ALBERT

Description: Abstract 3645 Introduction: PI3Kδ drives proliferation and survival in malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor of PI3Kδ that has shown considerable monotherapy activity when given at dose levels of ≥100 mg BID in patients with heavily pretreated indolent non-Hodgkins lymphoma (iNHL). Methods and Patients: This Phase 1 combination study has evaluated repeated 28-day cycles of GS-1101 with rituximab and/or bendamustine in patients with previously treated iNHL. GS-1101 was administered starting on Day 1 of Cycle 1 with rituximab (R) (375 mg/m2 given weekly for 8 doses) (GS-1101/R regimen), with bendamustine (B) (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/B regimen), or in combination with R (375 mg/m2, on Day 1 of each cycle for 6 cycles) and B (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles (GS-1101/BR regimen). Initial cohorts received a GS-1101 dose of 100 mg/dose BID. Thereafter, all patients received a GS-1101 dose of 150 mg/dose BID. Tumor response was evaluated according to standard criteria (Cheson 2007). Chemokine/cytokine plasma levels were assessed at baseline and on Day 28 of therapy using multiplexed bead suspension arrays. Results: The study enrolled 76 patients with iNHL. Patient characteristics, histological sub-typing, safety, and efficacy results are depicted in the table. The majority of patients were 〉60 years of age and had undergone extensive prior therapy. Grade ≥3 adverse events and lab abnormalities were generally consistent with those expected with each of the single agents. Lymph node shrinkage was rapid and all evaluable patients had reductions in lymphadenopathy, resulting in overall response rates (ORR) of 77%, 85%, and 77% for the GS-1101/R, GS-1101/B, and GS-1101/BR regimens, respectively. Complete responses (with bone marrow confirmation) were observed in 13%, 16%, and 30% of patients. With median follow-up duration ranging from 28 to 48 weeks, 1-year progression- free survival (PFS) rates were 〉75% in all treatment groups. Disease-associated chemokines/cytokines were commonly elevated at baseline and were significantly reduced by GS-1101-based combination treatment. Conclusions: A lack of overlapping toxicities allows the oral PI3Kδ inhibitor, GS-1101, to be delivered at the full single-agent starting dose when coadministered with chemoimmunotherapies in heavily pretreated patients with iNHL. GS-1101-based combination therapy with rituximab and/or bendamustine offers major and rapid reductions in lymphadenopathy. All 3 regimens provide durable tumor control. The data from this trial support the development of Phase 3 combination trials of GS-1101 with rituximab- and/or bendamustine-containing regimens in patients with iNHL. Disclosures: Fowler: Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Phase I trial of GS-1101, a PI3K delta inhibitor, in B cell malignancies. de Vos:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Schreeder:Gilead Sciences: Research Funding. Leonard:Gilead: Consultancy. Coutre:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Sharman:Gilead: Honoraria, Research Funding. Boccia:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Holes:Gilead: Employment. Lannutti:Gilead Sciences Inc: Employment. Johnson:Gilead Sciences: Employment. Jahn:Gilead: Employment. Miller:Gilead: Employment. Godfrey:Gilead Sciences: Employment.

