaceuticals, Inc.: Consultancy, Research Funding. Horwitz:Celgene, Allos, Seattle Genetics, Bristol-Myers Squibb, Genzyme, Kyowa, Janssen, Johnson & Johnson, Millenium: Consultancy; Celgene, Allos, Seattle Genetics, Kyowa, Infinty, Millenium: Research Funding. Foss:Eisai, Celgene, Spectrum, Millenium: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding. Oki:Infinity Pharmaceuticals, Inc.: Research Funding. Porcu:United States Cutaneous Lymphoma Consortium (USCLC) Cutaneous Lymphoma Foundation (CLF): Membership on an entity’s Board of Directors or advisory committees; Infinity Pharmaceuticals, Inc.: Research Funding. Sweeney:Infinity Pharmaceuticals, Inc.: Employment. Allen:Infinity Pharmaceuticals, Inc.: Employment. Faia:Infinity Pharmaceuticals, Inc.: Employment. Harris:Infinity Pharmaceuticals, Inc.: Employment. Dunbar:Infinity Pharmaceuticals, Inc.: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Kelly:Infinity Pharmaceuticals, Inc.: Employment. O'Brien:Infinity Pharmaceuticals, Inc.: Research Funding.

Description: Background: The neoplastic B cells of indolent non-Hodgkin lymphoma (iNHL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) rely upon the support of non-neoplastic cells within their microenvironment for proliferation and survival. Support cells include T cells, myeloid-derived cells, and mesenchymal stromal cells, which provide phosphoinositide-3 kinase (PI3K)-dependent survival and growth signals for the neoplastic cells, as well as signals that maintain the tumor microenvironment (TME). Duvelisib (IPI-145) is an oral inhibitor of PI3K-δ,γ in clinical development for iNHL and CLL/SLL. To better understand the roles of the PI3K-δ and PI3K-γ isoforms in mediating signaling between the tumor and TME cells in B-cell malignancies, Infinity’s highly potent (low nM) PI3K isoform-selective compounds that target either PI3K-δ or PI3K-γ with 〉100-fold selectivity over the other PI3K isoforms were utilized in in vitro experiments. Methods/Results: A mixture of cytokines (CD40L/IL-2/IL-10) was utilized in an assay that recapitulated TME-induced malignant B-cell proliferative responses. Duvelisib inhibited CD40L/IL-2/IL-10-induced proliferation of primary CLL cells with an average IC50 in the sub-nanomolar range. The use of PI3K isoform-selective inhibitory compounds revealed these proliferative signals are PI3K-δ dependent, as the PI3K-δ-selective inhibitor was more active than the PI3K-γ-selective inhibitor. While these experiments established the direct PI3K-δ dependence of TME-derived cytokines on CLL cell proliferation, the role of PI3K-γ in key functions such as the directed migration of normal immune cells of the TME was also tested. We hypothesized that chemokines that recruit immune cells to the TME would signal through G-protein coupled receptors linked to PI3K-γ. The stromally-derived chemokine CXCL12 resulted in upregulation of phospho (p)-AKT in both the CD3+ T-cell and CLL-cell populations in CLL patient total peripheral blood mononuclear cells (PBMCs). Using isoform-selective inhibitors, the increase in CXCL12-induced pAKT in CD3+ T cells was found to be mediated by PI3K-γ. Interestingly, within the malignant B-cell population, the increase in CXCL12-induced pAKT was PI3K-δ dependent, suggesting that CXCL12 signals through different PI3K isoforms in these varying cell types. Chemotactic assays demonstrated reduced migration of total CLL PBMCs towards CXCL12 in the presence of combined PI3K-δ and PI3K-γ inhibition by duvelisib. Flow cytometric analyses of the migrating populations revealed that the greatest effect of duvelisib on CXCL12-induced migration occurred primarily within the T-cell population. Utilizing PI3K isoform-selective compounds, the inhibition of T-cell migration toward CXCL12 was found to be a PI3K-γ mediated process, as the PI3K-γ-selective inhibitor was more potent than the PI3K-δ-selective inhibitor in blocking T-cell migration. Myeloid-derived cells and mesenchymal stromal cells can also support CLL cell survival as components of the TME. Recent reports suggest that CLL cytoprotective nurse-like cells may have an M2 polarization and be similar to the immunosuppressive myeloid-derived suppressor cells found in some solid tumors [Gianonni et al. Haematologica 2014, 99(6)]. To model these TME components, mouse bone marrow cells were differentiated into macrophages with murine MCSF and IL-4 (M2–polarized). CXCL12-induced pAKT in these M2 cells, which express CXCR4, was more potently inhibited by duvelisib and the PI3K-γ-selective inhibitor than the PI3K-δ-selective inhibitor. Finally, co-cultures of M2 macrophages with CLL cells led to extended CLL cell survival. These data show that CXCL12 mediated-M2 activation is dependent upon PI3K-γ and that M2-cells can act to support CLL cell survival. Conclusions: T cells and myeloid cells provide a survival and proliferative advantage to malignant CLL cells within the TME. The role of PI3K-γ in the migration and activation of these cells supports the potential for therapeutic benefit from inhibition of PI3K-γ. By inhibiting both the PI3K-δ and PI3K-γ isoforms, duvelisib is uniquely positioned to inhibit key signals important in the pathogenesis of B-cell malignancies. Disclosures Peluso: Infinity Pharmaceuticals, Inc.: Employment. Faia:Infinity Pharmaceuticals, Inc.: Employment. Winkler:Infinity Pharmaceuticals, Inc.: Employment. Patel:Infinity Pharmaceuticals, Inc.: Employment. Brophy:Infinity Pharmaceuticals, Inc.: Employment. White:Infinity Pharmaceuticals, Inc.: Employment. Douglas:Infinity Pharmaceuticals, Inc.: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Palombella:Infinity Pharmaceuticals, Inc.: Employment. McGovern:Infinity Pharmaceuticals, Inc.: Employment. Kutok:Infinity Pharmaceuticals, Inc.: Employment.

