ALBERT

Description: Introduction: PI3Kδ signaling is critical for the proliferation, survival and homing/tissue retention of malignant B cells. Idelalisib is a first-in-class, highly selective, oral inhibitor of PI3Kδ 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 anti-CD20 antibodies. Methods: This Phase 1 study evaluated idelalisib for relapsed/refractory CLL continuously given at 100 mg BID (4 of the pts receiving R) or 150 mg BID (all other pts) in combination with a total of 8 infusions of rituximab (R, 375 mg/m2 weekly x 8), or a total of 12 infusions of ofatumumab (O, 300mg initial dose either on Day 1 or Day 2 relative to the first dose of idelalisib, then 1,000 mg weekly x 7, then 1,000 mg every 4 wks x 4). Pts on treatment after 48 weeks were eligible to continue idelalisib on an extension study. Clinical response was evaluated according to published criteria (Hallek 2008; Cheson 2012). Results: 40 pts (12F/28M) with a median (range) age of 66 (43-87) years and a WHO performance status of 0 (24, 60%) or 1 (16, 40%) were enrolled. 19 pts received idelalisib in combination with R and 21 with O. Adverse disease characteristics (n, %) included Rai Stage III/IV (20, 50%), bulky lymphadenopathy (23, 58%), refractory disease (15, 38%), multiple prior therapies (median 2, range: 1-9). Almost all pts (39, 98%) had at least 1 prior therapy containing R, and 3 of the 21 pts (14%) receiving idelalisib + O had received prior O. 63% of the pts receiving idelalisib + R, and 48% of the pts receiving idelalisib + O were refractory to R. Prior therapies also included alkylating agents (31, 78%, [bendamustine: 20, 50%]) and purine analogs (31, 78%, [fludarabine: 28, 70%]). Data available from 39 pts showed that 11 (28%) pts had evidence of del(17p) and/or TP53 mutations and 30 (75%) had unmutated IGHV. As of 7/15/2014, the median (range) treatment duration was 18 (0-44) months. 23 (58%) pts have completed the primary study and enrolled into the extension study. Primary reasons for study discontinuation (as reported by investigators) included disease progression (14, 35%), adverse events (AEs) (12, 30%), investigator request (3, 8%), withdrawal of consent (n=1), BMT (n=1). There were a total of 8 deaths on study: 2 deaths occurred after disease progression, and 6 pts died because of AEs (all assessed as unrelated/unlikely related to idelalisib by investigators). A total of 4 pts (10%) were continuing idelalisib treatment on the extension study at time of analysis. Selected treatment-emergent AEs (any Grade/≥Gr 3, regardless of causality) included diarrhea/colitis (55%/23%), cough (40%/3%), pyrexia (40%/3%), dyspnea (30%/3%), fatigue (25%/0%) nausea (25%/0%), rash (20%/0%), pneumonia (20%/18%), and pneumonitis (8%/5%). Elevation of liver transaminases (TA, any Grade/≥Gr 3) was seen in 30%/10%. Re-exposure to idelalisib after resolution of TA elevation generally was successful; only 1 patient discontinued the study because of (recurrent) TA elevation. Other AEs leading to study discontinuation and reported as possibly/probably related to idelalisib included diarrhea/colitis (4, 10%), pyrexia (n=1), interstitial lung disease (n=1), pneumonia (n=1), rash (n=1), psoriasis (n=1). Secondary malignancies leading to discontinuation (all reported as unrelated) were breast cancer (n=1), recurrent colon cancer (n=1), AML (n=1). There was no obvious overall difference in the toxicity reported for pts receiving idelalisib with rituximab compared to those with ofatumumab. The ORR (N=40) was 83% (33/40), with 2 CRs (5%) reported. Median PFS (N=40) and duration of response (DOR) (n=33) were 24 months. Median (range) time to response was 1.9 (range 1.7-16.9) months. Median overall survival (OS) has not been reached with a KM estimate for OS of 80% at 24 months. For the 11 pts with del(17p) and/or TP53 mutations, the response rate was 73%, and the median PFS and DOR were 20 and 24 months, respectively. Conclusions: Combinations of idelalisib with anti-CD20 antibodies such as R or O represent non-cytotoxic regimens with acceptable safety profiles and considerable activity resulting in durable tumor control in pts with relapsed/refractory CLL, including those with high risk factors such as del(17p) or TP53 mutations. A Phase 3 trial evaluating the efficacy of idelalisib in combination with ofatumumab is ongoing (NCT01659021). Disclosures Furman: 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.. de Vos:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Fowler:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Kim:Gilead Sciences: Employment, Equity Ownership. Viggiano:Gilead Sciences: Employment, Equity Ownership. Jahn:Gilead Sciences: Employment, Equity Ownership. Coutre:Gilead Sciences: Research Funding.

