ALBERT

Description: The Marine Isotope Stage 16–15 boundary (Termination VII) is the first deglacial warming step of the late Quaternary following the Mid-Pleistocene Transition (MPT), when 41-kyr climatic cycles shifted to strong 100-kyr cycles. The detailed structure of this important climatic event has remained unknown until now. Core MV0508-19JPC from Santa Barbara Basin, California contains a decadal-scale climatic and geochemical sediment record of 4000 years duration that includes the early part of this deglacial episode. This record reveals that the climatic shift during the early deglacial occurred rapidly (〈700 yr), in a progression of three abrupt warming steps. The onset of MIS 15 was remarkably abrupt with 4–5 °C sea surface warming in ~50 years. The deglacial sequence contains the well-dated Lava Creek tephra (631.3±4 ka) from Yellowstone Caldera used to date the onset of Termination VII at 631.5 ka. The late MIS 16 and early MIS 15 interval exhibits multiple decadal-scale negative excursions in δ 13 C of planktic foraminifera, likely the result of repeated discharges of methane from methane hydrates associated with both ocean warming and low sea level. A warm interstadial that interrupts late MIS 16 is marked by elevated concentrations of redox-sensitive elements indicating sulfidic, oxygen-deficient bottom and pore waters, and elevated concentrations of TOC and Cd, reflecting increased surface productivity. Unlike younger sediments on the California margin, these indicators of increased productivity and low dissolved oxygen do not consistently correspond with each other or with preserved laminations, possibly reflecting instability of a still evolving ocean–atmosphere system following the MPT.

Description: Introduction: PAC is a kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R that does not inhibit JAK1. PAC has demonstrated activity in phase (Ph) 1-3 clinical studies. Nonclinical and clinical pharmacokinetic (PK) and pharmacodynamic studies support a 400 mg QD oral dosing regimen in ongoing Ph 3 studies in myelofibrosis. Here we present PK data from a series of Ph 1 studies of PAC. Methods: Seven Ph 1 studies were conducted in healthy subjects receiving a single 100, 200, or 400 mg dose of PAC. In an ADME mass balance study, [14 C]-PAC was administered to characterize routes of disposition. Separate drug interaction studies were conducted to assess effects of a strong CYP3A4 inhibitor (clarithromycin) or strong pan-CYP450 inducer (rifampin) on PAC PK. Cardiac safety of PAC was evaluated in a thorough QT (TQT) study. Food-effect, dose proportionality, and relative bioavailability studies were also conducted. Results: 140 subjects across 7 studies received single doses of PAC 100-400 mg. PK parameters of PAC 400 mg are presented in the Table (n=12). Following administration of single 100-400 mg PAC doses under fasted conditions, systemic exposure increased in a linear, but less than dose proportional manner. Among identified metabolites, the 2 major metabolites (M1, M2) exhibit relatively low pharmacological potency and are unlikely to contribute to PAC activity. Following a 400 mg single dose of [14 C]-PAC, the parent compound was the predominant moiety in plasma. Mean radioactivity recovery in urine = 3.22% of administered dose with intact PAC excreted in urine = 0.12% of administered dose. Of all 9 metabolites formed, M7, a glucuronidated metabolite, was the predominant radioactive component (3.03% of administered dose) excreted in urine. Mean radioactivity recovery in feces = 85.46% of administered dose and M2 (O- dealkylation metabolite) was the predominant component (24.08% of administered dose). When co-administered with clarithromycin (CYP3A4 inhibitor), PAC exposure increased with mean Cmax and AUC approximately 1.3- and 1.8-fold higher, respectively, with a similar mean t1/2 vs PAC alone. Co-administration with rifampin, a strong CYP3A4 inducer, reduced mean PAC Cmax and AUC by 51% and 87%, respectively vs PAC alone. Median Tmax was similar when co-administered with rifampin vs PAC alone (5-6 h), but t1/2 was shortened by approximately 65% (PAC: 43.3 h; PAC + rifampin: 15.1 h). Administration of single oral doses of PAC 400 mg in a placebo- and moxifloxacin-controlled TQT study had no clinically relevant effects on ECG parameters, including heart rate. There was no effect on QT prolongation (mean QTcF change

Description: Background : Ibrutinib is the only once-daily Bruton's tyrosine kinase inhibitor with significant progression-free survival (PFS) benefit demonstrated in 5 randomized phase 3 studies in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) compared with standard-of-care chemotherapy and/or immunotherapy (RESONATE, RESONATE-2, iLLUMINATE, Alliance 041202, and ECOG 1912), and significant overall survival (OS) benefit in 3 of these studies. To understand how treatment with single-agent ibrutinib in earlier lines impacts patient outcomes, we evaluated long-term follow-up data from RESONATE and RESONATE-2 to compare efficacy and safety by number of prior lines of therapy. Methods : This integrated analysis included patients treated with single-agent ibrutinib in the first-line (RESONATE-2, NCT01722487) and relapsed/refractory (R/R; RESONATE, NCT01578707) settings. R/R patients were grouped by number of prior lines of therapy (1-2 vs ≥3). Patients