OBJECTIVE Obexelimab is an investigational, bifunctional, noncytolytic monoclonal antibody that binds CD19 and FcyRIIb to inhibit B cells, plasmablasts, and plasma cells. This trial evaluated the efficacy and safety of obexelimab in the treatment of patients with systemic lupus erythematosus (SLE). METHODS During Screening, patients with active, non-organ-threatening SLE received corticosteroid injections to ameliorate symptoms while immunosuppressants were withdrawn (≤10 mg/day prednisone equivalent and ≤400 mg/day hydroxychloroquine allowed). Patients with improved disease activity were randomized 1:1 to obexelimab 5 mg/kg IV or placebo once every 2 weeks until Week 32 or loss of improvement (LOI). RESULTS 104 patients were randomized. Analysis of the primary endpoint, proportion of patients reaching Week 32 without LOI, used an efficacy-evaluable (EE) population defined as patients who completed the study or withdrew for flare or treatment-related toxicity. This endpoint did not reach statistical significance: 21/50 (42.0%) obexelimab-treated vs. 12/42 (28.6%) placebo-treated patients (p=0.183). Time to LOI was increased in obexelimab-treated vs. placebo-treated patients in the EE (HR 0.53, p=0.025) and intention-to-treat (HR 0.59, p=0.062) populations. In obexelimab-treated patients, B cells decreased approximately 50%, and trough concentration and inclusion in baseline gene expression clusters with high B cell pathway modules were associated with increased time to LOI. Obexelimab was associated with infusion reactions but was generally safe and well-tolerated. CONCLUSION Although the primary endpoint was not reached, secondary analysis showed time to LOI was significantly increased in obexelimab-treated patients, and analysis of patient subsets defined by gene expression patterns at baseline suggests a responding subpopulation.

BACKGROUND:Obexelimab is a bifunctional, non-cytolytic, humanised monoclonal antibody that binds CD19 and Fc gamma receptor IIb to inhibit B cells, plasmablasts, and CD19-expressing plasma cells. We aimed to evaluate the safety, clinical efficacy, and pharmacodynamic effects of obexelimab in patients with active IgG4-related disease. METHODS:We conducted an open-label, single-arm, single centre, phase 2 pilot trial at the Massachusetts General Hospital in Boston, MA, USA. Eligible patients were aged 18-80 years and had active IgG4-related disease confirmed by an IgG4-related disease responder index score of 3 or more. Patients received 5 mg/kg of obexelimab intravenously every 2 weeks for 24 weeks. Patients on glucocorticoids at baseline were expected to discontinue usage within 2 months following enrolment. The primary endpoint was the proportion of patients with a decrease of 2 or more from baseline in the IgG4-related disease responder index at day 169 (ie, primary responders). Patients who achieved a decrease of 2 or more at any visit were designated as responders. Adverse events were graded on a scale of 1-5 (ie, mild, moderate, severe, life-threatening, or death) according to the Common Terminology Criteria for Adverse Events grading scale (version 4.3). Exploratory analyses were quantification of B-cell CD19 receptor occupancy, plasmablast, total B-cell and CD4+ cytotoxic T-cell count by flow cytometry, and immunoglobulin concentrations by nephelometry. This study is registered with ClinicalTrials.gov, NCT02725476. FINDINGS:Between Feb 24, 2016, and Dec 21, 2016, we enrolled 15 patients. The median age was 63 years (IQR 52-65). Ten (67%) of 15 patients were male, five (33%) were female, and 12 (80%) were White. At baseline, 12 (80%) of 15 patients had an elevated median serum IgG4 concentration of 220 mg/dL (IQR 124-441), and the median IgG4-related disease responder index score was 12 (IQR 7-13). 12 (80%) of 15 patients achieved the primary endpoint (ie, primary responders), 14 (93%) were defined as responders. Reductions from baseline in serum B cells and plasmablasts were observed following treatment with obexelimab. However, in most patients with follow-up data, serum B cells recovered to 75% of baseline concentrations within 42 days of the final obexelimab dose. 13 (87%) of 15 patients reported adverse events, one of which (an infusion reaction) resulted in treatment discontinuation. INTERPRETATION:All patients except for one had clinical responses to obexelimab treatment. Both reductions in circulating B cells without evidence of apoptosis during obexelimab treatment and their rapid rebound after treatment discontinuation suggest that obexelimab might lead to B-cell sequestration in lymphoid organs or the bone marrow. These results support the continued development of obexelimab for the treatment of IgG4-related disease. FUNDING:Xencor, Zenas BioPharma, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute of Allergy and Infectious Diseases.

