John Nemunaitis

TPS11079 Background: Vigil, an immuno-stimulatory autologous cellular therapy, uses patient tumor cells transfected with a plasmid encoding genes for GM-CSF and furin (to down regulate TGFβ 1&2). A Phase I study in relapsed Ewing’s sarcoma. (N = 16) had one 9 month partial response and a two-year survival rate of 44% [1]. Rapid, durable systemic immune activation was seen in the majority of patients using an IFNƔ ELISPOT assay [2]. We seek to extend these early findings in a randomized Phase 2 study (NCT02511132). Methods: Following surgery (for Vigil manufacture), patients are randomized 1:1 to Vigil (1 x 10⁷cells/ml by monthly intradermal injection), or to chemotherapy with gemcitabine 675mg/m2 IV D1 and D8 and docetaxel 75 mg/m2 IV D8 every 21 days. Key eligibility criteria include: Age > 2, histologically documented metastatic Ewing's, refractory or intolerant to ≥2 prior lines of chemotherapy, and availability of at least 4 doses of manufactured Vigil. Patients with bone only disease are ineligible. The primary objective is to compare the overall survival of patients treated with Vigil vs. chemotherapy. The sample size of 62 patients assumes a one-year survival rate of 25% in the chemotherapy group vs. 60% in the Vigil group, corresponding to a hazard ratio of 0.383 favoring Vigil. Results: As of January 2017, thirteen patients have been randomized at 10 centers in the U.S. The design allows for reduction in disease burden prior to surgery using modalities like SBRT and interventional radiology. Toxicity of Vigil has been low compared to chemotherapy. Time to disease progression is being assessed in patients who crossover to Vigil after progressing on chemotherapy. Systemic control of metastatic lesions using cryoablation is also being assessed in other patients (e.g. DSRCT liver metastases) using a separate IND. Conclusions: Although associated with systemic immune activation, additional means to reduce disease burden such as SBRT and cryoablation can possibly improve patient health and augment Vigil efficacy. References: 1.Ghisoli M, Barve M, et al. Mol Ther. 2016 Apr 25 2. Oh J, Barve M, et al. Gynecologic Oncology 2016; 143: 504–510. Clinical trial information: NCT02511132.

TPS5604 Background: Vigil is an immuno-stimulatory autologous cellular therapy, which uses patient tumor cells transfected with a plasmid encoding genes for GM-CSF and furin (to down regulate TGFβ 1&2). In Phase I, systemic immune activation was demonstrated in the majority of patients using an IFNƔ ELISPOT assay. A randomized Phase 2 assessment of Vigil maintenance therapy vs. observation in ovarian cancer demonstrated prolonged relapse free survival (RFS) (Oh J, Barve M, et al. Gynecologic Oncology, 2016; 143: 504–510.). Based on these observations, a Phase 3 study of maintenance Vigil therapy in patients with advanced ovarian cancer was initiated (NCT02346747). Methods: This is a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study of maintenance Vigil in women with Stage IIIb,c or IV high-grade papillary serous/clear cell/ endometrioid ovarian, fallopian tube or primary peritoneal cancer. Patients will have a minimum of 4 and a maximum of 12 Vigil doses manufactured from tumor obtained at primary debulking surgery. Patients must achieve a complete clinical remission following primary surgery and chemotherapy before being randomized 1:1 to receive either monthly intradermal Vigil or placebo. Randomization is stratified by extent of surgical cytoreduction (complete/microscopic vs. macroscopic residual disease) and neoadjuvant vs. adjuvant chemotherapy. The primary objective is to compare RFS of subjects randomized to Vigil vs. placebo, and the key secondary objective is overall survival (OS). The sample size calculation of 222 patients assumes 24 months for accrual and 36 months of follow-up with a median RFS of 19 months from randomization, in the control group. This provides 90% power to detect a hazard ratio (HR) of 0.6 favoring Vigil at the 0.05 level of significance. To date, 61 patients have been randomized and an additional 55 patients are receiving chemotherapy in anticipation of randomization. Tumor tissue is being obtained from approximately 20 patients per month at multiple sites across the U.S. At their last meeting in January, 2017 the independent DSMB recommended that the study continue without change. Clinical trial information: NCT02346747.

Ewing sarcoma is a highly resistant disease with a

9553 Background: CAVATAK, an oncolytic immunotherapy, is a bio-selected oncolytic strain of Coxsackievirus A21 (CVA21). Intratumoral (IT) injection of CVA21 induces lytic tumor cell infection, up-regulation of immune checkpoint molecules and increased immune-cell infiltration. The Phase II CALM study investigated the efficacy and safety of IT CVA21 in 57 pts with advanced melanoma resulting in a confirmed ORR of 28.1% and DRR (continuously > 6 mths) of 21.1%. The CALM extension study (13 pts) investigated CVA21 induced changes in immune cell infiltrates within the tumor-microenvironment (TME). We describe factors regarding the nature of clinical responses in 70 pts with stage IIIC-IV melanoma given IT CVA21. Methods: The association of prior lines of therapy, tumor pseudo-progression, baseline tumor burden (BTB) and levels of immune cell infiltrates in the TME were examined with regard to clinical response. Results: Responders on the CALM study (16/57 pts, 28.1%) displayed reductions in both injected and non-injected lesions, suggesting the generation of significant host anti-tumor responses. A comparable ORR was observed in pts administered prior immunotherapy, 29.0% (9/31) vs other tx 27.0% (7/26). Interestingly, 26.7% (4/15) and 40% (2/5) of pts previously treated with ipilimumab and talimogene laherparepvec, respectively, developed confirmed responses. Three pts (18.8%) exhibited pseudo-progression (irRECIST criteria) prior to response. BTB of the 57 pts in the CALM study was 3.9 cm (95% CI 4.3, 6.5). A BTB less than median was associated with: superior ORR (39.3 vs 17.2 %), superior DRR (35.7 vs 6.9 %), and greater OS (p = 0.003). In the CALM extension study, CVA21 tx induced increases in immune cell infiltrates within the TME. In patients with responses, increases in CD8⁺ T-cells and PD-L1⁺ expression were observed in injected lesions. Reconstitution of immune cell infiltrates was observed in a number of CVA21 treated lesions from pts failing prior tx with immune-checkpoint blockade. Conclusions: IT administration of CVA21 can notably influence the dynamics of the TME and generate systemic anti-tumor immune responses as evidenced by increases in immune cell infiltrates and widespread non-injected lesion responses. Clinical trial information: NCT01227551.