with del(17p) were excluded from this analysis given their exclusion from RESONATE-2. Patients with high-risk prognostic features were defined as having TP53 mutation, del(11q), and/or unmutated IGHV. Outcomes included investigator-assessed PFS and objective response rate (ORR), OS, and safety. Results : This analysis of 271 patients included 136 patients in the first-line and 135 patients in the R/R groups (1-2 prior: n=68; ≥3 prior: n=67). Patients in the first-line group were older (median age [range], 73 years [65-89]) than those with 1-2 prior lines (65 years [30-86]) and ≥3 prior lines (67 years [44-83]). The proportion of patients with high-risk prognostic features was lower in the first-line group (first-line: 54%; 1-2 prior: 81%; ≥3 prior: 76%). Median follow-up was 59.8 months for first-line, 66.2 months for 1-2 prior, and 65.1 for ≥3 prior. Median PFS was not reached (NR) for first-line or 1-2 prior lines and was 40.1 months for ≥3 prior lines (Figure 1A). A greater proportion of patients treated with ibrutinib in earlier lines remained progression-free or alive at 60 months (first-line: 70%; 1-2 prior: 60%; ≥3 prior: 33%). First-line treatment resulted in a 34% reduction in risk of disease progression or death compared to 1-2 prior lines (HR: 0.66 [95% CI, 0.40-1.09]). PFS was significantly prolonged for first-line vs ≥3 prior lines (HR: 0.32 [95% CI, 0.21-0.49]) and 1-2 prior vs ≥3 prior lines (HR: 0.48 [95% CI, 0.30-0.77]). For patients with high-risk prognostic features, median PFS was NR for first-line or 1-2 prior lines and was 42.5 months for ≥3 prior lines (Figure 1B); treatment in earlier lines resulted in better PFS for these patients (first-line vs 1-2 prior, HR: 0.64 [95% CI, 0.35-1.18]; first-line vs ≥3 prior, HR: 0.33 [95% CI, 0.19-0.57]; 1-2 prior vs ≥3 prior HR: 0.51 [95% CI, 0.30-0.87]). Median OS for the overall population was NR (range, 0.10+-66.04+) for first-line, NR (5.98-71.56+) for 1-2 prior, and 67.4 months (1.15-69.78+) for ≥3 prior lines. The ORR was 91%, 94%, and 82% for first-line, 1-2 prior, and ≥3 prior lines, respectively. The CR rate (CR+CR with incomplete marrow recovery) was highest for the first-line group (first-line: 30%; 1-2 prior: 12%; ≥3 prior: 10%). At the time of analysis, 58% of patients remain on ibrutinib treatment in the first-line group. Prior to study closure, 38% of patients with 1-2 prior and 18% of patients with ≥3 prior lines remained on ibrutinib treatment. In the overall population, 8 patients (6%) in the first-line group discontinued due to progressive disease while it was the most common reason for discontinuation for patients with 1-2 (n=15, 22%) and ≥3 prior lines (n=25, 37%). Across all three groups, 52 patients (19%) discontinued due to adverse events (AEs) (first-line: n=29, 21%; 1-2 prior: n=13, 19%; ≥3 prior: n=10, 15%). AEs leading to dose reduction occurred in 20% of first-line, 13% of 1-2 prior, and 22% of ≥3 prior lines. Conclusions : Overall, this integrated analysis of data with up to 6 years of long-term follow-up demonstrates that using single-agent ibrutinib in earlier lines of treatment results in better PFS, OS, and ORR with sustained efficacy for patients with CLL, including patients with high-risk prognostic features. During this extended follow-up, only 6% of patients treated in the first-line setting discontinued due to progressive disease. Ibrutinib was well tolerated with only 19% of patients across all lines of therapy discontinuing due to AEs. Disclosures Barr: Gilead: Consultancy; Verastem: Consultancy; Seattle Genetics: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Merck: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding. Tedeschi:Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Munir:AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy; Pharmacyclics: Other: TBC; Acerta: Membership on an entity's Board of Directors or advisory committees. Hillmen:Acerta: Membership on an entity's Board of Directors or advisory committees; Apellis: Research Funding; Gilead: Research Funding; Roche: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Byrd:Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Genentech: Research Funding; BeiGene: Research Funding. Ghia:ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Juno/Celgene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy. Mulligan:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Participant, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Participant, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Clinical Trial participant, Research Funding, Speakers Bureau; Commonwealth Serum Laboratories (CSL): Other: Clinical Trial participant; Sanofi-Aventis: Other: Clinical Trial participant; Acerta: Other: Clinical Trial participant. Dai:AbbVie: Equity Ownership; Celgene: Equity Ownership; Exelixis: Equity Ownership; Gilead: Equity Ownership; GSK: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. Amaya-Chanaga:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. Dean:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. o'Brien:Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy; Astellas: Consultancy; Celgene: Consultancy; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Kite: Research Funding; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Regeneron: Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy.