In a phase-2 study, the telomerase inhibitor imetelstat induced rapid hematologic responses in all patients with essential thrombocythemia who were refractory or intolerant to prior therapies. Significant molecular responses were achieved within 3-6 months in 81% of patients with phenotypic driver mutations in JAK2, CALR and MPL. Here, we investigated the dynamics of additional somatic mutations in response to imetelstat. At study entry, 50% of patients carried 1-5 additional mutations in the genes ASXL1, CBL, DNMT3A, EZH2, IDH1, SF3B1, TET2, TP53 and U2AF1. Three patients with baseline mutations also had late-emerging mutations in TP53, IDH1 and TET2. Most clones with additional mutations were responsive to imetelstat and decreased with the driver mutation, including the poor prognostic ASXL1, EZH2 and U2AF1 mutations while SF3B1 and TP53 mutations were associated with poorer molecular response. Overall, phenotypic driver mutation response was significantly deeper in patients without additional mutations (P = 0.04) and correlated with longer duration of response. In conclusion, this detailed molecular analysis of highly pretreated and partly resistant patients with essential thrombocythemia reveals a high individual patient complexity. Moreover, imetelstat demonstrates potential to inhibit efficiently co-incident mutations occurring in neoplastic clones in patients with essential thrombocythemia. (ClinicalTrials.gov number, NCT01243073. N Engl J Med 2015; 373:920-928, DOI: 10.1056/NEJMoa1503479.)

Background: XmAb5871 is a humanized anti-CD19 antibody Fc-engineered for increased affinity to FcγRIIb. Co-ligation of CD19 and FcγRIIb inhibits B lineage cells key to SLE pathogenesis. Objectives: This Phase 2 study was designed to minimize background medications and placebo responses to improve interpretation of a small trial in a complex, heterogenous disease. Methods: SLE patients were enrolled with active disease, ameliorated during screening with ≥160 mg of IM Depo-Medrol. Improvement was required before randomization, defined by decrease in SLEDAI ≥4 points or ≥1 grade in a BILAG A or B score. Immunosuppressive drugs were stopped except antimalarials and/or ≤10 mg/day prednisone or equivalent. Subjects were randomized to IV XmAb5871 (5 mg/kg) or placebo and given Depo-Medrol 80 mg IM on Days 1 and 15, after which, steroid impact was expected to withdraw gradually. Study treatments were given Q14 days for up to 16 doses or loss of improvement (LOI), defined as SLEDAI increase ≥4 points OR new BILAG A or B, with investigator-determined significance. At LOI, patients could receive immediate standard treatments. The primary endpoint was the proportion with no LOI by Day 225 in the efficacy evaluable group (those completing Day 225 or withdrawn for LOI or drug-related adverse event). Results: 104 subjects were randomized: 99 female, median age 45 (20-65). The primary endpoint was met by 21 (42%) of XmAb5871-treated patients vs 12 (28.6%) of the placebo group (p=0.18). All but one responder also fulfilled the SRI-4 response definition from screening to completion. Results did not differ in those with or without anti-dsDNA and/or ENA antibodies. Time to flare was significantly longer in the XmAb5871 group (p=0.025) (figure 1). XmAb5871-treated patients with LOI had less recurrent disease after IM steroid cessation than those in the placebo group; 6 (20%) of placebo patients developed BILAG A scores vs 3 (13%) in the active arm. 9 (30%) of worsening placebo patients had SLEDAI increase ≥7 vs 0 in the XmAb5871 group. SLEDAI scores were higher and increased sooner after disease nadir with placebo vs XmAb5871 (figure 2); 16 (30.8%) of XmAb5871 patients vs 7 (13.5%) placebo patients sustained LLDAS (low disease) during months 6-8 (p=0.0453). Transient, infusion-related gastrointestinal side effects occurred in XmAb5871-treated patients during the 1st or 2nd infusion. There were 8 SAEs in 7 XmAb5871-treated subjects, 5 in 4 placebo patients, no opportunistic infections, and no deaths. Infection rate was low compared to other SLE trials. Conclusion: XmAb5871 was well-tolerated. Preliminary data from this small trial indicates suppression of disease recurrence after treatment withdrawal, supporting further evaluation of XmAb5871 in SLE. Disclosure of Interests: Joan Merrill Grant/research support from: Genentech, UCB, GSK, EMD Serono, Pfizer, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Amgen, Xencor, Neovacs, Consultant for: Genentech, UCB, GSK, EMD Serono, Pfizer, RemeGen, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Immupharma, Amgen, Janssen, Sanofi, Neovacs, Anthera, Speakers bureau: UCB, GSK, EMD Serono, Bristol Myers Squibb, Medimmune/Astra Zeneca, Janssen, Joshua June: None declared, Fotios Koumpouras: None declared, Wambui Machua: None declared, Mohammad Faisal Khan: None declared, Anca Askanase: None declared, Arezou Khosroshahi: None declared, Saira Sheikh: None declared, Judith A. James: None declared, Joel Guthridge: None declared, Gaurav Rathi Shareholder of: Xencor Inc, Employee of: Xencor Inc, Bart Burington Shareholder of: Xencor Inc, Employee of: Xencor Inc, Paul Foster Shareholder of: Xencor Inc, Employee of: Xencor Inc, Debra Zack Shareholder of: Xencor Inc, Employee of: Xencor Inc