Description: This study was designed to evaluate the efficacy and safety of bortezomib as monotherapy in patients (pts) with indolent B-cell lymphoma who have relapsed following, or who are refractory to, rituximab therapy. A total of 60 patients enrolled and 59 were treated with 1.3 mg/m2 of bortezomib (IV bolus over 3–5 secs) Days 1, 4, 8, and 11 for up to eight 21-day cycles; pts with a CR could receive 4 additional cycles. Pts with

Description: Background Entospletinib (GS-9973) is an orally bioavailable, selective inhibitor of spleen tyrosine kinase (Syk). Syk is a mediator of B-cell receptor signaling in normal and transformed B-cells. Targeting the B-cell receptor (BCR) signaling pathway has been a successful therapeutic strategy for chronic lymphocytic leukemia (CLL), with both ibrutinib, an inhibitor of BTK (BTKi) and idelalisib, an inhibitor of PI3Kdelta (PI3Ki), approved for this indication. Entospletinib activity in CLL was recently reported, and preclinical data suggested that entospletinib may be effective even in the context of resistance to BTK therapy, including that conferred by activation of PLCγ2. (Liu, Blood -2015-02-626846) Methods GS-US-339-0102 is an ongoing phase2 trial of entospletinib in CLL and NHL (NCT01799889). The study protocol was amended to add 40 patients in each of 2 CLL cohorts who have been previously treated with BCR signaling pathway (BTK/PI3K) inhibitors. These patients were treated with entospletinib monotherapy (400mg BID) and evaluated using modified Hallek/IWG-CLL criteria every 2-3 months as previously described in Sharman, Blood 2015:125(5). Results As of July 20, 2015, 8 patients with preceding BCR pathway signaling inhibitor treatment have been enrolled, 5 with preceding BTKi therapy (4 with ibrutinib, 1 with AVL-292) and 3 with preceding PI3Ki therapy (idelalisib). The median duration of preceding BTKi treatment was 51 weeks (range 2-85 weeks) and the median duration of preceding PI3Ki treatment was 106 weeks (range 74-168 weeks). Two patients had progressed on prior BTKi and 2 were intolerant (cause missing for 1 patient), while 2 patients progressed on PI3Ki and 1 was intolerant. All 5 patients with preceding BTKi and 2 out of 3 patients with prior PI3Ki remain on entospletinib treatment. Of the 5 patients who were previously treated with BTKi, the ongoing duration of treatment with entospletinib is 8, 8, 13, 25, and 39 weeks. For the 3 patients with preceding PI3Ki, two patients have ongoing treatment of 18 and 26 weeks; one patient stopped treatment and died after 23 weeks due to a cardiac arrest that is not believed to be related to the study drug. The most common treatment-emergent AEs (N=number; any Grade/≥Gr 3, independent of causality) were decreased appetite (3/0), contusion (2/0), dyspepsia (2/0), fatigue (2/0), dehydration (1/1), cardiac arrest (1/1); common laboratory abnormalities were anemia (5/1), neutropenia (4/1), thrombocytopenia (3/2), increased lipase (1/1). Early responses were seen with entospletinib treatment (3 partial response (PR), 1 stable disease, & 3 patients were too early to evaluate) and 1 PD. PR occurred in 1 BTKi and 2 PI3Ki previously treated patients. One patient with preceding PI3Ki developed progressive disease after 8 weeks. Conclusions Early experience from this trial with ongoing enrollment demonstrates that entospletinib has clinical activity following therapy with either BTKi or PI3Ki. No additional safety signals were seen from earlier studies. Additional investigation of treatment with entospletinib following progression with B-cell receptor signaling pathway inhibitors is warranted. Disclosures Sharman: Celgene Corporation: Consultancy, Research Funding; TG Therapeutics, Inc.: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Calistoga: Honoraria; Janssen: Research Funding. Shustov:Celegene, BMS: Consultancy, Honoraria, Research Funding. Smith:celegene, spectrum, genentech: Honoraria. Boyd:US Oncology: Research Funding; Celgene: Speakers Bureau; Genentech, Inc.: Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; GSK: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding. Abella:Gilead: Employment. He:Gilead Sciences: Employment. Eng:Gilead: Employment. Hu:gilead: Employment. Reddy:gilead: Employment. Mitra:Gilead: Employment. Yasenchak:Seattle Genetics, Inc.: Research Funding.

