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: Introduction: Longitudinal changes in health-related quality of life (HRQoL) are important in patients with chronic lymphocytic leukemia (CLL). GIBB (NCT02320487) is an open-label, single-arm phase II study of obinutuzumab (GA101; G) in combination with bendamustine (G-Benda) in patients with previously untreated CLL. A previous report from the GIBB study demonstrated an investigator-assessed objective response rate of 89.2%, a complete response rate of 49.0%, and no unexpected safety signals with G-Benda (Sharman et al. J Clin Oncol 2017). Here we report the final HRQoL data over 3 years from the GIBB study. Methods: Enrolled patients received G-Benda by intravenous infusion over six 28-day cycles: G 100mg on Day (D)1, 900mg on D2, and 1000mg on D8 and D15 of Cycle (C)1, then 1000mg on D1 of C2-6; benda 90mg/m2 on D2-3 of C1, and on D1-2 of C2-6. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) includes a global health status measure, 5 functional scales (physical, emotional, cognitive, social, and role functioning), 8 symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea), and an item on financial difficulties (Aaronson et al. J Natl Cancer Inst 1993). The EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) is a 16-item module, specific to CLL, containing 4 multi-item scales (fatigue, treatment side effects, disease symptoms, and infection) and 2 single items (social activities and future health worries). Both questionnaires were completed by patients on C1D1 (baseline), C3D1, and C6D1, at the end of induction (EOI) treatment (defined as +28 days from C6D1 or early treatment termination visit), at the response visit (defined as 2-3 months after the EOI treatment for all patients who received study treatment and had not experienced disease progression), and every 3 months thereafter at follow-up visits for up to 2 years. In total, there were 14 timepoints where data were collected. HRQoL scores were linear transformed to a 0-100-point scale. Mean baseline scores and mean score changes from baseline at each visit were evaluated. A threshold of ≥10-point change in score represents a clinically meaningful difference. For symptoms, negative change scores from baseline reflect an improvement in symptom burden. For global health status and functioning, positive change scores from baseline reflect improvements. Results: The trial enrolled 102 patients. Median age was 61 years and 68.4% of patients were male. Ninety-eight patients (96%) completed a questionnaire at baseline and at least 1 other questionnaire during a follow-up visit. Questionnaire completion rates at 14 time points ranged from 96% at baseline to 66% at 27 months follow-up (Table 1). According to the EORTC QLQ-C30 (Figure 1), improvements were observed for global health status at all follow-up visits, and clinically meaningful improvements were observed at the response visit, 3 months follow-up, and 27 months follow-up. Clinically meaningful improvements in role functioning were observed at EOI and persisted throughout the 27-month follow-up. For fatigue, clinically meaningful improvements were observed at every visit starting from the end of treatment (EOT) visit. Improvements were also observed for insomnia with mean reductions from baseline ≥10 points at various time points during follow-up. There was no worsening in other patient-reported symptoms or functional status over time. Similarly, with the EORTC QLQ-CLL16 (Figure 2), clinically meaningful improvements in symptoms were observed for fatigue, disease symptoms, and future health worries during treatment, at the EOT and/or throughout the follow-up. The largest improvement was observed for fatigue (-24.7) at the 24-month follow-up and future health worries (-25.4) at the 27-month follow-up. Conclusions: We previously reported that G-Benda is an effective regimen for first-line treatment of CLL with no unexpected safety signals. The HRQoL data from the GIBB trial suggest that G-Benda treatment consistently improved patient HRQoL over