Description: Introduction: As outcomes in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) remain suboptimal, new, effective treatment options with a favorable safety profile are needed. Ibrutinib is a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase (BTK), a key component of B-cell signaling involved in B-cell survival, proliferation and function. In lymphomas, ibrutinib is FDA-approved for treatment of mantle cell lymphoma in pts with ≥1 prior therapy. A phase 1 dose-escalation study with ibrutinib showed single-agent activity in pts with R/R B-cell malignancies (overall response rate [ORR] 60%; complete remission [CR] in 16%) including FL (Advani JCO 2013). In this trial, the 560 mg/day fixed dose was well tolerated and led to full BTK occupancy. We evaluated the efficacy, safety, and tolerability of single-agent ibrutinib by low- vs. high-dose groups with longer follow-up in pts with relapsed FL. Methods: Data were analyzed for pts with R/R FL (N=16) treated with oral ibrutinib in the phase I study (PCYC-04753), where pts received escalating doses of ibrutinib 1.25-12.5 mg/kg/day per cycle (1 cycle = 28 days + 7 days rest) or continuous doses of ibrutinib 8.3 mg/kg/day or 560 mg/day fixed dose (1 cycle = 35 days). Pts with stable disease or better, who received therapy for 6 months, continued ibrutinib at a fixed dose of 560 mg/day in the extension study (PCYC-1103) until progression or unacceptable toxicity. Pt data categories included low-dose (1.25 mg/kg/day, 2.5 mg/kg/day, or 5 mg/kg/day) or high-dose (8.3 mg/kg/day or 12.5 mg/kg/day) groups. Results: Eight pts each were categorized into low-dose and high-dose groups. Baseline characteristics were similar, but median treatment duration was longer for the high-dose group (Table; 12 vs. 4 months). Increased ORR (63% vs. 25%) and CR rates (38% vs. 0%) were observed in the high-dose compared with low-dose group (Table). Median duration of response (DOR) was longer in the high-dose group (12 vs. 3 months), as was median progression-free survival (PFS; 24 vs. 9 months). Median overall survival (OS) was not reached (NR) in either group. Grade ≥3 adverse events (AEs) occurred in 3 pts in each group. Common grade ≥3 AEs reported in ≥3 pts in the combined groups included (low-dose, high-dose) diarrhea (n=2, 6), fatigue (n=3, 4), nausea (n=2, 4), cough (n=3, 2), myalgia (n=1, 3), headache (n=0, 3), muscle spasms (n=1, 2), pruritus (n=0, 3), and rash (n=0, 3). Serious AEs occurred in 3 pts in the low-dose and 1 pt in the high-dose group. AEs leading to treatment discontinuation occurred in 2 pts in each group. No fatal AEs occurred. Among 4 pts (high-dose group) receiving ibrutinib beyond 1 year (range, 18 to 61 months), no unexpected or increased AEs were observed; 1 pt experienced 2 grade 3 AEs (non-cardiac chest pain and vomiting), both within 60 days from start of treatment and lasting 1 day. No other grade ≥3 AEs occurred among these 4 pts. Conclusions: Higher doses of single-agent ibrutinib were associated with increased response rates and prolonged PFS in pts with R/R FL. A higher dose was not associated with increased AEs or with cumulative toxicity during extended therapy. In the current analysis, pts with FL derived the most benefit from ibrutinib doses at 8.3 mg/kg/day or higher. A study testing single-agent ibrutinib at 560 mg/day in pts with R/R FL is ongoing (Bartlett Blood 2014) as is a phase 2 study evaluating ibrutinib 560 mg/day in chemoimmunotherapy refractory FL. Table 1. Patient Characteristics and Efficacy Low dose(n=8) High dose(n=8) Median age, yrs (range) Age ≥ 70 yrs, n (%) 57 (48-70)1 (13) 62.5 (41-71)1 (13) Median no. of prior therapies (range) 3 (1-4) 2 (1-5) Ann Arbor stage III/IV disease, n (%) 6 (75) 6 (75) FLIPI score, % (low / intermediate / high)* 25 / 38 / 38 13 / 38 / 50 Median treatment duration, months (range) 3.8 (0.5-11.1) 12.4 (0.2-61.5) ORR, n (%) CR, n (%) 2 (25)0 (0) 5 (63)3 (38) Median DOR, months (range) n=2; 3.4 (1.8-4.9) n=5; 12.3 (4.8-51.3) Median PFS, months (95% CI) 9.2 (0.5, 13.4) 23.7 (2.2, NE) 10-month PFS, % 35.7 70 Median OS, months (95% CI) NR NR 10-month OS, % 100 100 *FLIPI scores from baseline data. NE, not estimable Disclosures Off Label Use: single-agent ibrutinib therapy in patients with relapsed FL. Boyd:Celgene: Research Funding, Speakers Bureau; Genentech: Research Funding; US Oncology: Research Funding; GSK: Research Funding. Sharman:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics, Inc.: Research Funding; Janssen: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Calistoga: Honoraria. Smith:Pharmacyclics: Consultancy; Celgene: Consultancy. Clow:Pharmacyclics LLC, an AbbVie Company: Employment. Chu:Pharmacyclics LLC, an AbbVie Company: Employment.

