Lebovic, Daniel

Abstract Background LGH447 is a novel, specific pan-Pim kinase inhibitor in development for the treatment of patients with multiple myeloma (MM) and other hematologic malignancies. The PIM kinase gene family encodes 3 serine/threonine protein kinases that have roles in cell cycle progression and survival. In human disease, elevated levels of Pim1 and Pim2 are associated with hematologic malignancies, with MM showing the highest level of Pim2 expression. In preclinical studies, a majority of MM cell lines proved sensitive in vitro to LGH447-mediated Pim inhibition, exhibiting a dose-dependent decrease in cell proliferation. Furthermore, LGH447 was well tolerated and demonstrated significant inhibition of tumor growth in xenograft mouse models of MM as compared with control animals, supporting the clinical development of LGH447 in MM patients. Methods Patients with relapsed/refractory MM for whom no effective treatment options exist were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CLGH447X2101). Escalating doses of single-agent LGH447 were administered orally on a continuous daily dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to estimate the maximum tolerated dose (MTD) of LGH447 administered as a single agent, orally, once daily. Secondary objectives included assessing the safety, tolerability, preliminary antimyeloma activity, and pharmacokinetic (PK) profiles of LGH447. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events v4.03. Efficacy assessments were made by investigators according to International Myeloma Working Group (IMWG) uniform response criteria with modifications. Following determination of the MTD for LGH447, additional patients will be enrolled in an expansion cohort to further characterize the safety and tolerability profile of LGH447. Results At the data cutoff, 19 patients have been treated at the following doses: 70 mg (n = 5), 150 mg (n = 6), 200 mg (n = 4), 250 mg (n = 4), with enrollment ongoing in dose escalation. Median age was 66 years (range, 41-75 years). Most patients (94.7%) presented with baseline Eastern Cooperative Oncology Group performance status 0-1. Most patients (73.7%) had received ≥ 2 prior regimens (median 4; range, 1-11), 89.5% had received prior bortezomib, and 84.2% had received prior lenalidomide and/or thalidomide (68.4% and 47.4%, respectively). Ten patients are ongoing at doses between 150-250 mg, with a median duration of exposure of 6 weeks (range, 1-26.6 weeks), and 9 patients discontinued (disease progression [n = 6], AEs [n = 2], withdrawal of consent [n = 1]). There was 1 DLT consisting of grade 3 thrombocytopenia at the 200 mg dose level and no reported suspected unexpected serious AEs. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs were thrombocytopenia (31.6%), anemia (21.1%), and neutropenia (15.8%). No deaths have occurred on study. LGH447 displayed time-dependent PK with a 3- to 6-fold accumulation from day 1 to steady state (day 14). After a single oral dose, area under the curve and maximum concentration increased somewhat more than in proportion to the dose from 70 to 250 mg. Evidence of single-agent activity, as determined by investigators using IMWG criteria, has been seen in multiple patients, with best response to date being a very good partial response (VGPR). Conclusion In heavily treated patients with relapsed/refractory MM, LGH447 was generally well tolerated and exhibited evidence of single-agent efficacy in multiple patients, validating Pim kinase inhibition as a promising therapeutic rationale and supporting its further clinical development in patients with MM and other hematologic malignancies. Dose escalation is ongoing and updated results will be presented. Disclosures: Ocio: BMS: Consultancy; Arry-520: Consultancy; Pharmamar: Research Funding; Celgene: Honoraria, Research Funding; Onyx: Consultancy, Research Funding; Novartis: Honoraria. Thomas:Novartis: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees; Millenium: Research Funding. Günther:Novartis: Consultancy, Research Funding. Lebovic:Celgene: Speakers Bureau; Allos/Spectrum: Speakers Bureau; Genentech: Speakers Bureau; Onyx: Speakers Bureau. Kumar:Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Jakubowiak:Onyx: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria. Song:Novartis: Employment. Xiang:Novartis: Employment. Hynds:Novartis: Employment. Vanasse:Novartis: Employment. Goh:Jannsen: Research