time. Several clinically meaningful improvements were observed in HRQoL, including global health status, functioning, symptoms, and future health worries. Disclosures Danilov: AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; MEI: Research Funding; Bristol-Meyers Squibb: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; Bristol-Meyers Squibb: Research Funding; Takeda Oncology: Research Funding; Aptose Biosciences: Research Funding; Aptose Biosciences: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Gilead Sciences: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Curis: Consultancy; Seattle Genetics: Consultancy; MEI: Research Funding; TG Therapeutics: Consultancy; Celgene: Consultancy; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy; Abbvie: Consultancy. Yimer:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria; Celgene: Honoraria; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Amgen: Consultancy. Boxer:Gerson Lerman: Consultancy; Best Doctors: Consultancy; Takeda: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau. Burke:Celgene: Consultancy; Gilead: Consultancy; Roche/Genentech: Consultancy. Babu:Genentech: Research Funding. Li:Genentech: Employment; Roche: Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Trask:Genentech: Employment, Equity Ownership. Masaquel:Roche: Equity Ownership; Genentech: Employment. Sharman:Acerta: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated: in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia; in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen

Description: Background: Ibrutinib (ibr), a first-in-class, once-daily, covalent, Bruton's tyrosine kinase inhibitor, is approved in the US for treatment of patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), including pts with del(17p). The activity and safety of ibr in this early phase pivotal study was investigated in pts receiving first line ibr and pts with relapsed/refractory (R/R) CLL/SLL. We report data on the longest follow up available, up to 7 y, for pts receiving single-agent ibr. Methods: Phase 1b/2 (PCYC-1102; NCT01105247) and extension study (PCYC-1103; NCT01109069) included pts receiving 420 mg (first line n=26; R/R n=67) or 840 mg QD ibr (first line n=5; R/R n=34) in the first line (≥65 y) or R/R (≥1 prior therapy) settings. Ibr was administered until disease progression (PD) or unacceptable toxicity. Efficacy was evaluated by investigator-assessed overall response rate (ORR, including partial response with lymphocytosis [PR-L]) using consensus criteria for CLL and SLL, duration of response (DOR; PR-L or better), progression free survival (PFS), and overall survival (OS). Responses were assessed for Döhner hierarchical subgroups. Median (95% CI) survival outcomes are reported. Adverse event (AE) monitoring was from first ibr dose until 30 days after the last dose; generally only grade ≥3 AEs and other significant AEs were collected on PCYC-1103. Results: Of 132 pts, 31 received first line ibr and 101 had R/R disease. As of the cutoff, 17 (55%) first line and 21 (21%) R/R pts continued ibr, with median (range) follow-up of 67 mo (0.7+, 87). Median (range) age for all pts was 68 y (37‒84); 43% of pts were ≥70 y (first line, 74%; R/R, 34%). Baseline genomic characteristics have been reported and included many high-risk features such as complex karyotype (first line, 13%; R/R, 37%) and unmutated IGHV (first line, 48%; R/R, 78%). R/R pts received a median (range) of 4 prior therapies (1‒12). ORR was 89% for all pts (complete response [CR], 15%), with similar rates in first line (87% [CR, 32%]) and R/R pts (89% [CR, 10%]). Median DOR was not reached (NR; 95% CI: not estimable [NE], NE) for first line and was 57 mo (38, 80) for R/R pts. Median PFS was NR (95% CI: NE, NE) for first line and was 51 mo (37, 70) for R/R pts (Fig 1); estimated 7 y PFS rates were 80% and 32%, respectively. Median OS was NR in first line (95% CI: 80, NE) or R/R pts (63, NE), with estimated 7 y OS rates of 75% and 52%, respectively. Median OS for pts with PD within 1, 3, and 5 y of treatment initiation