Description: Bcl-2 is an anti-apoptotic protein that has been closely linked to chemotherapy resistance and inferior survival in patients (pts) with CLL. Preliminary studies showed that oblimersen, an antisense oligonucleotide that targets Bcl-2, enhanced apoptosis induced by fludarabine (Flu), dexamethasone, and rituximab in cultured CLL cells. In a Phase 1 study, oblimersen displayed modest single-agent activity in CLL pts who had received extensive prior therapy. We conducted a randomized, multinational, Phase 3 trial of chemotherapy given with or without oblimersen in pts with advanced CLL. Eligibility included: symptomatic disease; intermediate or high-risk Rai stage; ≥ 1 Flu-containing regimen; ECOG PS ≤ 2; adequate organ function. Exclusions: stem cell/allogeneic transplant; autoimmune anemia/thrombocytopenia. Pre-randomization strata: prior treatment (1 or 2 vs. ≥ 3 regimens); response vs. refractory to prior Flu; and response duration to last therapy (〉 or ≤ 6 mos). All pts received Flu 25 mg/m2/d, plus cyclophosphamide (Cy) 250 mg/m2/d, daily for 3 days. Pts randomized to oblimersen received 3 mg/kg/d x 7 days by IV infusion, beginning 4 days before Flu/Cy and on each day of Flu/Cy treatment. Subsequent cycles were repeated every 28 days, for a maximum of 6 cycles, or to the time of CR, intolerable toxicity, or progression. All pts received prophylactic filgrastim, TMP/SMZ, and acyclovir. Response assessment was conducted at every cycle during treatment, and every 2 months thereafter for up to 36 months. The primary endpoint of the study was to compare the proportion of pts who achieved complete (CR) and nodular partial (nPR) responses. Secondary endpoints included: overall response rates (CR/nPR/PR); durable responses; response duration; time-to-progression; clinical benefit; and safety. Bone marrows in responding pts underwent central blinded review. A total of 241 pts were randomized; the last patient was enrolled in the 2nd quarter 2003. All pts have completed ≥ 1 year of follow-up, and results of this trial will be presented.

Description: Abstract 156 Background Bruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling and is essential for normal B-cell development. Subtypes of non-Hodgkins lymphoma (NHL) may be dependent on chronic activation of the BCR pathway and primary follicular lymphoma (FL) cells have been found to maintain enhanced signaling when compared to normal B-cells (Irish JM, et al. Blood 2006; 108: 3135). Ibrutinib is an orally administered, covalently-bound inhibitor of BTK which induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. Based on promising preclinical data in B-cell malignancies, a phase I study was conducted to test the safety, tolerability, pharmacokinetics, and pharmacodynamics of ibrutinib in relapsed NHL. We report the long-term tolerability and sustained activity of ibrutinib in FL patients in this study with extended follow-up. Methods Adult patients with relapsed or refractory B-cell lymphoma were eligible for trial entry and 16 patients with FL were enrolled in this Phase I study. Ibrutinib was administered orally with dose escalation according to protocol-defined dose-limiting toxicities (DLT) to define a maximum tolerated dose (MTD) or until 3 dose levels above attainment of full BTK occupancy. A 28-day on/7-day off (intermittent) schedule was evaluated in 5 cohorts (1.25–12.5 mg/kg PO qd) and a once daily oral dose (without a drug holiday) in 2 cohorts (8.3 mg/kg and 560-mg fixed dose). Patients were evaluable for safety if they received study drug. Efficacy was evaluated in all patients who received 2.5 mg/kg or higher (which achieves full BTK occupancy) and had one on-study imaging assessment. Efficacy was also analyzed at higher doses to determine if there was improved efficacy. Responses were assessed every 2 months using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results Median age 60 (41–71), equal numbers of males and females, median time from diagnosis 54 months (19–186), median number of prior therapies 3 (1–5) including: stem cell transplantation (6%), alkylators (88%), anthracyclines (56%), nucleoside analogs (19%), and rituximab (100%). FLIPI scores at baseline: low risk = 19%, intermediate risk = 37%, high risk = 44%. Treatment-emergent AEs occurring in ≥ 25% included: diarrhea (50%), fatigue (44%), nausea (38%), cough (31%) and myalgia (25%). Observed grade 3 AEs included: anemia, anxiety, hypersensitivity, hypokalemia, hypophosphatemia, decreased neutrophil count, non-cardiac chest pain, pancytopenia, pneumonia and vomiting (one event each). A Grade 4 hypokalemia occurred and was considered to be related to study drug by the investigator. One case of myelodysplastic syndrome occurred 29 days after the last dose of ibrutinib in a patient with pre-existing anemia and multiple lines of prior treatment and was considered to be unrelated by the investigator. One patient in the 2.5 mg/kg/day intermittent cohort experienced DLTs of grade 2 neutropenia resulting in the ibrutinib dose being held 〉 7 days and a grade 4 hypokalemia. One patient in the 8.3 mg/kg/day intermittent cohort experienced a Grade 3 hypersensitivity reaction. No DLTs were observed in the 12.5 mg/kg/day cohort and the MTD was not reached. In the 16 patients with FL, 11 patients received ibrutinib at 2.5 mg/kg or higher and were evaluable for efficacy (2 patients at 2.5 mg/kg, 1 at 5 mg/kg, 3 at 8.3 mg/kg intermittent, 3 at 12.5 mg/kg, 2 at 8.3 mg/kg continuous dosing). Median time on ibrutinib was 7 months (0–29). Overall response rate (ORR) 54.5% (3 CRs, 3 PRs), duration of response (DOR) 12.3 months, median PFS 13.4 months. In the 9 patients who received ibrutinib at 5 mg/kg or higher, the median time on ibrutinib, ORR and DOR were similar to the efficacy in the 11 patients. However, there was a slight trend toward improved PFS of 19.6 months; 2 patients are still responding to ibrutinib at 25 and 29 months. Conclusions The BTK inhibitor ibrutinib (PCI-32765) is well tolerated and active in patients with relapsed FL. Based upon drug occupancy and clinical responses, a dose of 5 mg/kg/day or above is recommended for phase II studies. Extended dosing did not appear to increase toxicity and response rates improved with continued treatment in some patients. Phase II studies with ibrutinib in FL are planned. Disclosures: Advani: Pharmacyclics, Inc: Research Funding. Sharman:Celgene: Consultancy; Pharmacyclics: Honoraria; Calistoga: Honoraria; Portola pharmaceuticals: Consultancy. McGreivy:pharmacyclics: Employment. Kunkel:Pharmacyclics: Employment, Equity Ownership. Troung:Pharmacyclics, Inc: Employment, Equity Ownership. Zhou:Pharmacyclics, Inc.: Employment, Equity Ownership.

Description: Abstract 191 Introduction: PI3Kdelta drives proliferation and survival in malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor of PI3Kdelta that has shown considerable monotherapy activity when given at dose levels of 3100 mg BID in patients with heavily pretreated CLL. Methods and Patients: This Phase 1 combination study has evaluated repeated 28-day cycles of GS-1101 in combination with rituximab and/or bendamustine in patients with previously treated CLL. GS-1101 was administered starting on Day 1 of Cycle 1 with rituximab (R) (375 mg/m2 given weekly for 8 doses) (GS-1101/R regimen), with bendamustine (B) (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/B regimen), or in combination with R (375 mg/m2, on Day 1 of each cycle for 6 cycles) and B (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/BR regimen). Initial cohorts of patients received a GS-1101 dose of 100 mg/dose BID in the GR or GB regimens. Thereafter, all patients received a GS-1101 dose of 150 mg/dose BID. Tumor response was evaluated according to standard criteria (Hallek 2008). Chemokine/cytokine plasma levels were assessed at baseline and on Day 28 of therapy using multiplexed bead suspension arrays. Results: The study enrolled a total of 51 patients with CLL. Patient characteristics and safety and efficacy results are depicted in the table The majority of patients had bulky adenopathy and had undergone extensive prior therapy, with virtually all patients receiving prior rituximab and many receiving prior bendamustine. Grade 33 adverse events and lab abnormalities