Funding; BMS: Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Hospira: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Abstract Introduction Multiple Myeloma is not a single disease. There is increasing support for risk classification in combination with treatment decision making because of its impact on clinical outcomes. Here we demonstrate additional evidence of the prognostic value of SKY92, an established genetic marker of high risk Multiple Myeloma in a multicenter collection of samples with undisclosed treatments. Materials Methods A public GEP dataset (MMRC, MMGI portal) contained 114 cases of untreated Multiple Myeloma and was used for SKY92 high risk OS prediction (Kuiper et al. Leukemia 2012). In collaboration with MMRC, OS (with a minimum of at least 2 year follow-up) was collected for 91 of 114 cases for the purpose of this analysis. Briefly, CD138-positive plasma cells had been purified prior to total RNA extraction and subsequent gene expression profiling on Affymetrix U133Plus2.0 GeneChips. The 91 cases represented 9 different clinical sites and their CEL files were normalized as a single batch against a reference cohort of 329 cases after which the SKY92 risk scores were determined as either standard risk or high risk. Results SKY92 resulted in 19 high risk (20.9%) versus 72 standard risk (79.1%) cases in the unselected 91 case-cohort. Comparisons with other high risk GEP signatures will be performed. The OS analysis (Figure 1) shows that the HR cases have significantly shorter survival (Hazard Ratio 11, p = 7 x 10-5). Table 1 shows that high risk patients had more elevated B2M (26.3% vs 13.9%), more low albumin (26.3% vs 16.7%) and more high creatinine (26.3% vs 11.0%). There was no difference between high and standard groups in diagnosis dates (not shown). Cause of the 16 (84.2%) deaths among the high risk cases, and 21 (29.1%) deaths among the standard risk cases indicates that high risk contains less disease progression deaths (57.1% vs 31.3%), and more unknown deaths (56.3% vs 23.8%). Conclusions The SKY92 classifier identified 19 of 91 cases (21%) as high risk, recapitulating the percentage of high risk in previously studied cohorts (Kuiper et al. 2012). Moreover the hazard ratio of 11 when events up to 24 months or 8.18 when all events are considered, emphasizes the unmet medical need of high risk cases identified with SKY92 as 69% of all deaths within 2 years (9/13 death events) were in this category. Acknowledgments This research was performed within the framework of CTMM, the Center for Translational Molecular Medicine, project BioCHIP grant 03O-102. Rafael Fonseca is a Clinical Investigator of the Damon Runyon Cancer Research Fund. This work is supported by grants R01 CA83724, ECOG CA 21115T, Predolin Foundation, Mayo Clinic Cancer Center and the Mayo Foundation. Disclosures: van Beers: Skyline Diagnostics: Employment. Van Vliet:Skyline Diagnostics: Employment. Anderson:celgene: Consultancy; onyx: Consultancy; gilead: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership. Jagannath:Celgene: Honoraria; Millennium: Honoraria. Jakubowiak:BMS: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Kumar:Celgene: Clinical Trial Support Other, Membership on an entity’s Board of Directors or advisory committees; Cephalon: Clinical Trial Support, Clinical Trial Support Other; Millennium: Clinical Trial Support, Clinical Trial Support Other, Membership on an entity’s Board of Directors or advisory committees; Novartis: Clinical Trial Support, Clinical Trial Support Other; Onyx: Clinical Trial Support Other, Membership on an entity’s Board of Directors or advisory committees. Lebovic:Celgene: Speakers Bureau; Onyx: Speakers Bureau. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy. Reece:Onyx: Honoraria; Novartis: Honoraria; Millennium: Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Research Funding. Siegel:Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Vij:Celgene: Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau. Zimmerman:Celgene: Honoraria; Millennium: Honoraria; Onyx: Honoraria. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy, Research Funding; Binding Site: Consultancy; Millennium: Consultancy; AMGEN: Consultancy; Cylene: Research Funding; Prognostication of MM based on genetic categorization of the disease: Prognostication of MM based on genetic categorization of the disease, Prognostication of MM based on genetic categorization of the disease Patents & Royalties.