was 13 (95% CI: 1, 25), 28 (17, 54), and 57 mo (28, NE), respectively. In R/R pts, median PFS was 26 mo (95% CI: 18, 37) in 34 pts with del(17p), 51 mo (31, 62) in 28 pts with del(11q), 82 mo (7, NE) in 5 pts with trisomy 12, and NR (63, NE) in 13 pts with del(13q). Median PFS was NR (95% CI: 40, NE) in 16 R/R pts with no abovementioned cytogenetic abnormalities. Among R/R pts, median PFS trended longer for 27 pts with 1‒2 prior lines of therapy (66 [95% CI: 37, NE]) versus 14 pts with 3 (59 [22, NE]) or 60 pts with ≥4 prior lines of therapy (39 [26, 51]). The primary reason for treatment discontinuation in first line pts was AEs (23%), whereas in R/R CLL it was PD (35%). Most common AEs (≥2 pts) leading to discontinuation were diarrhea, subdural hematoma, and sepsis (n=2 each). Grade ≥3 AEs were reported in 74% of first line and 89% of R/R pts, and serious AEs were reported in 61% of first line and 76% of R/R pts. Hypertension (first line, 32%; R/R, 26%) and pneumonia (first line, 10%; R/R, 27%) were among the most common grade ≥3 treatment-emergent AEs. A similar proportion of first line (10%) and R/R pts (9%) experienced major hemorrhage. Grade ≥3 atrial fibrillation (first line, 6%; R/R, 10%) and infection (first line, 23%; R/R, 55%) were more common in R/R pts. In all pts, grade ≥3 treatment-emergent AEs were highest during the first year of treatment and subsequently declined. Conclusions: With up to 7 y of follow-up, sustained activity of single-agent ibr was observed with first line ibr and for R/R pts with CLL/SLL, including those with high risk genomic factors. Responses were durable, with stable or improved CR rates, and sustained PFS and OS rates (estimated 7 y rates: 80% and 75% for first line pts and 32% and 52% in the highly pretreated R/R population, respectively). In R/R CLL, ibr administration in earlier lines of therapy resulted in improved PFS outcomes, with longer PFS after 1‒2 versus ≥3 prior lines of therapy. Ibr was acceptably tolerated, and most grade ≥3 AEs declined over time. Disclosures Furman: Loxo Oncology: Consultancy; Genentech: Consultancy; Verastem: Consultancy; Sunesis: Consultancy; Incyte: Consultancy, Other: DSMB; TG Therapeutics: Consultancy; Janssen: Consultancy; Gilead: Consultancy; AbbVie: Consultancy; Acerta: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy. Coutre:Beigene: Consultancy; Gilead: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; AbbVie: Consultancy, Research Funding. Flinn:Janssen: Research Funding; Kite: Research Funding; Novartis: Research Funding; Agios: Research Funding; Merck: Research Funding; Calithera: Research Funding; Curis: Research Funding; Portola: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Verastem: Consultancy, Research Funding; Incyte: Research Funding; Trillium: Research Funding; Pharmacyclics: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; ArQule: Research Funding; Forty Seven: Research Funding; Constellation: Research Funding; Celgene: Research Funding; Infinity: Research Funding; BeiGene: Research Funding; Verastem: Research Funding; Forma: Research Funding. Blum:Morphosys: Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding. Sharman:Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Acerta: Consultancy, Research Funding. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Luan:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Liu:AbbVie: Equity Ownership; Pharmacyclics, an AbbVie Company: Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Dean:CTI BioPharma Corp.: Employment, Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. O'Brien:Gilead: Consultancy, Research Funding; Regeneron: Research Funding; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Consultancy; Astellas: Consultancy; Aptose Biosciences Inc.: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy, Research Funding; Acerta: Research Funding; Janssen: Consultancy; TG Therapeutics: Consultancy, Research Funding; Amgen: Consultancy; Alexion: Consultancy; GlaxoSmithKline: Consultancy; Kite Pharma: Research Funding; Vaniam Group LLC: Consultancy.