were generally consistent with those expected with each of the single agents. Lymph node shrinkage was rapid, and almost all evaluable patients had reductions in lymphadenopathy. As reported by investigators, the overall response rates (ORR) for the GS-1101/R, GS-1101/B, and GS-1101/BR regimens were 78%, 82% and 87%, respectively. With a minimum follow-up of 340 weeks for all regimens, 1-year progression-free survival (PFS) rates were 74%, 88% and 87% in the GS-1101/R, GS-1101/B, and GS-1101/BR treatment groups, respectively. Disease-associated chemokines/cytokines were commonly elevated at baseline and were significantly reduced by GS-1101-based combination treatment. Conclusions: A favorable safety profile and lack of overlapping toxicities allows the oral PI3Kdelta inhibitor, GS-1101, to be delivered at the full single-agent starting dose when coadministered with chemoimmunotherapies in heavily pretreated patients with CLL. GS-1101-based combination therapies with rituximab and/or bendamustine offer major and rapid reductions in lymphadenopathy and durable tumor control. Based on these results, Phase 3 trials evaluating the efficacy of GS-1101 in combination with R or BR have been initiated (NCT01539512 [GS-1101/placebo+R], NCT01569295 [GS-1101/placebo+BR]). Disclosures: Coutre: Gilead: Consultancy. Off Label Use: Phase 1 trial of GS-1101 (CAL-101)-based combination therapy. Leonard:Gileade: Consultancy. Barrientos:Gilead: Research Funding. de Vos:Gilead: Consultancy. Sharman:Gilead: Honoraria, Research Funding. Holes:Gilead: Employment. Lannutti:Gilead Sciences Inc: Employment. Johnson:Gilead Sciences: Employment. Miller:Gilead: Employment. Jahn:Gilead: Employment.

Description: Introduction New therapies are needed for patients (pts) with chronic lymphocytic leukemia (CLL). BCL2 is an anti-apoptotic protein that is overexpressed in CLL and may be associated with resistance to available therapies; GDC-0199 is an orally available, selective BCL2 inhibitor. The combination of bendamustine (B) and rituximab (R) has demonstrated efficacy in relapsed/refractory (R/R) and previously untreated pts with CLL and is often used in these pts. Preclinical data suggest that GDC-0199 combined with BR may show synergistic activity in CLL. Moreover, clinical data from single-agent studies of GDC-0199, and in combination with rituximab in pts with CLL, support combining GDC-0199 with BR in this population. Data presented here are from an ongoing phase 1b study that is evaluating the maximum tolerated dose of GDC-0199 when given in combination with BR, as well as the safety, tolerability, and order of administration of this combination in R/R or previously untreated pts with CLL. Methods Pts with an ECOG PS ≤1, adequate marrow, hepatic, renal and coagulation function are being enrolled in dose finding cohorts ranging from 100 to 600 mg/day of GDC-0199 using a 3+3 dose escalation design. Pts are assigned to one of two dosing schedules (Figure 1) with GDC-0199 (Schedule A) or BR (Schedule B) introduced first, both incorporating a gradual dose ramp-up of GDC-0199 to reduce the risk of tumor lysis syndrome (TLS). Prophylaxis measures to mitigate TLS include IV hydration, treatment to prevent hyperuricemia and hospitalization. After completing combination therapy, R/R pts will continue single-agent GDC-0199 until disease progression. Previously untreated pts will continue single-agent GDC-0199 for up to 18 months. Dose-limiting toxicity (DLT) data are identified after all pts in a cohort have completed ³21 days of combination treatment at the target dose of GDC-0199 and focus on treatment emergent TLS and cytopenias. Figure 1 Figure 1. Results As of May 2014, 6 pts with R/R CLL have been enrolled in the dose finding stage of the study with a median time on study of 67 (range 43-113) days. All 6 pts were enrolled on Schedule A; 3 pts were enrolled in the 100 mg GDC-0199 cohort and 3 pts were enrolled in the 200 mg cohort. Baseline characteristics of the 6 pts are as follows: median age 67 (range 52-71) years, 3 male pts, median of 2 prior CLL therapies (range 1-3, including 4 pts with previous exposure to