Key Points Clinically relevant imetelstat concentrations significantly inhibit CFU-MEG formation from MNCs of ET patients and reduce hTERT expression. However, similar concentrations of imetelstat do not inhibit cytokine-induced CFU-MEG from MNCs of healthy donors.

Abstract Background/Aims: Myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF), are clonal disorders characterized by unlimited proliferation of hematopoietic cells. Besides the dominant clone, in the majority of cases defined by a driver mutation (JAK2V617F, CALR or MPL mutation), sub-clones carrying additional mutations (e. g. in the genes ASXL1, CBL, DNMT3A, EZH2, IDH1, U2AF1, SF3B1, TET2, TP53) and/or normal polyclonal hematopoiesis coexist. Due to the loss of telomere sequences with each cell division, the length of telomeres can be used to describe clonal dynamics of hematopoietic cells. In neoplastic cells with a high mitotic rate shorter telomeres are typically found compared to the telomere length (TL) in normal counterparts. In the ET phase 2 study with the telomerase inhibitor imetelstat we demonstrated rapid and durable hematologic and molecular responses (Baerlocher et al. N Engl J Med 2015) and suppression of clones with non-driver mutations (Oppliger Leibundgut et al, ASH 2015). Here, our aims were 1) to evaluate the TL in subsets of leukocytes from patients (pts) with MPN compared to healthy individuals and 2) to study the TL dynamics in ET pts treated with imetelstat and to correlate those with hematologic and molecular responses. Patients and Methods: Blood samples from 63 standard of care (SOC)-treated or untreated pts with MPN (15 ET, 36 PV, 12 MF) diagnosed according to WHO 2008 criteria as well as from 14 ET pts treated with imetelstat after failure or intolerance to ≥1 prior therapy were analyzed for TL. TL percentiles from over 400 healthy individuals served as reference. Leukocytes were extracted from the peripheral blood and TL was measured in subsets of leukocytes by automated multicolor flow-FISH (Baerlocher et al, Nat Protoc. 2006). Results: 81% of the 62 MPN pts (11/15 ET, 32/35 PV, 7/12 MF) carried a JAK2 mutation, 6 (1 ET, 5 MF) a CALR mutation, 1 ET pt had a MPL mutation, 2 ET pts were triple negative and 3 PV pts were JAK2 wild type. 23 pts were treated with phlebotomy, 32 with hydroxyurea, 3 with anagrelide and 3 with IFN-alpha. The median age at study entry was 62 yrs (23-89, ET/PV/MF 64/58/66 yrs) and the median time since diagnosis was 2.7 yrs (0.3-14.2) in the ET SOC cohort. In the imetelstat cohort, 9/14 ET pts carried a JAK2V617F mutation and 5 a CALR mutation. The median age at study entry was 60.5 yrs (21-80) and the median time since diagnosis was 6.7 yrs (0.3-21). The telomere length values (TLV) in granulocytes from the 63 MPN pts on SOC were around the 10th percentile for pts with ET and PV and below the 1st percentile for most pts with MF. In the imetelstat cohort, 8 of 14 ET pts with a median of 2 prior therapies demonstrated TLV in granulocytes <1st percentile before the imetelstat treatment, which is significantly lower than in ET pts on SOC (p < 0.01). In 6 of 9 ET pts on imetelstat the TLV were higher after 9 months. In addition, this difference in TL correlated significantly with the maximum reduction of the JAK2V617F mutational burden (p = 0.0137). Of interest, the 3 pts with lower or steady TLV after 9 months of treatment had the highest number of additional mutations before imetelstat treatment and despite a good suppression of the clone with the driver mutation these sub-clones were only partially responsive to imetelstat (i.e. 3 to 5 additional mutations in