Abstract Introduction Gene Expression Profiling studies have resulted in signatures capable of providing robust prognosis for Multiple Myeloma (MM) patients, such as the EMC92 [SKY92, Kuiper et al. Leukemia 2012]. Recently, data from 4720 MM patients from the HOVON-65/GMMG-HD4, UAMS-TT2, UAMS-TT3, MRC-IX, APEX and IFM trials were employed to assessed the majority of currently identified prognostic markers and their combinations (GEP, FISH, and biochemistry data, [Kuiper et al ASH 2014]). The "SKY92 + ISS" was identified and validated as the statistically most optimal (i.e. most significant and robust) prognostic marker combination for MM patients. The combination of the EMC92 (=SKY92) and ISS prognostic features proves to be a very powerful, unprecedented and straightforward prognostic system. It identifies four prognostic risk classes: low risk (ISS I-SKY92 standard risk (SR)), intermediate-low (ISS II-SKY92 SR), intermediate-high (ISS III-SKY92 SR) and high risk (ISS I-III, SKY92 high risk). Previously, the SKY92 has been validated on the 91 MM cases in the MMGI cohort [Van Beers et al. ASH 2013]. Here we present an extension of that validation with the SKY92 + ISS combination on the 78 MM cases for whom both GEP and ISS is available, by both assessing as the "4 risk group" model defined above, but also a "3 risk group" model (the two intermediate groups combined) as this may be more relevant and useful for clinical application. Materials and Methods A public untreated MM dataset (Multiple Myeloma Genomics Initiative, MMGI) had n=78 cases for which OS, GEP, and ISS were available for analysis. The prognostic markers SKY92 and ISS were applied as proposed [Kuiper et al ASH 2014] to classify cases into the risk categories. Results The risks for the 4 group classification model are shown in Table 1 and Figure 1, and the 3 risk group model is shown in Table 2 and Figure 1. In the 4 group model, the intermediate-low group (SKY92 standard + ISS II) was a small and not significantly different (p=0.79) from the low risk. The intermediate-high group (SKY92 standard + ISS III) was also a small group, with significantly worse outcome compared with the low risk group (p=0.012). Although stratification into four groups was statistically superior in the training and validation data [Kuiper et al ASH 2014] the interpretability benefits from aggregation of the middle two groups [Fig 1 right]. Table 1. Classification results for the four risk groups (Fig 1 left) Risk group n % Median OS HR vs low risk SKY92 High Risk regardless of ISS 19 24 28.4 m 10.8 SKY92 standard risk + ISS-III 10 13 63.0 m 4.1 SKY92 standard risk + ISS-II 16 21 NR (0.8) SKY92 standard risk + ISS-I (low risk) 33 42 NR NA NR= Not Reached at 96 months, HR= hazard ratio Table 2. Classification results for the three risk groups (Fig 1 right) Risk group n % Median OS HR vs low risk SKY92 High Risk regardless of ISS 19 24 28.4 m 10.1 SKY92 standard risk + ISS-II/III 26 34 78.5 m (1.8) SKY92 standard risk + ISS-I 33 42 NR NA NR= Not Reached at 96 months, HR= hazard ratio, () not significant Conclusions By applying the SKY92 + ISS risk stratification model in an independent validation cohort of newly diagnosed Multiple Myeloma patients, besides a high risk group of 19 patients (24%), a group of 33 patients (42%) with superior prognosis could be predicted (SKY92 standard risk and ISS I) that translated into 62% OS at 96 months. The 19 high risk (SKY92 high risk) cases had very poor prognosis (median survival of 28 months). The combination of SKY92 Standard Risk and ISS II and III seems useful for definition of "intermediate risk" although sample size currently is insufficient for significance compared to low risk. The intention is to also perform this validation on the relapsed samples from the MMGI cohort, once OS data has been collected. This validated risk model could play a role in the design of future treatment strategies for high and low risk MM patients. Figure 1. Kaplan Meier curves on the 78 MMGI cases, split into four (left) or three (right) risk groups based on the combination of SKY92 + ISS. Hazard Ratios (HR) are from a Cox proportional Hazards model comparing a particular group to the low risk group. Figure 1. Kaplan Meier curves on the 78 MMGI cases, split into four (left) or three (right) risk groups based on the combination of SKY92 + ISS. Hazard Ratios (HR) are from a Cox proportional Hazards model comparing a particular group to the low risk group. Disclosures van Beers: SkylineDx: Employment. van Vliet:SkylineDx: Employment. de Best:SkylineDx: Employment. Chari:Novartis: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Other: Institutional Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Onyx: Consultancy, Research Funding. Jagganath:Millennium: Honoraria; Celgene: Honoraria. Jakubowiak:Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: institutional funding for support of clinical trial conduct, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kumar:Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Janssen: Research Funding; AbbVie: Research Funding; Sanofi: Research Funding; Millenium/Takeda: Research Funding; Celgene: Research Funding; Onyx: Research Funding; Skyline, Noxxon: Honoraria. Lebovic:Onyx: Speakers Bureau; Celgene: Speakers Bureau. Lonial:Millennium: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Reece:Onyx: Honoraria; Novartis: Honoraria; Millennium: Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Research Funding. Richardson:Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Stewart:SkylineDx: Membership on an entity's Board of Directors or advisory committees. Vij:Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Zimmerman:Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria; Amgen: Honoraria, Speakers Bureau. Fonseca:Onyx/Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Applied Biosciences: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Abstract Background: LGH447 is a novel, specific pan-Pim kinase inhibitor in development for the treatment of patients with multiple myeloma (MM) and other hematologic malignancies. The PIM (Provirus Integration site for Moloney leukemia) kinase gene family encodes 3 serine/threonine protein kinases that have roles in cell cycle progression and survival. In human disease, elevated levels of Pim1 and Pim2 are associated with hematologic malignancies, with MM showing the highest level of Pim2 expression. In preclinical studies, a majority of MM cell lines proved sensitive in vitro to LGH447-mediated Pim inhibition, exhibiting a dose-dependent decrease in cell proliferation. LGH447 demonstrated significant tumor growth inhibition in xenograft mouse models of MM as compared with control animals, supporting the clinical development of LGH447 in MM patients. Methods: Patients with relapsed/refractory MM for whom no effective treatment options exist were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CLGH447X2101). Escalating doses of single-agent LGH447 were administered orally on a continuous daily dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to estimate the maximum tolerated dose (MTD) of LGH447 administered as a single agent, orally, once daily. Secondary objectives included assessing the safety, tolerability, preliminary anti-myeloma activity, and pharmacokinetics of LGH447. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded according to NCI-CTCAE v4.03. Efficacy assessments were made by investigators according to International Myeloma Working Group (IMWG) uniform response criteria with modifications. Results:At the data cutoff, 54 patients have been treated at the following doses: 70 mg (n = 5), 150 mg (n = 6), 200 mg (n = 6), 250 mg (n = 7), 300 mg (n = 4), 350 mg (n=10), 500 mg (n=10), 700 mg (n=6), with the MTD determined to be 500 mg once daily. Median age was 65 years (range, 41-87 years). Most patients (92.6%) presented with baseline Eastern Cooperative Oncology Group performance status 0-1. Patients were heavily pretreated with a median of 4 prior lines of therapy (range, 1-16). 81.5% had received prior proteasome inhibitor therapy, 83.3% had received prior immunomodulatory therapy (70.4% lenalidomide and 48.1% thalidomide), 68.5% were treated with both proteasome inhibitor and immunomodulatory therapies, and 87.0% had received prior stem cell transplant. Seventeen patients are ongoing at doses between 250-700 mg, with a median duration of exposure of 10.6 weeks (range, 0.1-56.1 weeks), and 37 patients discontinued (disease progression [n = 29], AEs [n = 4], withdrawal of consent [n = 4]). There were 8 DLTs, consisting of four grade 3/4 thrombocytopenia (1 each at 200, 250, 350, 500 mg dose levels), two grade 3 fatigue (1 each at 500 and 700 mg dose levels), one grade 3 hypophosphatemia (300 mg), and one episode of vaso-vagal syncope (700 mg). This last event was the only reported unexpected serious AE that was suspected to be due to LGH447 treatment. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs were thrombocytopenia (18.5%), anemia (18.5%), neutropenia (13%), and fatigue (11.1%). No deaths have occurred on study. Forty-eight individuals (70-500 mg) were evaluable for disease response assessments. Evidence of single agent activity was noted at doses ≥ 150 mg, including 1 VGPR at 200 mg (exposure duration > 55 weeks) and 4 PRs noted at doses ranging from 150-500 mg (respective exposure durations of 32, 29, 24, and 21 weeks). Five additional patients achieved MR, resulting in a clinical benefit rate (≥ MR) of 20.8%, and 23 patients were noted to have SD, resulting in a remarkable disease control rate (≥ SD) of 68.8%. In addition, of those patients with SD, 8 had exposure durations for > 20 weeks. Conclusions:In heavily treated patients with relapsed/refractory MM, LGH447 was generally well tolerated and exhibited evidence of durable single-agent efficacy in multiple patients, with the best response being a VGPR. These findings validate Pim kinase inhibition as a promising therapeutic rationale in MM patients and support further clinical development in patients. Disclosures Ocio: Novartis: Honoraria. Thomas:Novartis: Research Funding; Celgene: Consultancy, Research Funding; Millennium: Research Funding; Idera Pharmaceuticals: Research Funding; Immunomedics: Research Funding. Günther:Novartis: Consultancy, Research Funding. Goh:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jannsen Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Lebovic:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millennium: Consultancy. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Song:Novartis: Employment. Xiang:Novartis: Employment. Patel:Novartis: Employment. Vanasse:Novartis: Employment, Equity Ownership. Kumar:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Novartis: Research Funding; Array: Research Funding; Cephalon: Research Funding.