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: Introduction: Myelofibrosis (MF) is a life-threatening hematologic malignancy characterized by splenomegaly and debilitating symptoms including fatigue, abdominal pain, night sweats, bone pain, pruritus, and unintentional weight loss. The myeloproliferative neoplasm symptom assessment form (MPN-SAF) is a PRO tool designed to measure MF-related symptom burden and was developed and validated at Mayo Clinic. It was modified (MPN-SAF total symptom score [TSS] and TSS 2.0) for use in the PERSIST-1 and PERSIST-2 phase 3 trials. For PERSIST-1, when examining the 6 common symptoms in both TSS versions (tiredness, night sweats, early satiety, itchiness, bone pain, and abdominal pain), pacritinib-treated patients (pts) had significant improvements in TSS overall and in individual symptoms vs BAT; Pt Global Impression of Change (PGIC) was also significantly improved for pts receiving pacritinib. Improvements in EORTC-QLQ-C30 scales were noted in the pacritinib arm (Mesa, EHA 2015). The proportion of pts achieving spleen volume reduction (SVR) ≥35% at Week 24 was significantly greater with pacritinib vs BAT (ITT: 19.1% vs 4.7%, p=0.0003; evaluable at baseline and Week 24: 25.0% vs 5.9%; p=0.0001). This analysis examines relationships between TSS improvement and changes in splenomegaly and HRQoL outcomes. Methods: Pts who received no prior JAK inhibitor therapy were randomized 2:1 to oral pacritinib 400 mg once daily or BAT. Pts were stratified by DIPSS risk (Int-1/Int-2 vs High) and platelet count (

Description: Background Pacritinib (SB1518) is a novel oral JAK2-FLT3 inhibitor. To date, once-daily (QD) dosing of pacritinib has been evaluated in two pharmacokinetic studies in healthy volunteers (n = 42) and in two phase 1/2 clinical trials in patients with advanced myeloid malignancies (n = 129). Due to less-than-proportional increase in systemic exposure with dose, administration of QD doses higher than 400 mg does not appreciably increase systemic exposure of pacritinib. Hence, the twice-daily (BID) regimen was conceived as an alternate dosing regimen to achieve higher systemic pacritinib exposure and potentially enhance clinical response of pacritinib. Aims Characterize exposure-response relationship of pacritinib in early stage clinical development. Methods Two pharmacokinetic (PK) studies were conducted in healthy volunteers to assess the inter- and intra-individual PK variability and the effect of food on the PK of pacritinib. Two Phase 1/2 trials were also undertaken to characterize the population pharmacokinetics, safety, and efficacy of pacritinib in patients with advanced myeloid malignancies following oral administration of 100-600 mg QD. Safety (i.e., incidence and severity of key AEs including GI, thrombocytopenia and anemia) and efficacy (i.e., spleen size reduction) of pacritinib were assessed in patients. Based on the safety, tolerability and anti-tumor activity observed in the completed Phase 1/2 trials, the 400 mg QD regimen of pacritinib was selected for further clinical development in MF. A total of 65 patients received 400 mg QD regimen in Phase 2 trials for pacritinib. To construct the exposure-response relationship following QD dosing of pacritinib, patients with pharmacokinetic exposure data from completed Phase 1/2 trials (n = 129) were divided into quartiles [Q1-Q4] based on their model predicted area under the curve at steady-state (AUCss). For each exposure quartile, the mean reduction in spleen size was determined. In addition, exposure-response analysis on key safety parameters was similarly performed by comparing AE distributions across exposure quartiles. The key PK parameters were simulated for the 200 mg BID regimen and distribution of patients that fell into QD regimen-defined exposure quartiles was determined. Results PK simulation data indicated that administration of the 200 mg BID regimen is likely to result in a mean systemic exposure that is 41% higher relative to that of the 400 mg QD regimen. This is thought to be due to higher drug accumulation and reduced effect of saturable absorption processes on oral pacritinib bioavailability