fludarabine, cyclophosphamide and rituximab [FCR] and 1 with previous exposure to FCR and B), beta-2 microglobulin ≥3.5 mg/L in 2 pts, and unmutated IGHV in 5 pts. Prior to starting therapy, the median lymphocyte count was 40.85 x 109 cells/L (range 2.11-169 x 109 cells/L), hemoglobin level was 101.5 g/L (range 99-134 g/L), neutrophil count was 2.54 cells/μL (range 1.81-3.8 cells/μL), and platelet count was 83.5 x 109/L (range 49-250 x 109/L). Pts were assigned to 1 of 3 TLS risk groups based on screening ALC and tumor bulk: low risk 1 pt, medium risk 4 pts, and high risk 1 pt. Cytogenetic data are available for 3 pts: 1 pt had del17p, 2 pts had del 11q, and 3 pts had del 13q. No DLTs were observed. All 6 pts have experienced adverse events (AEs, Figure 2). The most common AE was anemia with most Grade ³3 AEs being hematological toxicities (Figure 2). One serious AE of bronchitis was observed in a pt enrolled in the 100 mg GDC-0199 cohort and resolved after treatment. Two pts in the 100 mg GDC-0199 cohort discontinued BR after the 21-day DLT window secondary to treatment emergent cytopenia: 1 with neutropenia after completing 1 cycle of BR (previous treatment FCR without baseline cytopenia) and the second with thrombocytopenia after completing 3 cycles of BR (previous treatment FCR and chlorambucil with thrombocytopenia at screening). Both pts remain on single-agent GDC-0199. No TLS events (laboratory or clinical) were observed and no deaths reported. Figure 2 Figure 2. Conclusion This is the first study to evaluate the combination of GDC-0199 and BR in pts with CLL. Despite 5 pts being identified as medium or high risk for TLS, no pts developed TLS as a result of the ramp-up dosing of GDC-199 and prophylactic measures. The most frequent AEs were hematological toxicities and generally manageable; however, 2 pts had to discontinue BR (after 1 and 3 cycles) but were able to remain on GDC-0199. Dose escalation in R/R pts is continuing in order to evaluate the optimal dose/schedule with a plan to enroll previously untreated pts in the near future. Disclosures Boyd: Genentech: Research Funding; US Oncology/McKesson: Research Funding; Celgene: Consultancy. Morschhauser:Genentech: Travel grant Other; Gilead, Mundipharma, Bayer, Spectrum, Celgene: Honoraria. Wendtner:AbbVie, Genentech, Hoffman-La Roche, Mundipharma: Consultancy, Research Funding. Lymp:Genentech: Employment. Hilger:Genentech: Employment. Vosganian:Genentech: Employment. Huang:Genentech: Employment. Stilgenbauer:Genentech, Hoffman La Roche: Honoraria, Research Funding.

Description: Introduction: PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib, a selective oral inhibitor of PI3Kd, demonstrated considerable clinical activity as monotherapy in recurrent (Flinn, Blood 2014) or refractory iNHL subjects (Gopal, NEJM 2014). FDA granted accelerated approval for Idelalisib (ZYDELIG®) in patients who have received at least two prior systemic therapies with relapsed FL or SLL. This study evaluated Idelalisib in combination with rituximab, bendamustine, or both. We now present mature safety and response data with up to 4 years of follow up. Methods: Eligible patients had relapsed/refractory indolent NHL. Idelalisib (Z) was administered continuously with rituximab (R) (375 mg/m2 given weekly for 8 doses) (R/Z regimen), with bendamustine (B) (90 mg/m2 given on Days 1 and 2, for 6 cycles) (B/Z regimen), or in combination with R (375 mg/m2, on Day 1) and B (90 mg/m2 given on Days 1 and 2 of each cycle, for 6 cycles (BR/Z regimen). Initial subjects in the R/Z and B/Z groups (n=8 each), received Idelalisib 100 mg/dose BID. Thereafter, all patients received an Idelalisib dose of 150 mg/dose BID. Tumor response was evaluated according to standard criteria (Cheson 2007). The cutoff date for this analysis was June 2014, 26 months after the last patient enrolled. Results: Between April 2010 and May 2012, 79 subjects with iNHL were enrolled (including 59 with FL, 15 with SLL, and 5 with MZL). Median [range] age was 61 [37-84] years. At baseline patients had elevated beta-2 microglobulin (59%), stage IV disease (58%), bulky adenopathy (〉 5cm) (48%), anemia (Hgb