Description: Introduction: Peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) are uncommon lymphoid malignancies. Approved agents in the relapsed setting have overall response rates (ORR) in the range of 25-35%. Phosphoinositide-3-Kinases (PI3K) are pivotal in cell signaling and regulate multiple cellular functions relevant to oncogenesis. PI3K-δ and PI3K-γ isoforms are preferentially expressed in leukocytes with distinct roles in T-cell function. PI3K-δ and PI3K-γ are central to the growth and survival of certain T-cell malignancies and inhibition of PI3K is a therapeutic strategy for PTCL and CTCL. Duvelisib (IPI-145), an oral inhibitor of PI3K-δ and PI3K-γ, was studied in a phase 1 trial in hematologic malignancies with disease-specific expansion cohorts at the maximum tolerated dose (MTD). Responses were seen in a substantial number of patients with relapsed or refractory PTCL and CTCL. Methods: This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of duvelisib administered twice daily (BID), continuously in 28-day cycles. Patients with relapsed or refractory leukemia or lymphoma received doses ranging from 8 mg to 100 mg BID. A disease-specific cohort at the MTD included PTCL and CTCL patients. The pharmacodynamics of duvelisib were assessed by early positron-emission tomography (PET) in a subset of patients and in serum through evaluation of a panel of cytokines, chemokines, and matrix metalloproteinase. Results: Thirty-three patients with TCL (17 CTCL, 16 PTCL) received duvelisib primarily at the MTD of 75 mg BID (25 mg, n=1; 50 mg, n=1; 60 mg, n=4; 75 mg, n=25; 100 mg, n=2). The median age was 64 years (range: 34-86), and the median number of prior therapies was 4 (range: 1-11). The median time from last prior therapy to first dose of duvelisib was 1.05 months (range: 0.2-36). Thirty-one patients were evaluable for efficacy, with an ORR of 42% (13/31). The ORR in PTCL was 47% (7/15, 2 complete responses [CR], 5 partial responses [PR]) and in CTCL 38% (6/16, 6 PR). The median time to response was 1.9 months (range: 1.5-3.8). Median overall survival (OS) was 36.4 weeks (95% CI: 18.6, –) for patients with PTCL. The median OS was not yet reached for patients with CTCL. The median number of treatment cycles was 3.1 (range: 0.5-12.5), with 14 (42%) on treatment ≥4 cycles (16 weeks). Pharmacodynamic results showed that within 8 days of starting treatment with duvelisib, modulation of serum cytokines and chemokines known to play a role in leukocyte migration and support the tumor microenvironment was observed. Furthermore, a reduction in standard uptake value (SUV) from baseline was observed in 6/11 patients evaluated by PET at Cycle 1 Day 22. (All 6 patients with reduction in SUV received duvelisib ≥60 mg BID). Twenty-six (79%) patients had adverse events (AEs) ≥Grade 3, with the most common (≥10%) being increased ALT/AST (n=12, 36%), rash (combined terms) (n=7, 21%), and neutropenia (n=5, 15%). Ten (30%) patients discontinued treatment due to an AE, with the most common (〉1 patient) being increased ALT/AST [n=5 (4 CTCL, 1 PTCL), 15%]. Three TCL patients died on treatment or within 30 days of the last dose of duvelisib, one due to disease progression, one who declined supportive therapy, and one due to HSV pneumonia (patient was not receiving HSV prophylaxis). Conclusions: Duvelisib has shown clinical activity in patients with relapsed/refractory TCL (ORR 42%, including 2 CR) with an acceptable safety profile that supports continued assessment in this heavily pretreated patient population. The preliminary results support further evaluation of duvelisib in patients with TCL, including additional studies in both CTCL and PTCL to determine the optimal dose and identify appropriate combination therapy. Disclosures Horwitz: Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, SpectrumConsulting: Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Millennium, seattle genetics: Consultancy, Honoraria, Research Funding. Off Label Use: ipi-145 is not an approved drug. Porcu:Actelion (e), Cutaneous Lymphoma Foundation (h), United States Cutaneous Lymphoma Consortium (h), Infinity (d), Celgene (d), : Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Infinity Pharmaceuticals: Consultancy. Kahl:Infinity Pharmaceuticals: Consultancy, Research Funding. Sweeney:Infinity Pharmaceuticals: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Douglas:Infinity Pharmaceuticals, Inc.: Employment. Allen:Infinity Pharmaceuticals: Employment. Kelly:Infinity Pharmaceuticals: Employment. Foss:Eisai, Celgene, Seattle Genetics: Consultancy, Research Funding, Speakers Bureau.