ASXL1, CBL, DNMT3A, EZH2, TET2, TP53, SF3B1 and U2AF1). Overall, pts with high level additional mutational burden had shorter TLV (age-adjusted mean difference from 50th percentile ±STD -3.6 ± 0.5 kb) at baseline than pts with no or low level additional mutational burden (age-adjusted mean difference from 50th percentile ±STD -2.9 ± 1 kb), and in both sets of pts mean TLV were higher after 9 months of imetelstat treatment. Conclusions: The lower TLV found in granulocytes of pts with MPN and especially with MF compared to healthy individuals reflect the higher mitotic history of malignant clones. In the ET imetelstat cohort, the very low TLV found at baseline might result from longer disease duration and resistance and/or intolerance to prior therapies. The higher TLV observed after 9 months of treatment with imetelstat and correlation with the reduction in the driver mutational burden suggests that imetelstat treatment in ET pts may suppress neoplastic clones and, in the absence of a high additional mutational burden, favor recovery of normal hematopoiesis. Disclosures Oppliger Leibundgut: Geron: Research Funding; Novartis: Research Funding. Burington:Geron Corporation: Employment. Ottmann:Fusion Pharma: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Spitzer:Trovagene Inc: Consultancy; Moldx Palmetto GBA: Consultancy; Incyte: Consultancy. Odenike:CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Research Funding. McDevitt:Salamandra Inc: Consultancy; Alexion: Membership on an entity's Board of Directors or advisory committees. Röth:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Research Funding. Snyder:Ariad: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Baerlocher:Geron: Research Funding; Janssen: Research Funding; Novartis: Research Funding.

BACKGROUNDImetelstat, a 13-mer oligonucleotide that is covalently modified with lipid extensions, competitively inhibits telomerase enzymatic activity. It has been shown to inhibit megakaryocytic proliferation in vitro in cells obtained from patients with essential thrombocythemia. In this phase 2 study, we investigated whether imetelstat could elicit hematologic and molecular responses in patients with essential thrombocythemia who had not had a response to or who had had unacceptable side effects from prior therapies.METHODSA total of 18 patients in two sequential cohorts received an initial dose of 7.5 or 9.4 mg of imetelstat per kilogram of body weight intravenously once a week until attainment of a platelet count of approximately 250,000 to 300,000 per cubic millimeter. The primary end point was the best hematologic response.RESULTSImetelstat induced hematologic responses in all 18 patients, and 16 patients (89%) had a complete hematologic response. At the time of the primary analysis, 10 patients were still receiving treatment, with a median follow-up of 17 months (range, 7 to 32 [ongoing]). Molecular responses were seen in 7 of 8 patients who were positive for the JAK2 V617F mutation (88%; 95% confidence interval, 47 to 100). CALR and MPL mutant allele burdens were also reduced by 15 to 66%. The most common adverse events during treatment were mild to moderate in severity; neutropenia of grade 3 or higher occurred in 4 of the 18 patients (22%) and anemia, headache, and syncope of grade 3 or higher each occurred in 2 patients (11%). All the patients had at least one abnormal liver-function value; all persistent elevations were grade 1 or 2 in severity.CONCLUSIONSRapid and durable hematologic and molecular responses were observed in patients with essential thrombocythemia who received imetelstat. (Funded by Geron; ClinicalTrials.gov number, NCT01243073.).