Description: Introduction BCL2 is an anti-apoptotic protein overexpressed in CLL and critical in the pathogenesis of the disease; venetoclax (VEN) is an orally available, selective BCL2 inhibitor. Bendamustine (B) and rituximab (R) combination has demonstrated efficacy in relapsed/refractory (R/R) and previously untreated (frontline, 1L) patients (pts) with CLL. Preclinical data suggest that VEN+BR may provide synergistic activity in pts with CLL. Clinical data from VEN, both as a single-agent and in combination with R, support VEN+BR combination in CLL. We report an ongoing phase 1b study (NCT01671904) that is evaluating as primary objectives the maximum tolerated dose (MTD) of VEN when combined with BR, plus safety, tolerability, and order of administration to reduce toxicities of this combination in R/R or 1L CLL pts. Methods Pts with ECOG PS ≤1, 0-3 prior chemotherapy lines, and adequate marrow, hepatic, renal and coagulation function are being enrolled in dose finding cohorts and subsequent safety expansion cohorts, ranging from VEN 100 to 400 mg/day (3+3 dose escalation design). Pts are assigned to one of two dosing schedules (Fig 1) with VEN (Schedule A) or BR (Schedule B) introduced first; both include a gradual VEN dose ramp-up and other prophylactic measures to reduce the risk of tumor lysis syndrome (TLS) and risk stratification for TLS (high, intermediate and low). On completing combination therapy, pts continue single-agent VEN until disease progression (R/R CLL) or up to 18 months (1L CLL). Dose-limiting toxicity (DLT) data are reviewed after all pts in a cohort have completed 21 days of combination treatment at the target VEN dose and focus on TLS and cytopenias. Efficacy is assessed by investigators (iwCLL guidelines; Hallek et al. 2008). Results At data cutoff (April 30, 2015), 30 pts have been treated; 20 R/R pts, 12 on Schedule A (3 at 100 mg, 3 at 200 mg, and 6 at 400 mg) and 8 on Schedule B (all at 400 mg), and 10 1L pts, 6 on Schedule A and 4 on Schedule B (all at 400 mg). Baseline characteristics are shown in Fig 2. Of 10 pts with reported cytogenetics, 2 have del(17p). Median time on study is 5.5 (range, 0.03-15.2) months. No safety difference between Schedules A and B was seen in the DLT observation period for R/R CLL pts; neither schedule exhibited any toxicities precluding choice of the highest administered dose of 400 mg daily VEN. Schedule B was chosen for R/R safety expansion due to potential for tumor debulking prior to VEN. Dose finding in 1L Schedule A also selected 400 mg; dose finding for Schedule B is ongoing. Of 30 safety-evaluable, 27 (90%) pts experienced any adverse event (AEs; Fig 3). Most common AEs were neutropenia and nausea. Most G3 AEs were hematological toxicities; common non-hematological included diarrhea and hypertension. No TLS events (laboratory or clinical) were observed. There were 13 serious AEs in 10 (33.3%) pts, 8 (26.7%) due to study treatment. No deaths were reported. Of all 30 pts, 25 received VEN, with 5 still completing the BR only portion of Schedule B. Dose interruptions were seen in 13 pts mainly due to neutropenia for both VEN and BR; 8 pts had a VEN dose reduction. Early drug discontinuations (any reason): VEN, 2pts (gastroenteritis norovirus, progressive disease); BR together, 3 pts; B, 7 pts (commonly for neutropenia or physician decision); R, 1 pt. Across cohorts, 17/20 R/R CLL pts had response assessments; 100% responded, with 3 CRi. Response evaluation for 1L pts is early and evaluation across all cohorts and patients is ongoing. Full MRD data will be presented at the meeting, but early analysis shows pts exhibiting MRD negativity in peripheral blood, many as early as Cycle 4. Conclusion These early results report the first study evaluating the VEN+BR combination in pts with CLL. Daily VEN 400 mg can be safely combined with BR in patients with R/R CLL using both administration schedules (VEN or BR first), with 400 mg also established as safe for 1L pts with CLL under Schedule A. No TLS was observed with either administration schedule, despite many pts at medium (53%) or high (33%) TLS risk. VEN+BR is, as expected, associated with frequent hematologic toxicity, which appears manageable in most pts being treated, although 10 