Abstract Introduction Programmed cell death-1 (PD-1) is an immune checkpoint receptor that inhibits T cell activation upon interaction with its ligands PD-L1 or PD-L2. Increased PD-L1 expression has been reported in various lymphoid malignancies, and may allow these tumors to circumvent host anti-tumor immunity. Nivolumab, a fully human IgG4 monoclonal PD-1 receptor blocking antibody, potentiates T cell activity, and has clinical efficacy in various solid tumors. We hypothesized that nivolumab might also have clinically important anti-tumor activity in patients with lymphoid malignancies. Methods This open-label study enrolled patients with relapsed or refractory lymphoid malignancies including B-cell non-Hodgkin lymphoma (B-NHL), T-cell NHL (T-NHL), multiple myeloma (MM), and classical Hodgkin lymphoma (cHL). Patients were treated using a dose escalation design (1 mg/kg and 3 mg/kg) of nivolumab administered every two weeks for up to two years. Responses were assessed using standard criteria. The primary endpoint was safety; key secondary endpoints included anti-tumor activity and expression of immunomodulatory proteins in tumor biopsies. The preliminary results for the cHL patients will be reported separately. Results Twenty-nine patients with B-NHL, 2 patients with primary mediastinal B-cell lymphoma; 23 patients with T-NHL; 27 patients with MM; and 1 with chronic myelogenous leukemia were enrolled. Patients were heavily pretreated with 67%, 69%, and 78% of MM, B-NHL, and T-NHL patients, respectively, having received ≥ 3 prior treatment regimens. Previous autologous stem cell transplantation was reported for 56% of MM, 14% of B-NHL, and 9% of T-NHL patients. Prior brentuximab treatment was reported in 7% of B-NHL and 26% of T-NHL patients. When this pre-planned interim analysis was performed, six patients had been treated at the 1 mg/kg dose with 2 dose-limiting toxicities (DLTs) occurring in the same patient: grade 3 pneumonia and pneumonitis. At the 3mg/kg dose, seven patients were treated with one patient experiencing two DLTs: grade 3 eosinophilia and diplopia. Additional patients were enrolled in the cohort expansion at 3 mg/kg. Drug-related adverse events (AEs) occurred in 72%, 65%, and 52% of B-NHL, T-NHL, and MM patients, respectively. Serious AEs in B-NHL patients were pneumonitis (7%), acute respiratory distress syndrome, dermatitis, diplopia, enteritis, eosinophilia, mucosal inflammation, pyrexia and vomiting, each occurring in 3%. In the T-NHL patients, serious AEs were pneumonitis, rash, and sepsis, each occurring in 4%, and in MM patients, serious AEs were pneumonitis, myositis, and increased creatine phosphokinase, each occurring in 4%. The incidence and severity of drug related AEs were similar across tumor types. Efficacy results are shown for each tumor type in the table. The overall response rate (ORR) and complete response (CR) rate in patients with B-NHL were 28% and 7%, respectively, including an ORR of 36% in patients with diffuse large B-cell lymphoma (DLBCL), and 40% in patients with follicular lymphoma (FL). In patients with T-NHL, ORR was 17% (no CR), including an ORR of 40% in the 5 patients with peripheral T cell lymphoma. No objective responses were observed in MM. Analysis of PD-L1 expression and correlation to clinical outcome is being performed and will be presented. Conclusions Nivolumab administered at a dose of 3 mg/kg every two weeks was tolerable and the safety profile was similar to that of the agent in solid tumors. Objective responses were observed in DLBCL, FL, mycosis fungoides (MF), and peripheral T cell lymphoma (PTCL). Durable stable disease was observed in relapsed MM. The results of this phase 1 study have led to phase 2 studies in DLBCL and FL, which are ongoing. Table: Efficacy Results Tumor N