BACKGROUND:Continuation or 'switch' maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC. PATIENTS AND METHODS:The primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0-1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization. RESULTS:Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54-1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41-1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14-1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11-1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39-1.88; and HR = 0.51; 95% CI 0.2-1.28; P = 0.145). CONCLUSIONS:Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat.

PRO131921 is a third-generation, humanized anti-CD20 monoclonal antibody with increased antibody-dependent cytotoxicity and complement-dependent cytotoxicity compared to rituximab. In this phase I study, PRO131921 was administered as a single agent to patients with CD20+, relapsed or refractory, indolent non-Hodgkin lymphoma (NHL) who had been treated with a prior rituximab-containing regimen. The primary aim of this study was safety and tolerability of PRO131921. The secondary aim of the study, and focus of this report, was to determine the pharmacokinetics (PK) profile of PRO131921 and establish a correlation between drug exposure and clinical efficacy. Patients were treated with PRO131921 by intravenous infusion weekly for 4 weeks and the dose was escalated based on safety in a 3+3 design. Twenty-four patients were treated with PRO131921 at doses from 25mg/m(2) to 800 mg/m(2). Analysis of PK data demonstrated a correlation between higher normalized drug exposure (normalized AUC) and tumor shrinkage (p = .0035). Also, normalized AUC levels were higher among responders and subjects displaying tumor shrinkage versus subjects progressing or showing no regression (p = 0.030). In conclusion, PRO131921 demonstrated clinical activity in rituximab-relapsed and refractory indolent NHL patients. The observation that higher normalized AUC may be associated with improved clinical responses has potential implications in future trials of monoclonal antibody-based therapies, and emphasizes the importance of early PK studies to optimize antibody efficacy.

Background: In essential thrombocythemia (ET), mutations in the calreticulin gene (CALR) are found in the majority of patients that are negative for mutations in the JAK2 and MPL genes. Patients with mutated CALR have a better prognosis and lower thrombosis risk than those with mutated JAK2. Recently, decreases in the CALR mutant allele burden have been observed with interferon alpha after long-term treatment of two- and four-years, respectively (NEJM 2014, 371;2:188-9, Cassinat B. et al.). From the clinical phase II ET study with imetelstat (IT), a first in class, potent, specific inhibitor of telomerase, we reported a substantial and rapid decrease in the JAK2V617F allele burden. 7/8 patients (88%) reached a partial molecular response (MR: >50% reduction from baseline), 6 within the first 3 months and 1 after 12 months.

Tumor regrowth after chemotherapy may be driven by growth of tumor ‘stem cells’. Telomerase, required for indefinite replication, is upregulated both in putative ‘stem cells’ and bulk tumor cells. Imetelstat, a lipidated 13-mer oligonucleotide, is a potent and specific inhibitor of telomerase. A randomized phase II study was conducted to assess whether imetelstat, given as maintenance therapy, prolongs PFS in advanced NSCLC: results for the primary and secondary endpoints are reported separately. NSCLC cell lines and other tumor cells with short telomeres appear to be more sensitive to imetelstat in vitro than those with long telomeres. A planned exploratory analysis to determine PFS as a function of tumor telomere length (TL) was performed. Tumor TL was assessed in archival tumor specimens from pts by quantitative PCR (qPCR). TL data were available for 57 of the 116 pts accrued in the clinical trial. PFS was evaluated in patients grouped into the shortest 1/2, shortest 1/3 and shortest 1/4 of TL. In 19 pts with the shortest 1/3 TL measured by qPCR, imetelstat maintenance increased PFS with a HR in favor of the imetelstat arm of 0.32 (95% CI 0.1 to 1.0), p=0.042 (un-stratified log rank). Median PFS was 4.0 months for the imetelstat-treated short TL sub-group and 1.5 months for the control short TL sub-group. In the 38 pts with the longest 2/3 TL HR was 0.83 (95% CI 0.36 to 1.9). Results in the group with the shortest 1/4 of TL were similar to the shortest 1/3 TL group, and in the shortest 1/2 group, results were consistent but attenuated, indicating that a smaller subset may contain patients with the most potential to benefit. In the control arm, short TL was associated with shorter median PFS (1.48 months) compared to patients with long TL (2.7 months), suggesting that short TL has a negative prognostic value. These findings suggest that imetelstat given as maintenance therapy prolongs PFS in pts with advanced NSCLC whose tumors have short telomeres as measured by qPCR. The data are consistent with the hypothesis that clinical benefit from telomerase inhibition is greater in patients with tumors possessing short telomeres. Prospective confirmation of these results in solid tumors and hematologic neoplasms is planned. Citation Format: Alberto Chiappori, Ekaterina Bassett, Bart Burington, Tatjana Kolevska, David R. Spigel, Steven Hager, Mark Rarick, Shirish Gadgeel, Normand Blais, Joachim Von Pawel, Lowell Hart, Hui Wang, Kevin Eng, Martin Reck, Joan Schiller. Improved progression-free survival (PFS) in patients with short tumor telomere length: Subgroup analysis from a randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced NSCLC . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2376. doi:10.1158/1538-7445.AM2013-2376

