Bensinger, William

Abstract Introduction eIF5A is the only known protein to be modified by hypusination and is highly conserved across species. Hypusinated eIF5A, the predominant form in normal and cancer cells, is involved in cell survival and inflammatory pathway activation. siRNAs targeting eIF5A inhibit NF-kB activation and reduce pro-inflammatory cytokine production. Accumulation of the unhypusinated lysine form of eIF5A is associated with apoptosis. Mutants of eIF5A that cannot be hypusinated (e.g. eIF5AK50R) are pro-apoptotic in vitro and have anti-tumoral activity in vivo in multiple cancer types including melanoma and lung cancer. SNS01-T is a novel therapeutic with a dual mechanism of eIF5A modulation: inducing cell death via siRNA-mediated inhibition of hypusinated eIF5A while simultaneously causing over-expression of pro-apoptotic eIF5AK50R via a DNA plasmid with a B-cell promoter to induce tumor cell death. SNS01-T significantly inhibited tumor growth and increased survival in mouse models of myeloma (MM), mantle cell and diffuse large B-cell lymphoma. The phase 1-2 study of SNS01-T has completed 4 planned dosing cohorts 0.0125, 0.05, 0.2 and 0.375 mg/kg twice weekly IV for 6 weeks in pts with refractory B-cell cancers. Methods PK and PD secondary endpoints included characterization of PK by measuring pExp5A plasmid DNA and eIF5A siRNA in blood and bone marrow (BM), assessing potential immunogenicity of SNS01-T by measuring serum concentrations of antibodies against SNS01-T nanoparticles, and measuring serum concentrations of select proinflammatory cytokines by enzyme-linked immunosorbent assay in serum and plasma samples. Blood PK timepoints were 30 minutes before the first infusion and at 30 minutes, 2, 6, and 24 hours after the first infusions on Week 1, Week 3, and Week 6 and at the 4, 8, and 12 week visits after the last infusion; BM samples were collected 1 day after the final infusion. Serum and plasma PD sampling timepoints were 30 minutes before and at 2, 6, and 24 hours after the first infusion on Week 1, Week 3, and Week 6, and at 4 weeks after the final infusion. Cytokines assayed included TNF-α, IFN-α, IFN-ß, IFN-g, CXCL1, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12. Results Table 1 shows data available for interpretation as of August 2014. The remaining samples are under analysis and will be presented. Abstract 2121. Table 1:Data available for interpretation (number of patients)SNS01-T DoseOverall(n=18)0.0125 mg/kg(n=6)0.05 mg/kg(n=4)0.2 mg/kg(n=4)0.375 mg/kg(n=4)Blood PK DNA and RNA156441Bone marrow PK82321Serum antibodies to SNS01-T nanoparticles186444Serum and plasma cytokines156441 Plasmid and siRNA blood levels generally peaked 30 minutes post-dosing at weeks 1, 3 and 6 of dosing. Both plasmid and siRNA exhibited rapid clearance from the blood, with levels dropping to near pre-dosing levels within 24 hours of administration. pExp5A plasmid DNA was detectable in the bone marrow of 2 pts at cohort 1, 2 at cohort 2, 1 at cohort 3 and 1 at cohort 4. eIF5A siRNA was not detectable in bone marrow. No antibodies to SNS01-T nanoparticles were detected at any timepoint at any dose level. Cytokines remained within the expected range of inter-patient variability, similar to baseline across all timepoints at the first 2 dose levels. At dose level 3, levels of IL-6, IL-8 and TNF-α in particular increased at the 2 and 6 hour timepoints but had recovered to baseline levels 24-hours post dosing. This effect was more pronounced at the first infusion. Conclusions PCR analysis demonstrated the presence of both plasmid DNA and siRNA components of SNS01-T in blood at all dose levels, with a dose-dependent increase in plasmid copy number. Plasmid DNA was also detected in bone marrow collected 24 hours after the final infusion of SNS01-T. Pro-inflammatory cytokines did increase within hours of infusion but returned to baseline within 24 hours, synchronous with the clinical infusion reactions (see Abstract 70148). No evidence of an anti-SNS01-T antibody response was observed in any subject. Phase 2 trials are planned. Disclosures Bexon: Senesco: Consultancy. Craig:Senesco: PI Other. Siegel:Senesco: PI Other. Bensinger:Senesco: PI Other. Novitzky:Senesco: PI Other. McDonald:Senesco: PI Other. Gutierrez:Senesco: PI Other. Libby:Senesco: PI Other. van Rhee:Senesco: PI Other. Heidel:Senesco: Consultancy. Thompson:Senesco: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Barranco:Senesco: Consultancy. Taylor:Senesco: Research Funding. Browne:Senesco: Employment. Kurman:Senesco: Consultancy. Lust:Senesco: PI Other. Dondero:Senesco: Employment.

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.

Key Points KRd has a favorable benefit-risk profile compared with Rd, regardless of baseline cytogenetic risk status, in patients with relapsed MM. KRd improves but does not abrogate the poor prognosis associated with high-risk cytogenetics in patients with relapsed MM.

Key Points Weekly oral proteasome inhibitor ixazomib appears generally well tolerated with manageable toxicity, limited grade 1/2 neuropathy. Data show that more than 25% of 30 evaluable relapsed/refractory myeloma patients who received the MTD had clinically meaningful responses.

AbstractThe role of high-dose therapy followed by autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. The choice of induction therapy has moved from conventional chemotherapy to newer regimens incorporating the immunomodulatory derivatives thalidomide or lenalidomide and the proteasome inhibitor bortezomib. These drugs combine well with traditional therapies and with one another to form various doublet, triplet, and quadruplet regimens. Up-front use of these induction treatments, in particular 3-drug combinations, has affected unprecedented rates of complete response that rival those previously seen with conventional chemotherapy and subsequent ASCT. Autotransplantation applied after novel-agent-based induction regimens provides further improvement in the depth of response, a gain that translates into extended progression-free survival and, potentially, overall survival. High activity shown by immunomodulatory derivatives and bortezomib before ASCT has recently led to their use as consolidation and maintenance therapies after autotransplantation. Novel agents and ASCT are complementary treatment strategies for MM. This article reviews the current literature and provides important perspectives and guidance on the major issues surrounding the optimal current management of younger, transplantation-eligible MM patients.

The past decade has witnessed a paradigm shift in the initial treatment of multiple myeloma with the introduction of novel agents such as thalidomide, lenalidomide, and bortezomib, leading to improved outcomes. High-dose therapy and autologous stem cell transplantation remains an important therapeutic option for patients with multiple myeloma eligible for the procedure. Before the advent of the novel agents, patients underwent stem cell collection prior to significant alkylating agent exposure, given its potential deleterious effect on stem cell collection. With increasing use of the novel agents in the upfront setting, several reports have emerged raising concerns about their impact on the ability to collect stem cells. An expert panel of the International Myeloma Working Group (IMWG) was convened to examine the implications of these therapies on stem collection in patients with myeloma and to develop recommendations for addressing these issues. Here we summarize the currently available data and present our perspective on the problem and potential options to overcome this problem. Specifically, we recommend early mobilization of stem cells, preferably within the first 4 cycles of initial therapy, in patients treated with novel agents and encourage participation in clinical trials evaluating novel approaches to stem cell mobilization.