with the BID regimen. Evaluation of the efficacy time-course by exposure quartile revealed that patients in the highest quartile (Q4) exhibited the highest maximal response as well as the most durable clinical response over time relative to those that fell in the lower exposure quartiles (Figure 1). Whereas approximately 25% of patients from the completed Phase 1/2 trials fell in Q4 exposure zone with the 400 mg QD regimen, approximately 48% of patients on the 200 mg BID regimen are projected to fall in this exposure zone or higher. Moreover, assessment of key AEs including GI, anemia, and thrombocytopenia AEs by the exposure quartile, showed that these AEs were not worse with higher systemic exposure of pacritinib. Conclusions Together, the exposure-safety and exposure-efficacy analyses support the potential utility of the 200 mg BID regimen of pacritinib in addition to the 400 mg QD regimen for the clinical development of pacritinib for myelofibrosis as well as other indications such as FLT3 mutated AML. The higher proportion of patients expected to achieve the Q4 exposure levels with the 200 mg BID regimen is predicted to correlate with higher splenic response rates relative to the 400 mg QD regimen. There was no significant exposure-response relationship on key AEs including GI, anemia and thrombocytopenia AEs. The lower local concentration of pacritinib in the GI tract with BID regimen may potentially decrease the incidence of GI adverse events such as diarrhea. Disclosures: Al-Fayoumi: Cell Therapeutics, Inc: Employment. Wang:Cell Therapeutics, Inc.: Employment. Li:Cell Therapeutics, Inc: Consultancy. Dean:Cell Therapeutics, Inc: Employment.

Description: Background: Currently, kinases are an attractive target class for small molecule inhibitors. However, the high similarity of the ATP binding site among protein kinases presents a significant challenge when developing selective small molecule inhibitors for this target class. Notably, optimal evaluation of covalently bound inhibitors requires consideration of the two-step process involving the initial binding (driven by affinity) and a time-dependent inactivation (driven by covalent bond formation). Accordingly, the kinetic parameters Kinact and Ki are important measures to assess selectivity (Singh et al., Nat Rev Drug Discov, 2011 10:307-317). Furthermore, selectivity evaluated in a cell-based system is useful to confirm kinase occupancy by drug in a more physiologically relevant context. Here we apply three approaches to evaluate the selectivity of two FDA approved drugs, ibrutinib (ibr) and acalabrutinib (aca), against their BTK target and its closely related family member TEC. Methods: Ibr and aca were evaluated in three assays of BTK and TEC activity, with selectivity defined as the ratio of BTK/TEC parameters. For each drug molecule, BTK and TEC biochemical potency was first determined by a mobility shift assay in which substrate phosphorylation was assessed after 3 hr, allowing sufficient time for binding and time-dependent inactivation. IC50 based on drug concentration and percent inhibition was determined accordingly. A second biochemical analysis, also based on a mobility shift assay, was performed in which reaction progression was continuously monitored for 5 hr to determine the kinetic parameters Kinact and Ki. The respective ratios of Kinact/Ki were then used to calculate the BTK/TEC selectivity. A third TEC occupancy assay, similar to a previously described BTK occupancy assay, was further developed to evaluate selectivity between the two kinases in a more physiologically relevant cell lysate system. Both cellular BTK and TEC occupancies were measured after incubation for 0.5, 1, and 3 hr with the two drugs at 8 concentrations, ranging from 0 to 1 µM, using the MWCL-1 cell line and commercially available antibodies. Occupancies of the two kinases by ibr and aca were additionally quantified in 3-month treatment-free human CLL samples after incubation for 3 hr with each drug. Results: The biochemical IC50 values for kinase inhibition demonstrated selectivity of 1.0 and 4.2 fold for ibr and aca, respectively (Table 1). These results indicate much