Abstract Abstract 179 Background: Myeloproliferative neoplasms (MPNs), such as essential thrombocythemia (ET), are driven by neoplastic progenitor cells. The JAK2 V617F mutation can be detected in approximately 50% of patients (pts) with ET, and the JAK2 V617F allele burden can be used to measure the treatment-induced molecular response (MR) over time. Telomerase is upregulated in neoplastic progenitor cells and sustains indefinite replication. Imetelstat is a first in class, potent, specific inhibitor of telomerase which selectively distributes to bone marrow and inhibits thrombopoiesis. In vitro studies demonstrate that imetelstat selectively inhibits spontaneous megakaryocytic colony-forming unit (CFU-Meg) growth from the blood of pts with ET but not from healthy individuals. Phase I studies have demonstrated that imetelstat inhibits telomerase activity in pts at doses of 7.5 mg/kg and above. Therefore, unlike conventional cytoreductive therapy and JAK2 kinase inhibitors, imetelstat may be uniquely able to selectively inhibit proliferation of neoplastic clonogenic cells in pts with ET and modify the biology and progression of the disease. Methods: A phase II study enrolled pts with ET who had failed or were intolerant to at least one prior therapy, or who refused standard therapy. Pts were treated with imetelstat 7.5 mg/kg or 9.4 mg/kg IV weekly. After attainment of best platelet response in the induction phase, maintenance dosing with imetelstat was commenced with dosing based upon platelet count. Primary endpoint was best overall hematologic response (HR) with complete response (CR) defined as platelet count <400 × 103/μl maintained for at least 4 consecutive weeks in the absence of new thromboembolic events. A key secondary endpoint was rate of MR in patients with JAK2 V617F molecular mutations. JAK2 V617F allele burden was measured by allele-specific quantitative real-time PCR with a limit of detection of 0.1%. CFU-Meg growth pre- and post-treatment and tolerability were also assessed. Results: As of July 9, 2012, 13 pts were treated. Median age was 60 yrs (range 21–83) with a median of 2 prior treatments (range 1–3). Median years since initial diagnosis were 5.8 (range 0.3 to 24.9) and initial platelet count was 809 × 103/μl (range 601 to 1359 × 103/μl). Best overall HR was 100%, with 11 of 13 pts achieving a confirmed CR after a median of 6.1 weeks (range 5.1 to 14.1 wks). Twelve of 13 pts remain on maintenance therapy (median time on study 26.1 weeks) and despite transient elevations of platelets above best response, pts continue to be responsive to imetelstat. Four pts have reached 1 year of therapy and continue to be treated with ongoing HR. Dosing frequency on maintenance therapy was generally reduced with time. A substantial decrease in JAK2 V617F allele burden was demonstrated in all 5 JAK2 V617F-positive pts (mean allele burden reduction of 82%; range of 59–94%, see table below). Four pts who were eligible for MR assessment by LeukemiaNetcriteria (initial JAKV617F allele burden >10%) reached molecular partial responses (PR): one pt after 12 weeks, which has been maintained through 1 year, and 3 other pts at 24, 36 and 48 weeks of therapy. One additional pt with JAK2 V617F levels of 4.8% prior to therapy has also had a 75% reduction after 12 weeks of treatment. A reduction in the spontaneous growth of CFU-Meg was also observed in the 2 pts tested, with 93% and 96% reduction from baseline, respectively. Long-term administration of imetelstat was generally well tolerated. Common adverse events reported on therapy were mild to moderate gastrointestinal toxicities, reductions in neutrophil counts, and fatigue. Conclusions: Imetelstat rapidly induces and maintains hematologic responses in pts with ET who have failed or are intolerant to conventional therapies. Importantly, substantial MR is observed in all JAK2 V617F-positive pts and inhibition of the neoplastic clonogenic growth ex-vivo is demonstrated. The reduction in JAK2 V617F allele burden and cytokine-independent growth of CFU-Meg suggests that imetelstat has a relatively selective inhibitory effect on the growth of the neoplastic clone(s) which drive ET and has the potential to modify the underlying biology of MPNs. Additional data will be presented from this ongoing study. Disclosures: Baerlocher: Geron Corporation: Research Funding. Oppliger Leibundgut:Geron Corporation: Research Funding. Ayran:Geron Corporation: Employment. Blaney:Geron Corporation: Employment. Burington:Geron Corporation: Employment. Morfeld:Geron Corporation: Employment. Odenike:Sanofi Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Reddy:Geron Corporation: Employment. Roeth:Geron Corporation: Research Funding. Stuart:OncoMed Pharmaceuticals: Consultancy; Geron Corporation: Consultancy, Employment.