Description: Background: This comparative 52 week clinical study (NCT02213263) evaluated the efficacy, safety, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of PF-05280586 (a potential rituximab biosimilar) vs. rituximab reference product sourced from the European Union (MabThera®; rituximab-EU). Methods: Subjects with previously untreated CD20-positive, low tumor burden follicular lymphoma (LTB-FL) were randomized (1:1) to PF-05280586 or rituximab-EU (375 mg/m2 intravenously [once weekly for 4 weeks at days 1, 8, 15 and 22]). Subjects were stratified at randomization using the Follicular Lymphoma International Prognostic Index 2 (FLIPI2) classification and had an Eastern Cooperative Oncology Group performance status 0-1. The primary endpoint was overall response rate (ORR) at Week 26, defined as the percentage of subjects achieving complete response (CR) or partial response (PR), based on central review. Therapeutic equivalence could be concluded if the 2-sided 95% confidence interval (CI) for the difference in ORR between treatment groups was within the pre-specified margin of ±16% (per US and EMA regulatory agreement). Key secondary endpoints included progression-free survival (PFS), CR rate at Week 26, time to treatment failure, duration of response, overall survival, safety, immunogenicity, PK and PD. Once all subjects completed Week 26 assessments (or early study withdrawal), the primary endpoint was evaluated. Results: 394 subjects were randomized to PF-05280586 (n=196) or rituximab-EU (n=198); 54.8% were female, median age was 60.0 years, and 28.4% had low, 66.0% medium, and 5.6% had high risk, according to FLIPI2. 26.9% of subjects had Ann Arbor Stage II, 44.2%, Stage III, and 28.9%, Stage IV. ORR at Week 26 was 75.5% (PF-05280586) vs 70.7% (rituximab-EU) for a difference of 4.66%, and the corresponding 95% CI (-4.16-13.47) was entirely contained within the pre-specified equivalence margin of ±16%. Rates of CR were 29.3% vs 30.4% in the PF-05280586 and rituximab-EU groups, respectively. At Week 26, 11.5% vs 19.6% had stable disease, and 3.4% vs 4.3% had progressive disease (PF-05280586 vs rituximab-EU, respectively) (Table). Estimated 1-year PFS rates were 76.4% (95% CI: 67.2-83.4) and 81.2% (95% CI: 72.1-87.6) in the PF-05280586 and rituximab-EU groups, respectively. The incidence of treatment-emergent adverse events (TEAEs) (all-causality) was similar (78.6% [PF-05280586] vs 72.1% [rituximab-EU]). The most frequently reported TEAEs were infusion-related reactions (IRRs) (25.5% vs 29.9%), pruritus (6.6% vs 11.2%) and headache (8.2% vs. 9.6%) (PF-05280586 vs. rituximab-EU, respectively). The incidence of serious AEs was similar (7.7% and 6.6% in the PF-05280586 and rituximab-EU groups, respectively). All causality grade 3 TEAEs were reported in 13.3% (PF-05280586) vs 11.7% (rituximab-EU) subjects. The most frequently reported Grade 3 TEAEs were IRR (2.6% vs 0.5%) and hypertension (1.0% vs 2.0%) in the PF-05280586 and rituximab-EU groups, respectively. The incidence of grade 3 treatment-related TEAEs was similar (PF-05280586: 13.8% vs rituximab-EU: 12.2%). One treatment-related TEAE (grade 4 neutropenia) was reported in 1 subject in the rituximab-EU group, but was not associated with any signs or symptoms of infection. No subjects in the PF-05280586 group reported grade 4 treatment-related TEAEs. Two deaths occurred during the study (1 in each group) due to disease progression and were deemed not to be treatment-related. Overall, 19.5% and 18.8% of subjects in the PF-05280586 and rituximab-EU groups, respectively, tested positive for antidrug antibodies (ADA) post-dose; none were positive for neutralizing antibodies. No clinically meaningful differences were observed in immune-related AEs in subjects who were treatment-emergent ADA positive vs those who were ADA negative. Mean serum concentrations of PF-05280586 and rituximab-EU were similar, and no notable differences were observed in mean serum concentrations between ADA positive and ADA negative subjects in either treatment group. In both groups, rapid depletion in CD19 positive B-cell counts was observed after initial dosing, with recovery by week 39 and a sustained increase until end of Week 52. Conclusions: Efficacy, safety and immunogenicity, PK and PD of PF-05280586 and rituximab-EU were similar up to Week 26 in subjects with previously untreated CD20-positive, LTB-FL. Disclosures Sharman: Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Acerta: Consultancy, Research Funding. Aurer:Pfizer: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Robbins:Pfizer: Employment, Equity Ownership. Rosenberg:Pfizer: Employment, Equity Ownership. Khan:Pfizer: Employment, Equity Ownership. Alcasid:Pfizer: Employment.