lower selectivity for aca than previously published estimates based on affinity-based kinome profiling alone (Barf, et al, J Pharmacol Exp Ther, 2017, 363:240-252). Aca was also found to be highly potent for TEC with an IC50 of 9.7±2.6 nM. Kinact/Ki determinations for ibr and aca produced nearly equivalent selectivity ratios of 1.5 and 3, respectively, consistent with data published by Liclican et al. (Blood, 2016 128:1594). In the MWCL-1 cell line, similar relative selectivity was also observed in the occupancy assay for ibr and aca, ranging 0.4-1 fold for both compounds across three timepoints. In the four human CLL samples, the relative selectivity for BTK/TEC of ibr was 0.8 and aca was 0.9 (Figure 1). Conclusions: The current data indicate that the selectivity of aca for BTK versus TEC is no more than 3-fold based on kinetic analyses. Cellular target occupancy data further confirm that the BTK and TEC selectivity for ibr and aca is approximately equivalent. Collectively, this study contrasts with prior published reports of BTK/TEC selectivity, demonstrating that selectivity evaluation of these covalent kinase inhibitors based on kinome binding data alone is suboptimal and does not reflect true physiological selectivity when accounting for exposure, binding mechanism, enzymatic activity, and possible protein turn-over in the cellular milieu. Disclosures Hopper: Pharmacyclics LLC, an AbbVie Company: Employment. Gururaja:Pharmacyclics LLC, an AbbVie Company: Employment, Equity Ownership. Kinoshita:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Dean:CTI BioPharma Corp.: Employment, Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Equity Ownership. Hill:AbbVie: Equity Ownership; Principia Biopharma: Patents & Royalties: Patent for Principia Biopharma ; Pharmacyclics LLC, an AbbVie Company: Employment. Mongan:Pharmacyclics LLC, an AbbVie Company: Employment, Other: Travel, accommodations, expenses; AbbVie: Equity Ownership; Thermo Fisher Scientific: Patents & Royalties: Patents.

Description: Background: PAC is an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CSF1R that has demonstrated significant and sustained spleen volume reduction (SVR) and symptom control vs BAT (excluding JAK2 inhibitors) in MF pts regardless of platelet count (PERSIST-1). The PERSIST-2 study was a randomized, controlled, open-label, phase 3 trial of PAC 200 mg BID and PAC 400 mg QD vs BAT (including JAK1/JAK2 inhibitor ruxolitinib [RUX]) in pts with 10 or 20 MF whose platelet counts were ≤100,000/µL, a recognized adverse prognostic variable. Prior JAK2 inhibitor use was allowed. Methods: Pts were randomized 1:1:1 to PAC BID, PAC QD, or BAT. The co-primary efficacy endpoints were the percentages of pts achieving ≥35% SVR (MRI or CT) and ≥50% reduction in total symptom score (TSS; MPN-SAF TSS 2.0), both from baseline to Week 24. The primary objective was to compare the efficacy of pooled PAC (BID+QD) to BAT and the secondary objectives were to compare PAC BID and PAC QD individually to BAT. PK samples were collected and analyzed for PAC. Safety analyses were based on all pts exposed to study treatment of any duration (safety population); efficacy analyses were based on ITT pts with a randomization date allowing Week 24 endpoint evaluations prior to the full clinical hold* (ITT efficacy population). Results: 311 pts were randomized (107 PAC BID, 104 PAC QD, 100 BAT), 308 received study drug, and 221 were included in the ITT efficacy population (74 PAC BID, 75 PAC QD, 72 BAT). Demographics and baseline disease characteristics were generally balanced among the treatment arms (Table) and analysis populations. A total of 32 (44%) BAT pts in the ITT efficacy population received RUX as treatment at some point on study. Population PK analyses showed that the steady-state plasma levels achieved with BID were higher than with QD, however the Cmax levels were lower. A significantly higher percentage of pts in the pooled PAC arm achieved SVR ≥35% (18% [27/149]) vs the BAT arm (3% [2/72]; p=0.001; Figure 1A). 