pts discontinued either B or BR prior to completing 6 cycles of administration. Early response and MRD data are promising. Disclosures Salles: Celgene Corporation; Roche: Speakers Bureau; Celgene Corporation; Roche and Gilead Sciences: Research Funding; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication. Boyd:Genentech, Inc.: Research Funding; Celgene: Speakers Bureau; US Oncology: Research Funding. Morschhauser:Genentech Inc./Roche: Other: Advisory boards. Wendtner:Roche: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Hallek:Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding. Eichhorst:AbbVie: Consultancy; Mundipharma: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau. Kozloff:Genentech: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy. Cartron:Gilead: Honoraria; GSK: Honoraria; Celgene: Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Li:Genentech, Inc.: Employment. Hilger:Genentech, Inc.: Employment. Mobasher:Genentech, Inc.: Employment. Stilgenbauer:Roche: Honoraria, Research Funding.

Description: Major objective response (durable complete remission [CR]) is considered evidence of clinical benefit in acute or chronic leukemias. Time-to-progression has recently been proposed as an endpoint for therapeutic trials in CLL, but includes patients who do not achieve objective partial response (PR). Methods: We prospectively collected data regarding clinical benefit in a phase 3 trial of fludarabine (Flu) plus cyclophosphamide (Cy) with or without Genasense (oblimersen sodium), an anti-Bcl-2 agent. Extent of symptom relief was then correlated with the level of objective response, as assessed by blinded review of clinical data, radiology (including CT scanning), and bone marrow histopathology. Patients who had relapsed from or failed to respond to prior fludarabine-based treatment were eligible for this study. After baseline assessment, they were randomized to receive either Flu/Cy alone (n = 121; Flu, 25 mg/m2/day IV 30–60 min; Cy, 250 mg/m2/day IV 30–60 min) on days 1–3, or continuous infusion of Genasense (3 mg/kg/day) on days 1–7 in combination with the same doses of Flu/Cy given on days 5–7 (n = 120). Treatment was repeated every 4 weeks for up to 6 cycles. The primary endpoint was the proportion of patients achieving a CR or nodular PR (nPR). Symptoms evaluated included: fever; night sweats; fatigue; abdominal discomfort or early satiety due to hepatosplenomegaly; impaired cosmesis or mobility due to lymphadenopathy; and other complaints. “Durable benefit” was defined as a minimum of 6 cumulative months without these disease-related symptoms in patients who were initially symptomatic, up to the date of recurrent symptoms, objective disease progression, or introduction of non-protocol therapy for CLL. Results: The addition of Genasense to Flu/Cy increased the confirmed Cr/nPR rate from 7% to 17% (P =0.025). Safety profiles for both treatment arms were tolerable. Grade 5 tumor lysis syndrome and infusion reaction (1 pt. each), and an increase in thrombocytopenia, were observed in the Genasense group, whereas neutropenia and anemia were not increased. With 2 years of minimum followup, the duration of CR/nPR was significantly longer in the Genasense group (median, NR vs. 22 mo. for Flu/Cy; P = .03). Durable benefit closely correlated with the level of objective response. Irrespective of treatment assignment, 94% of patients who achieved CR/nPR also attained durable clinical benefit, compared with 59% of patients whose best response was PR. Only 6% of patients whose best response was less than PR attained durable symptomatic relief. Conclusions: The results of this prospective trial strongly suggest that objective response, in particular CR/nPR, is associated with meaningful symptomatic relief in patients with relapsed/refractory CLL. We confirm that PR can confer meaningful benefit, but we observed durable relief in only 59% of patients with this level of response. In contrast, meaningful benefit occurred infrequently in patients whose best response was less than PR. These results suggest that lack of progression (or measurement of time-to-progression) may not represent a primary or surrogate measure of patient benefit in patients with relapsed or refractory CLL.