Description: Abstract 964 Introduction: Bruton's tyrosine kinase (Btk) is a downstream mediator of B-cell receptor signaling. PCI-32765 is a potent, selective, irreversible and orally bioavailable small molecule inhibitor of Btk. We have previously reported initial efficacy and safety data with this agent in various B-cell malignancies (ASCO 2010 abstract # 8012). We now report updated efficacy and safety of PCI-32765 in patients (pts) with long-term dosing. Pts and Methods: Pts on the Phase 1 study were treated with escalating doses over 6 cohorts. Cohort 1 was dosed at 1.25 mg/kg/day with subsequent dose escalation (2.5, 5.0, 8.3, 8.3 continuous dosing, and 12.5 mg/kg/day) based on safety evaluation. Pts were analyzed according to histology, pretreatment clinical and laboratory characteristics, PCI-32765 dose levels, overall response (OR), and response duration. Results: Responses and time on study (≥ 6 months) are summarized in Table 1. Of 47 pts enrolled in the Phase 1 study, 20 pts (43%) achieved an OR including 3 complete remissions (CR) and 17 partial remissions (PR). Fourteen of 47 pts have been on study ≥ 6 months; of these 8 pts demonstrated a PR or better and 6 pts maintained stable disease (SD). Responses were observed irrespective of pretreatment risk factors such as performance status, lactate dehydrogenase (LDH) levels, or disease burden. Durable responses were seen at all dose levels and across various histologic subtypes (Table 1) and currently 9 of 14 pts with treatment ≥ 6 months are still on study. Study-drug related Grade ≥ 3 toxicities were reported in 9/47 pts (19%). Five of 47 pts discontinued study drug due to adverse events: neutropenia (Grade 3) lasting 〉 7 days, hypersensitivity reaction (Grade 3), small bowel obstruction (Grade 3), anemia (Grade 2), and exacerbation of chronic obstructive pulmonary disease (Grade 3). No evidence of cumulative hematologic toxicity or long-term safety signals have been observed. No treatment-related deaths have been reported. Conclusion: PCI-32765 is a novel oral Btk inhibitor that induces durable objective responses in various relapsed or refractory B-cell malignancies. The favorable safety profile and lack of cumulative hematologic toxicities support further studies of both monotherapy and combination treatment with PCI-32765. Disclosures: Fowler: Pharmacyclics: Consultancy, Research Funding. Off Label Use: This phase I trial describes the results of a first in human Phase I trial. This drug is not FDA approved for the treatment of malignancy. Sharman:Pharmacyclics, Inc: Honoraria, PI grant. Smith:pharmacyclics: Research Funding. Boyd:pharmacyclics: Research Funding. Grant:pharmacyclics: Research Funding. Kolibaba:pharmacyclics: Research Funding. Furman:Pharmacyclics, Inc: Research Funding. Buggy:pharmacyclics: Employment. Loury:Pharmacyclics: Employment, Equity Ownership. Hamdy:pharmacyclics: Employment. Advani:Pharmacyclics, Inc: Honoraria, PI grant.

Description: Key Points Entospletinib is a selective inhibitor of spleen tyrosine kinase, which is implicated in the pathobiology of B-cell lymphoid malignancies. Entospletinib shows clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity.

Description: Key Points Our 5-year experience shows sustained single-agent efficacy of ibrutinib in CLL patients, with complete response rates increasing over time. Long-term ibrutinib was well tolerated with no new safety signals; rates of grade ≥3 cytopenias decreased with continued therapy.

