Hsu, Frank J.

Abstract Abstract 2319 Poster Board II-296 Background: Data from two phase 3 clinical trials indicate that plerixafor plus G-CSF is safe and more effective than G-CSF alone in mobilizing CD34+ hematopoietic stem cells (HSC) for autologous HSC transplantation (auto-HSCT) in patients with non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM). Herein we report 1-year overall survival in patients with NHL or MM who have undergone auto-HSCT with cells mobilized with plerixafor plus G-CSF compared to placebo plus G-CSF. Furthermore, we also report 1-year overall survival in patients with NHL who failed mobilization on either arm and entered a rescue protocol. Methods: Data were obtained from two prospective, randomized, double-blind, placebo-controlled, phase 3 clinical trials that compared the safety and efficacy of plerixafor (0.24 mg/kg/day SQ) plus G-CSF (10 mg/kg/day) with placebo plus G-CSF for mobilization of HSC for autologous HSCT in patients with NHL or MM. In the NHL study, patients in either study arm who failed mobilization (&0.8 ×106 CD34+ cells/kg in 2 days or &2 × 106 CD34+ cells/kg in 4 days) were eligible to enter the rescue protocol and received plerixafor + G-CSF mobilization. Overall survival in patients was estimated by the Kaplan-Meier method. Results: In the NHL study, 135/150 (90.0%) patients in the plerixafor group compared with 82/148 (55.4%) patients in the placebo group, underwent transplantation (p&0.001) with a median (range) of 5.41 (1.95-17.6) and 3.85 (1.98-8.74) × 106 CD34+ cells/kg, respectively (p&0.001). A total of 62 patients (10 from the plerixafor arm and 52 from the placebo arm) failed mobilization and proceeded to rescue mobilization with plerixafor + G-CSF. Of these, 52 patients (84%) proceeded to transplantation with a median (range) of 3.8 (1.1-10.5) x 106 CD34+ cells/kg. Kaplan-Meier estimates of 1-year overall survival for patients in the plerixafor and placebo groups in the primary ITT population (rescue patients were censored as of consent date for rescue) were 76.0% and 64.7%, respectively. Kaplan-Meier estimate of 1-year overall survival in the rescue group was 83.7%. The Log rank p-value comparing all 3 survival estimates (plerixafor, placebo and rescue) was 0.765 (Figure 1A). In the MM study, 142/148 (95.9%) patients in the plerixafor group and 136/154 (88.3%) patients in the placebo group underwent transplantation (p=0.014) with a median (range) of 5.40 (1.20-16.74) and 3.96 (1.76-16.88) × 106 CD34+ cells/kg, respectively (p&0.001). In this trial, Kaplan-Meier estimates of 1-year overall survival in the plerixafor and placebo groups were 93.6% and 95.8%, respectively (Log-rank p-value=0.771; Figure 1B). Conclusions: These data suggest that overall survival at 1 year is similar between patients with MM or NHL mobilized with plerixafor plus G-CSF compared to placebo plus G-CSF. Furthermore, in the NHL study, patient survival in the rescue protocol was similar to that seen in the phase III trial. Collection of follow-up data on overall survival is ongoing. Disclosures: Micallef: Genzyme Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stiff:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stadtmauer:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bolwell:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marulkar:Genzyme Corporation: Employment, Equity Ownership. Hsu:Genzyme Corporation: Employment, Equity Ownership. DiPersio:Genzyme: Honoraria.

Abstract Purpose: LV305 is a modified, third-generation, nonreplicating, integration-deficient lentivirus-based vector designed to selectively transduce dendritic cells in vivo. LV305 induces expression of the New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) cancer testis antigen in dendritic cells, promoting immune responses against NY-ESO-1–expressing tumors. This phase I study evaluated the safety, immunogenicity, and preliminary efficacy of LV305 in patients with sarcoma or other solid tumors. Patients and Methods: Adults with previously treated, advanced, NY-ESO-1–positive solid tumors and limited tumor burden were eligible. LV305 was administered every 3 weeks by intradermal injection in four dose cohorts (Cohort 1: 108 vector genomes (vg) x 3 doses; Cohorts 1A, 2, and 3: 108 vg, 109 vg, 1010 vg x 4 doses). Results: Thirty-nine patients were enrolled: 3 patients each in Cohorts 1, 1A, and 2, and 30 patients in Cohort 3. No dose-limiting toxicities were observed. Tumor types included sarcoma (n = 24), ovarian (n = 8), melanoma (n = 6), and lung cancer (n = 1). All treatment-related adverse events were grade 1 or 2. Common treatment-related adverse events were fatigue (49%), injection site reactions (46%), and myalgia (21%). The disease control rate was 56.4% in all patients and 62.5% in sarcoma patients. One patient with synovial sarcoma achieved a partial response lasting >36 months. Anti–NY-ESO-1-specific CD4+ and/or CD8+ T cells were induced in 57% of evaluable sarcoma patients. Induction of an anti–NY-ESO-1 immune response was associated with improved 1-year survival in an exploratory analysis. Conclusions: This first-in-class, first-in-human study of LV305 demonstrated a favorable safety profile, induction of antigen-specific responses, and potential clinical activity in patients with advanced cancer.

3090 Background: The correlation of immune response (IR) and clinical benefit in patients (pts) who receive active immunotherapy remains controversial. CMB305 is an active immunotherapy designed to generate and expand anti-NY-ESO-1 T cells, consisting of LV305 (a DC targeting lentiviral vector encoding NY-ESO-1) and a boost (NY-ESO-1 recombinant protein plus GLA-SE, a TLR-4 agonist). Phase 1 studies of LV305 and CMB305 evaluated the IR and survival of pts with NY-ESO-1 positive tumors. Methods: 62 pts with recurrent NY-ESO-1 expressing (by IHC) solid tumors were enrolled in 2 Phase 1 trials (31 pts each: 43 sarcomas, 12 ovarian, 4 melanomas, and 3 NSCLC). Peripheral blood was assessed pre and post therapy for anti-NY-ESO-1 T cell responses (IFNγ ELISPOT) and antibodies (Ab) (ELISA) (n = 62), TCR-β CDR3 repertoire and conserved (public) TCR (n = 28), and antigen spreading (ELISA, ELISPOT) (n = 23). Relationship between progression-free survival (PFS), overall survival (OS) and up to 15 biomarkers were analyzed by the Kaplan-Meier method. Results: Preexisting anti-NY-ESO-1 T cells and Ab were identified in 34% and 40% of pts. LV305 and CMB305 induced (de novo or increased) anti-NY-ESO-1 T-cells in 51% and 65% pts, and anti-NY-ESO-1 Ab responses in 13% and 68% pts, respectively. LV305 and CMB305 induced antigen spreading in 17% and 36% pts. TCR clonality increased after CMB305 as compared to LV305. The TCRβ-CDR3 amino acid sequences of three NY-ESO-1 specific TCR clones in a patient with a > 2-year response were fully conserved in 20/28 patients. Biomarkers showing the strongest association with OS and PFS were pre-existing anti-NY-ESO-1 T-cell response and Ab, integrated IR (T cells and antibodies), and NY-ESO-1 expression level. Presence of public TCRs was associated with longer survival, particularly in pts with high ( > 50%) NY-ESO-1 expression. Conclusions: While LV305 and CMB305 are both immunogenic, CMB305 resulted in a stronger and broader integrated IR, including antigen spreading. The three identified survival variables, preexisting and treatment-induced NY-ESO-1 IR and the presence of public TCRs, warrant validation in randomized studies of CMB305.