Description: Abstract 3713 Poster Board III-649 Introduction B-cell receptor (BCR) signaling contributes to the growth of several types of B-cell non-Hodgkin lymphoma (NHL), and recent reports suggest there is clinical utility to targeting this pathway. Bruton's tyrosine kinase (Btk) is an important downstream mediator of BCR signaling as evidenced by genetic mutations in Btk that cause X-linked agammaglobulinemia, a B-cell specific immunodeficiency disease. PCI-32765 is an oral, potent and selective covalent inhibitor of Btk which blocks BCR signaling and inhibits tumor growth in both mouse and spontaneous canine NHL models. Here we report preliminary results of the first-in-human study with this novel agent. Patients and Methods In this Phase I dose escalation trial, patients with relapsed or refractory B-cell NHL are being enrolled in cohorts of 6 patients each, with predefined criteria for dose escalation from 1.25 mg/kg/day in cohort 1 to 17.5 mg/kg/day in cohort 6. Dose escalation proceeds if ≤1 patient experiences dose limiting toxicity (DLT). Each cycle includes 28 days of therapy followed by a 7 day observation period. Response assessments occur every 2 cycles, and patients without disease progression or DLT may receive a maximum of 6 cycles. The primary objectives are to determine the safety, pharmacokinetics (PK), and pharmacodynamic (PD) responses. The secondary objective is to evaluate tumor responses. The PD assays include a test for drug occupancy of Btk using a novel fluorescent probe derived from PCI-32765. The probe is added to peripheral blood mononuclear cell (PBMC) lysates ex vivo and probe-labeled Btk is visualized by fluorescent gel scanning. Because the probe binds to Btk at the same site as the drug, occupancy of Btk by PCI-32765 can be detected by the inhibition of probe labeling. The probe assay and other cell signaling assays are used to monitor target inhibition in patient blood samples collected pre-dose on days 1, 2, 8, 15, and 29 and at 4 hours after dosing on days 1 and 8. In the absence of DLTs, dose escalation will proceed to three cohorts above the dose level that achieves 〉90% occupancy of Btk by PCI-32765. Results The study is currently open and enrolling. Seven patients (1 DLBCL, 2 MCL, 4 FL) with a median of 3 prior therapies have been enrolled in the first cohort (one more patient than originally planned). Therapy has been extremely well tolerated with no DLT or greater than grade 2 hematological or non- hematologic toxicity. Six patients have completed at least 1 cycle. PD studies showed the average drug occupancy of Btk in patient PBMCs in this cohort was 89% at 4 hours post-dose and 77% at 24 hours post-dose. Ex vivo stimulation assays showed near complete functional inhibition of the FcεRI signaling pathway in basophils and significant inhibition of the BCR pathway. T-cell responses were not affected, and no significant depletion of peripheral blood B, T or NK cell counts was observed. Two of 7 patients have stable disease (65 days and 135 days), 3 patients are not yet evaluable for response, and 2 have progressed. Conclusion PCI-32765 is a novel agent which targets Btk and appears to be well tolerated. The unique PD endpoint suggests high levels of Btk inhibition even at the lowest dosing cohort. Dose escalation to subsequent cohorts is ongoing. Disclosures: Smith: Pharmacyclics: Research Funding. Fowler:Pharmacyclics: Research Funding. Boyd:Pharmacyclics: Research Funding. Smith:Pharmacyclics: Employment, Equity Ownership. Sirisawad:Pharmacyclics: Employment, Equity Ownership. Honigberg:Pharmacyclics: Employment, Equity Ownership. Hamdy:Pharmacyclics: Employment, Equity Ownership. Advani:Pharmacyclics: Research Funding.