Description: Signal transduction plays a key role in cell survival, and changes to signaling are frequently implicated in tumor initiation and progression. We sought to identify abnormal variation in signaling network activity within primary tumor samples obtained prior to treatment from patients with follicular lymphoma (FL). We previously showed that altered B cell receptor (BCR) signaling distinguishes tumor B cells from the non-malignant host B cells in FL tumors. Here we extend this approach and use flow cytometry to measure 648 signaling events in live lymphoid cells from more than 25 lymphoma specimens and healthy controls. We combined 9 previously identified BCR stimulation conditions with inputs from CD40, interleukin 4, interferons (IFNs), and more than 10 other environmental cues that govern the development and activity of lymphocytes. Fluorescent cell barcoding allowed simultaneous staining and analysis of phospho-protein activation under all 27 stimulation conditions within a single tube. The activation of key phospho-protein nodes throughout lymphocyte signaling networks, including Syk, Erk1/2, Btk, Src family kinases, cCbl, p38, NFkB, Akt, Stat1, Stat3, Stat6, and Stat5, was measured under each of the 27 stimulation conditions. Measurements of phospho-protein responses to stimulation were combined with detection of the Bcl-2 oncogene, B and T cell lineage markers in each cell. This panel allowed us to characterize signaling in the heterogeneous cell subsets found within each patient’s tumor sample. Tumor B cells, host tumor infiltrating T cells, non-malignant B cells were all distinguished by contrasting signaling profiles. In some cases, subsets of tumor B cells with differences in signaling network topology were observed within the tumor B cell population. This result suggests that signaling can distinguish between tumor sub-clones and could be used to measure tumor heterogeneity. As previously reported, little variation in signaling was observed among healthy peripheral blood B and T cell samples from different individuals. Abnormally low host T cell signaling was commonly observed within the tumor infiltrating T cells infiltrating FL tumors. Further analysis of tumor T cell subsets indicated that a high proportion of infiltrating T cells expressed CD4 and FoxP3. Taken together, these results support the hypothesis that FL tumor B cells promote suppressed signaling in the T cells of the patient and may modulate the immune response against the tumor. In FL tumor B cells, BCR and IFN signaling frequently triggered Stat5 phosphorylation, but not Stat1 phosphorylation. These results are consistent with the hypothesis that Stat5 initiates genetic programs that support cancer cell survival and proliferation, whereas Stat1 promotes immunogenicity and cooperates with the p53 tumor suppressor protein. In contrast with healthy B cells, loss of the response to CD40L, altered PKC signaling, and variable responses to BCR crosslinking were all seen in FL tumor B cells. The patterns of abnormal signaling we observed in tumor B cells and tumor infiltrating T cells suggest that measuring the activity of key signaling network nodes can identify targets for therapeutic attention in FL.

Description: Background : Prior to the approvals of ibrutinib (ibr), idelalisib, and venetoclax, data from the Connect CLL registry showed that across 199 US centers only 65% of patients (pts) had FISH testing and 6% had IGHV testing performed prior to the first chronic lymphocytic leukemia (CLL)-directed treatment (tx), and 40% had repeat FISH testing prior to a subsequent therapy (Mato, Br J Haematol 2016). In today's era, molecular-genetic testing should be universally performed to guide tx decisions for pts with CLL, particularly for pts with 17p deletion (del[17p]), TP53 mutation, and/or unmutated IGHV (U-CLL), as recommended by several guidelines. Whether the widespread availability of novel agents has improved prognostic testing patterns and if those results are appropriately utilized in selecting therapies remain important unanswered questions. InformCLL (NCT02582879) is a US, multicenter, prospective, observational real-world registry of pts with CLL receiving various lines of tx across 150 centers (96% community, 4% academic). This analysis describes rates of prognostic testing in pts with CLL stratified by line of therapy, proportions of pts with specific abnormalities, and current tx patterns in clinical practice in this registry. Methods : Enrollment began in Oct 2015. Eligible pts had to be ≥18 years (y), start approved anti-CLL tx within 30 days of enrollment, and provide consent. First tx at enrollment was classified into 5 groups: chemoimmunotherapy (CIT), chemotherapy (CT), immunotherapy (IT), ibr, and other novel agents. For this interim analysis (data cut: Feb 2018), the number of pts with CLL who had testing performed for FISH, TP53 mutational status, and