Complete Response n (%) Partial Response n (%) Stable Disease (SD) n (%) Progression Free Survival Rate at 24 Weeks (%) Diffuse Large B Cell Lymphoma (DLBCL) 11 1 (9) 3 (27) 3 (27) (24) Follicular Lymphoma (FL) 10 1 (10) 3 (30) 6 (60) (68) Other B Cell Lymphoma 8 0 0 5 (63) (38) Primary Mediastinal B Cell Lymphoma 2 0 0 2 (100) (0) Mycosis Fungoides (MF) 13 0 2 (15) 9 (69) (39) Peripheral T Cell Lymphoma (PTCL) 5 0 2 (40) 0 (30) Other T Cell Lymphoma 5 0 0 1 (20) (0) Multiple Myeloma (MM) 27 0 0 18 (67) (15) Chronic Myelogenous Leukemia 1 0 0 1 (100) (100) Disclosures Lesokhin: Bristol-Myers Squibb: Consultancy, Research Funding. Ansell:Bristol-Myers Sqibb: Research Funding. Armand:Merck: Consultancy. Cohen:Celgene: Member, Independent Response Adjudication Committee Other; Onyx: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Advisory Board, Advisory Board Other, Research Funding; Janssen: Advisory Board, Advisory Board Other. Lebovic:Genentech, Allos, Celgene, Onyx, Millennium: Consultancy, Research Funding, Speakers Bureau. Rodig:Bristol-Myers Squibb: Research Funding. Zhu:Bristol-Myers Squibb: Employment. Grosso:Bristol-Myers Squibb: Employment, Equity Ownership. Kim:Bristol-Myers Squibb: Employment. Shipp:Merck: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Janssen R&D: Membership on an entity's Board of Directors or advisory committees. Borrello:Bristol-Myers Squibb: Research Funding. Timmerman:Bristol-Myers Squibb: Research Funding.

Abstract Abstract 4029 Introduction: Chromosomal translocation of the FGFR3 oncogene in t(4;14)-positive multiple myeloma (MM) causes FGFR3 overexpression in plasma cells, chemoresistance, and poor prognosis leading to shorter overall survival in MM patients (pts). MFGR1877S is a human monoclonal antibody that targets FGFR3 to prevent ligand binding, receptor-receptor association, and FGFR3 signaling. In preclinical studies, anti-FGFR3 antibody suppresses FGFR3-mediated cell proliferation, and exerts strong anti-tumor activity in mouse xenograft models of both t(4;14)-positive MM and bladder carcinoma. Methods: This Phase I study assessed the safety, tolerability, and biologic activity of MFGR1877S given intravenously, weekly for 3 weeks, followed by every 28-day dosing, to eligible patients with t(4;14)-positive MM. Dose escalation started with single-pt cohorts at 1 and 2 mg/kg, followed by a standard 3+3 dose-escalation scheme at doses ranging from 4–15 mg/kg. Dose escalation decisions were made based on monitoring pts for dose-limiting toxicities (DLT) during the first 22 days on study. FGFR3 expression, safety, pharmacokinetics (PK), and response (EBMT/IMWG criteria) were assessed. Main efficacy outcome measures include serum/urine M protein and free light chain (FLC) quantities. Results: A total of 14 pts (median age 66, range 45–78; 43% female) with a baseline ECOG status of 0–2, and a median number of 5 prior therapies (range 1–10), received a median of 3.5 doses (range 1–7) of MFGR1877S. Adverse events (AEs) deemed related to MFGR1877S were diarrhea, fatigue, and nausea (14% each), and anemia, increased creatinine, bone pain, confusion, decreased appetite, myalgia, and fever (7% each). The only Grade ≥ 3 related AE was fatigue (7%). Six pts experienced 9 serious AEs (SAE), one of which was Grade 2 pyrexia attributed to MFGR1877S that occurred within 24 hours of infusion and required hospitalization. This pt later discontinued due to a second SAE of Grade 2 pyrexia requiring hospitalization not attributed to MFGR1877S. One pt died of intracranial hemorrhage not attributed to MFGR1877S. No Grade 4 SAEs were reported. Other reported SAEs included Grade 3 hypercalcemia, neutropenia, pain in extremity, and musculoskeletal chest pain (1 pt each), Grade 2 ankle fracture, pneumonia, and pyrexia × 2 (1 