The primary function of B cells, critical components of the adaptive immune response, is to produce antibodies against foreign antigens, as well as to perform isotype class switching, which changes the heavy chain of an antibody so that it can interact with different repertoires of effector cells. CD40 is a member of the tumor necrosis factor superfamily of cell surface receptors that transmits survival signals to B cells. In contrast, in B cell cancers, stimulation of CD40 signaling results in a heterogeneous response in which cells can sometimes undergo cell death in response to treatment, depending on the system studied. We found an association between sensitivity to CD40 stimulation and mutation of the tumor suppressor p53 in a panel of non-Hodgkin's lymphoma cell lines. Consistent with p53's tumor suppressor role, we found that higher levels of intrinsic DNA damage and increased proliferation rates, as well as higher levels of BCL6, a transcriptional repressor proto-oncogene, were associated with sensitivity to CD40 stimulation. In addition, CD40 treatment-resistant cell lines were sensitized to CD40 stimulation after the introduction of DNA-damaging agents. Using gene expression analysis, we also showed that resistant cell lines exhibited a preexisting activated CD40 pathway and that an mRNA expression signature comprising CD40 target genes predicted sensitivity and resistance to CD40-activating agents in cell lines and mouse xenograft models. Finally, the gene signature predicted tumor shrinkage and progression-free survival in patients with diffuse large B cell lymphoma treated with dacetuzumab, a monoclonal antibody with partial CD40 agonist activity. These data show that CD40 pathway activation status may be useful in predicting the antitumor activity of CD40-stimulating therapeutic drugs.

Background and objectives Understanding the time course of sexual partnerships is important for understanding sexual behaviour, transmission risks for sexually transmitted infections (STI) and development of mathematical models of disease transmission. Study design The authors describe issues and biases relating to censoring, truncation and sampling that arise when estimating partnership duration. Recommendations for study design and analysis methods are presented and illustrated using data from a sexual-behaviour survey that enrolled individuals from an adolescent-health clinic and two STD clinics. Survey participants were queried, for each of (up to) four partnerships in the last 3 months, about the month and year of first sex, the number of days since last sex and whether partnerships were limited to single encounters. Participants were followed every 4 months for up to 1 year. Results After adjustment for censoring and truncation, the estimated median duration of sexual partnerships declined from 9 months (unadjusted) to 1.6 months (adjusted). Similarly, adjustment for censoring and truncation reduced the bias in relative risks for the effect of age in a Cox model. Other approaches, such as weighted estimation, also reduced bias in the estimated duration distribution. Conclusion Methods are available for estimating partnership duration from censored and truncated samples. Ignoring censoring, truncation and other sampling issues results in biased estimates.