25% of PAC pts (37/149) had ≥50% reduction in TSS vs 14% of BAT pts (p=0.079; Figure 1B). In secondary analyses vs BAT, PAC BID demonstrated significant improvement over BAT for both efficacy endpoints with 22% achieving SVR ≥35% (BAT=3%; p=0.001) and 32% achieving ≥50% reduction in TSS (BAT=14%; p=0.011). The PAC QD arm had a significant SVR ≥35% (15% v 3%, respectively; p=0.017), but a similar proportion with ≥50% reduction in TSS (17% v 14%, respectively; p=0.652). More PAC pts reduced their red blood cell transfusion dependence at Week 24 (defined as a ≥50% reduction in average transfusions/month for 3 months relative to baseline) with 19% (7/37) in the PAC QD arm, 22% (8/36) in PAC BID, and 9% (3/35) in BAT. There was no significant difference observed in OS across the treatment arms (Figure 2). Hazard ratios for OS (95% confidence intervals) were 0.68 (0.30, 1.53) for PAC BID v BAT, 1.18 (0.57, 2.44) for PAC QD v BAT, and 0.61 (0.27, 1.35) for PAC BID v QD. PAC BID maintained this survival advantage vs BAT across nearly all demographic and MF-associated risk factors. During the course of the study, 10 (9%), 15 (14%), and 15 (14%) died on PAC BID, PAC QD, and BAT, respectively. The most common treatment-emergent adverse events (AEs) associated with PAC were gastrointestinal (diarrhea, nausea, vomiting) and hematologic (anemia and thrombocytopenia), and were generally less frequent for BID vs QD administration. Grade 3/4 cardiac AEs occurred in 7%, 13% and 9% of PAC BID, PAC QD, and BAT pts, respectively, and grade 3/4 bleeding AEs occurred in 14%, 7%, and 7%, respectively. Grade 3/4 bleeding AEs were associated with grade 3/4 thrombocytopenia, which was also more common in the PAC BID group. Nine pts had cardiac failure (2% PAC QD, 4% PAC BID, 3% BAT) and 1 (1%, PAC QD) had intracranial hemorrhage.* Conclusions: The PERSIST-2 study is the only randomized, controlled trial to date in pts with MF and thrombocytopenia (platelets ≤100,000/µL), allowed prior JAK2 inhibitor treatment exposure (including RUX), and allowed RUX as BAT comparator. Irrespective of prior JAK2 inhibitor treatment, both PAC arms were more effective at SVR than BAT; however, PAC BID appeared more active than QD dosing and achieved significance versus BAT for both SVR and TSS. The most frequent AEs with PAC were gastrointestinal and hematologic toxicities. *PAC on full clinical hold by the FDA on 2/8/2016 based on concerns around excess deaths and cardiac and hemorrhagic events in PERSIST-1. Disclosures Mascarenhas: Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; CTI BioPharma: Research Funding; Janssen: Research Funding; Roche: Research Funding; Promedior: Research Funding. Talpaz:CTI BioPharma: Research Funding; Pfizer: Research Funding; Incyte Corporation: Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Gilead: Other: Travel, Accommodations, Expenses, Research Funding; BMS - Canada: Consultancy. Gerds:CTI BioPharma: Research Funding; Astra-Zeneca: Research Funding; Roche: Research Funding; Incyte: Research Funding. Stein:Incyte Corporation: Consultancy. Gupta:Incyte Corporation: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Drummond:CTI BioPharma: Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Roche: Speakers Bureau. Granston:CTI BioPharma Corp.: Employment. Daly:CTI BioPharma Corp.: Employment. Dean:CTI BioPharma Corp.: Employment, Equity Ownership. Al-Fayoumi:CTI BioPharma Corp.: Employment, Equity Ownership. Callahan:CTI BioPharma: Employment. Singer:CTI BioPharma Corp.: Employment, Equity Ownership, Other: Leadership . Gotlib:Novartis: Other: Travel, Accommodations, Expenses; Steering Committee Chairman, Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding; Gilead: Research Funding; Incyte: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Jamieson:GSK: Research Funding; Johnson & Johnson: Research Funding; CTI BioPharma: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria, Speakers Bureau; Baxter: Consultancy, Honoraria; Shire: Speakers Bureau; Gilead: Speakers Bureau; Incyte: Speakers Bureau. Mesa:Novartis: Consultancy, Honoraria; Incyte: Research Funding; Gilead: Research Funding; CTI BioPharma: Research Funding; Celgene: Research Funding; Genetech: Research Funding; Promedior: Research Funding. Verstovsek:CTI BioPharma Corp: Research Funding.