pt each). No maximum tolerated dose was identified, as no DLTs were observed through the highest dose tested (15 mg/kg). Preliminary PK analysis for limited number of multiple myeloma patients (n=14) by non-linear mixed effect modeling demonstrated a trend of dose proportional increase of exposure (area under the concentration-time curve and maximal concentration) from 2 to 15 mg/kg. Population clearance of MFGR1877S was estimated to be ∼0.62 L/day, suggesting that MFGR1877S appeared to have a slightly faster clearance in MM patients, compared to the typical IgG1 monoclonal antibody clearance in human. The central volume of distribution of MFGR1877S was ∼3.4 L, which approximated human serum volume and appeared similar to the central volume of distribution of other typical IgG1 monoclonal antibodies. While some degree of FGFR3 expression was detected by immunohistochemistry in 10/14 patient bone marrow samples taken at screening, FACS analysis of FGFR3 surface expression on myeloma cells, although largely consistent with IHC measurements, also revealed heterogeneity in the levels of detectable surface FGFR3 expression. Six pts had stable disease as their best response: 2 pts up to 4 cycles, 1 pt up to 3 cycles, and 3 pts up to 1 cycle. Conclusions: MFGR1877S was well-tolerated overall in these patients with multiple relapsed or refractory MM. Although no objective responses were observed, stable disease was observed in 3 pts for 3–4 cycles. Disclosures: Off Label Use: MFGR1877S is a human monoclonal antibody that targets FGFR3 to prevent ligand binding, receptor-receptor association, and FGFR3 signaling. Singhal:Millennium and Celgene: Speakers Bureau. Niesvizky:Onyx, Millemium, Celgene. Speakers bureau: Millenium and Celgene: Consultancy, Research Funding. Comenzo:Millenium, Neotope; Onyx, Osiris, Millenium: Consultancy, Research Funding. Lebovic:Genentech: Speakers Bureau. Choi:Genentech: Employment. Lu:Genentech: Employment. French:Genentech: Employment. Penuel:Genentech: Employment. Ho:Genentech: Employment.

Purpose Cancer cells can exploit the programmed death-1 (PD-1) immune checkpoint pathway to avoid immune surveillance by modulating T-lymphocyte activity. In part, this may occur through overexpression of PD-1 and PD-1 pathway ligands (PD-L1 and PD-L2) in the tumor microenvironment. PD-1 blockade has produced significant antitumor activity in solid tumors, and similar evidence has emerged in hematologic malignancies. Methods In this phase I, open-label, dose-escalation, cohort-expansion study, patients with relapsed or refractory B-cell lymphoma, T-cell lymphoma, and multiple myeloma received the anti–PD-1 monoclonal antibody nivolumab at doses of 1 or 3 mg/kg every 2 weeks. This study aimed to evaluate the safety and efficacy of nivolumab and to assess PD-L1/PD-L2 locus integrity and protein expression. Results Eighty-one patients were treated (follicular lymphoma, n = 10; diffuse large B-cell lymphoma, n = 11; other B-cell lymphomas, n = 10; mycosis fungoides, n = 13; peripheral T-cell lymphoma, n = 5; other T-cell lymphomas, n = 5; multiple myeloma, n = 27). Patients had received a median of three (range, one to 12) prior systemic treatments. Drug-related adverse events occurred in 51 (63%) patients, and most were grade 1 or 2. Objective response rates were 40%, 36%, 15%, and 40% among patients with follicular lymphoma, diffuse large B-cell lymphoma, mycosis fungoides, and peripheral T-cell lymphoma, respectively. Median time of follow-up observation was 66.6 weeks (range, 1.6 to 132.0+ weeks). Durations of response in individual patients ranged from 6.0 to 81.6+ weeks. Conclusion Nivolumab was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory B- and T-cell lymphomas. Additional studies of nivolumab in these diseases are ongoing.