Description: BACKGROUND: PI3Kδ signaling is critical for the proliferation and survival as well as for homing and tissue retention of malignant B cells. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ with considerable activity as monotherapy and in combination with R in patients with relapsed/refractory CLL, and was recently approved for the treatment of relapsed CLL in combination with R. This report summarizes the long-term follow-up of the Phase 1 combination experience of idelalisib with chemo- and immuno-chemotherapies. METHODS: 74 subjects were sequentially enrolled into one of 5 regimens of idelalisib combined with either B (70 or 90 mg/m2 IV on D1,2 of cycles 1-6, N=18, enrolled Apr 2011-Nov 2011), BR (B: 70 mg/m2 IV on D1,2 of cycles 1-6; R: 375 mg/m2 IV on D1 of cycles 1-6, N=15, enrolled Apr 2011-Aug 2011), F (40 mg/m2 po D1-5 of cycles 1-6, N=12, enrolled Apr 2011-Aug 2011), Chl (10 mg/m2 po D1-7 x 3(min)-12(max) cycles, N=15, enrolled Mar 2012-Aug 2012), or ChlR (N=14, enrolled Mar 2012-Jul 2012). Idelalisib was administered at 100 (4 of the pts receiving B) or 150 mg po BID (all other patients) continuously. Patients on treatment after 48 weeks were eligible to continue idelalisib on an extension study. Clinical responses were evaluated according to published criteria (Hallek 2008; Cheson 2012). RESULTS: Of 74 subjects enrolled, 66% were male. Median age was 65 years, and median time since diagnosis was 8 years with a median of 3 (range 1-9) prior regimens. Overall, prior therapies included R (97%), F (78%), B (45%), and Chl (14%), and 55% of patients were refractory to last therapy. 65% of patients had Rai stage III/IV disease at enrollment. Adverse prognostic factors included del(17p) and/or TP53 mutation (30%), IGHV unmutated status (82%), NOTCH1 mutation (28%). As of 7/15/2014, the median idelalisib exposure for patients of all cohorts was 12.8 (range 1-48) months. 41 (55%) of patients completed the 48 weeks of the primary study, and 20 subjects (27%) were still on treatment on the extension study at the time of analysis. The most common reasons for discontinuation reported by investigators were adverse events (AEs) (15, 20%) or progressive disease (PD) (12, 16%). There were 13 deaths reported on study; 4 patients experienced PD before death. Selected treatment-emergent AEs (any Grade/≥Gr 3, regardless of causality) included diarrhea/colitis (51%/18%), pyrexia (47%/5%), fatigue (35%/7%), cough (35%/0%), nausea (31%/1%), pneumonia (23%/14%), rash (22%/7%), dyspnea (19%/3%), and pneumonitis (3%/3%). Elevation of liver transaminases (TA, any Grade/≥Gr 3) was seen in 37%/14%. Of those, only 1 patient discontinued the study because of (recurrent) TA elevation. Richter’s transformation as category of progressive disease was reported in 1 patient (3%). The ORR was 82% for all 74 patients with a CR rate of 10%. 4 of 74 patients (5%) were not evaluable because of missing follow-up assessments. Among 69 subjects with genetic data available, the ORR in the 22 subjects with either del(17p) and/or TP53 mutation was 68% vs. 87% among 47 subjects with neither aberration. The overall median PFS was not reached at the time of analysis (Figure 1); KM estimate of PFS was 57% [43-72%, 95% CI] at 24 months. Overall median time to response was 1.9 months, and overall median DOR was not yet reached. CONCLUSIONS: These preliminary results in patients with relapsed or refractory disease and multiple prior therapies suggest that idelalisib can be combined with B, BR, F, Chl, and ChlR with acceptable safety and that these combinations have substantial clinical activity. A Phase 3 study evaluating the combination of idelalisib with BR in relapsed CLL is ongoing (NCT01732926). Figure 1: Overall PFS Figure 1:. Overall PFS Disclosures Barrientos: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Coutre:Gilead Sciences: Research Funding. de Vos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Kim:Gilead Sciences: Employment, Equity Ownership. Viggiano:Gilead Sciences: Employment, Equity Ownership. Jahn:Gilead Sciences: Employment, Equity Ownership. Furman:Gilead Sciences: Research Funding.