IGHV mutational status, as well as CLL tx for subgroups of pts stratified by abnormality, was summarized as frequency counts and percentages. Results : At the time of this analysis, the registry had enrolled 840 pts (459 previously untreated; 381 relapsed or refractory [R/R]). The majority of pts were male (64%) and Caucasian (92%); median (range) age was 70y (34-95), and median (range) Charlson Comorbidity Index was 2 (0-9). Overall, prognostic biomarker testing was performed infrequently. Among all pts (N=840), 262 (31%) had FISH testing, 89 (11%) had testing performed for TP53 mutation, and 94 (11%) had testing for IGHV mutational status (Table 1). Among 459 pts tested prior to first-line tx, 164 (36%) had testing for FISH, 54 (12%) for TP53, and 55 (12%) for IGHV; among 381 R/R pts, 98 (26%) had testing for FISH, 35 (9%) for TP53, and 39 (10%) for IGHV. For tested pts, 70/262 (27%) pts had del(17p), 23/89 (26%) had mutated TP53, and 69/94 (73%) had U-CLL. For previously untreated tested pts, 47/164 (29%) had del(17p), 14/54 (26%) had mutated TP53, and 35/55 (64%) had U-CLL; for tested R/R pts, 23/98 (23%) had del(17p), 9/35 (26%) had mutated TP53, and 34/39 (87%) had U-CLL. Among 70 pts with del(17p), the most common tx was ibr (n=38; 54%); however, a considerable proportion of pts received CT/CIT (n=24; 34%) (Table 2). In 47 previously untreated pts with del(17p), 27 (57%) received ibr and 16 (34%) received CT/CIT; in 23 R/R pts with del(17p), 11 (48%) received ibr and 8 (35%) CT/CIT. Among 23 pts with mutated TP53, 15 (65%) were treated with ibr, while 7 (30%) with CT/CIT. Of 14 previously untreated pts with mutated TP53, 9 (64%) received ibr and 5 (36%) CT/CIT; of 9 R/R pts with mutated TP53, 6 (67%) received ibr and 2 (22%) CT/CIT. Among 69 pts with U-CLL, 30 (43%) were treated with ibr and 32 (46%) with CT/CIT. In 35 previously untreated pts with U-CLL, CT/CIT was more common (n=20; 57%) than ibr (n=13; 37%), while in 34 R/R pts with U-CLL, ibr was more common (n=17; 50%) than CT/CIT (n=12; 35%). Conclusions : There remains a considerable lack of prognostic marker testing among pts with CLL in the modern era. These findings, as compared to prior registry results, suggest that the advent of novel agents and specific testing guidelines (eg, iwCLL) have not improved prognostic testing patterns in the real-world setting. Moreover, of pts tested who had abnormalities such as del(17p), TP53 mutation, or U-CLL, approximately one-third still received CIT. These results underscore a need to educate on how to utilize these markers to guide CLL tx decisions for optimal clinical outcomes. Additional evaluations (eg, regression analyses) to identify factors associated with failure to perform FISH, TP53, and IGHV testing are planned. Disclosures Mato: Portola: Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy, Research Funding; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding; Prime Oncology: Honoraria; Regeneron: Research Funding; Johnson & Johnson: Consultancy; Acerta: Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding. Barrientos:Janssen: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding. Brander:BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Kadish:Pharmacyclics, an AbbVie Company: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau. Ghosh:Celgene: Consultancy; PCYC: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Pharmacyclics, an Abbvie Company: Consultancy, Research Funding, Speakers Bureau; SGN: Consultancy, Research Funding, Speakers Bureau; Forty seven Inc: Research Funding; TG Therapeutics: Honoraria, Research Funding; F. Hoffman-La Roche Ltd: Research Funding; Genentech: Research Funding; Spectrum: Consultancy; Abbvie: Consultancy, Speakers Bureau; Juno: Consultancy, Research Funding. Giafis:Pharmacyclics, an AbbVie Company: Employment, Other: Travel; AbbVie: Equity Ownership. Ipe:AbbVie: Equity Ownership; Pharmacyclics, an AbbVie Company: Employment, Other: Travel. Upasani:Pharmacyclics, an AbbVie Company (self and immediate family member): Employment; AbbVie (self and immediate family member): Equity Ownership. Sundaram:AbbVie: Employment, Equity Ownership, Other: Travel; Johnson & Johnson: Employment, Equity Ownership, Other: Travel. Ferrante:Janssen: Employment, Equity Ownership. Amaya-Chanaga:AbbVie: Equity Ownership, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.; Pharmacyclics, an AbbVie Company: Employment, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.. Iyengar:Pharmacyclics, an AbbVie company: Employment; AbbVie: Equity Ownership; Express Scripts: Patents & Royalties. Sharman:Acerta: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding.

Description: Key Points Obinutuzumab monotherapy demonstrates an increased ORR with 2000 mg over 1000 mg, but no difference in progression-free survival. No meaningful difference was observed in the overall safety profile across the 2 treatment arms.