Despite billions of dollars allocated to cancer research, cancer remains the number 2 cause of death in the United States with less than 50% of advanced cancer patients living one year following standard treatment. Cancer is a complex disease both intrinsically and in relation to its host environment. From a molecular standpoint no two cancers are the same despite histotypic similarity. As evidenced by the recent advances in molecular biology, treatment for advanced cancer is headed towards specific targeting of vulnerable signaling nodes within the reconfigured pathways created by "omic" rewiring. With advancements in proteo-genomics and the capacity of bioinformatics, complex tumor biology can now be more effectively and rapidly analyzed to discover the vulnerable high information transfer nodes within individual tumors. RNA interference (RNAi) technology, with its capability to knock down the expression of targeted genes (the vulnerable nodes), is moving into the clinic to target these nodes, which are integral to tumor maintenance, with a low risk of side-effects and to block intrinsic immunosuppressors thereby priming the tumor for immune attack. An RNAi based sequential approach, a so called "one-two punch," is being advocated comprising tumor volume reduction (ideally to minimal residual disease status) effected by integrated multi-target knockdown followed by immune activation. Examples and recent developments are provided to illustrate this highly powerful approach heralding the future of personalized cancer therapy.

Purpose Omacetaxine mepesuccinate is a first-in-class cephalotaxine demonstrating clinical activity in chronic myeloid leukemia. A subcutaneous (SC) formulation demonstrated efficacy and safety in phase 1/2 trials in patients previously treated with ≥1 tyrosine kinase inhibitor. This study assessed pharmacokinetics and safety of SC omacetaxine in patients with advanced cancers. Methods Omacetaxine 1.25 mg/m² SC was administered BID, days 1–14 every 28 days for 2 cycles, until disease progression or unacceptable toxicity. Blood and urine were collected to measure omacetaxine concentrations and inactive metabolites. Adverse events, including QT interval prolongation, were recorded. Tumor response was assessed at cycle 2 completion. Results Pharmacokinetic parameters were estimated from cycle 1, day 1 data in 21 patients with solid tumors or hematologic malignancies and cycle 1, day 11 data in 10 patients. Omacetaxine was rapidly absorbed, with mean peak plasma concentrations observed within 1 h, and widely distributed, as evidenced by an apparent volume of distribution of 126.8 L/m². Plasma concentration versus time data demonstrated biexponential decay; mean steady-state terminal half-life was 7 h. Concentrations of inactive metabolites 4′-DMHHT and cephalotaxine were approximately 10 % of omacetaxine and undetectable in most patients, respectively. Urinary excretion of unchanged omacetaxine accounted for 470 ms) were observed and were not correlated with omacetaxine plasma concentration. No objective responses were observed. Conclusions Omacetaxine is well absorbed after SC administration. Therapeutic plasma concentrations were achieved with 1.25 mg/m² BID, supporting clinical development of this dose and schedule.

Contusugene ladenovec (Advexin; INGN-201; Introgen Therapeutics Inc) is a replication-impaired, non-integrating, serotype 5 adenoviral vector that carries the p53 gene under the control of the CMV promoter. Deletion or mutation of the p53 gene has been observed in approximately half of malignancies in patients with cancer and p53 pathway dysfunction was observed in the majority of others, thereby providing the rationale for p53 restoration in the treatment of cancer. Advexin has demonstrated a consistent safety profile and clinical efficacy as a monotherapy, as well as in combined modality regimens with chemotherapy and radiation. Additive or synergistic effects have been observed in a variety of tumor types, including NSCLC, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, glioma, and breast, prostate and colorectal cancers. The identification of biomarkers may help direct research in tumor-specific therapeutics.

ONYX-015 is an attenuated chimeric human group C adenovirus, which preferentially replicates in and lyses tumor cells that are p53 negative. The purpose of this phase I, dose-escalation study was to determine the safety and feasibility of intravenous infusion with ONYX-015 in combination with enbrel in patients with advanced carcinoma. Enbrel is a recombinant dimer of human tumor-necrosis factor (TNF)- receptor, previously shown to reduce the level of functional TNF. Nine patients, three in each cohort received multiple cycles of ONYX-015 infusion (1 10¹⁰, 1 10¹¹ and 1 10¹² vp weekly for 4 weeks/cycle) in addition to subcutaneous enbrel (only during cycle 1) injections per FDA-indicated dosing. Of the nine patients, four had stable disease. No significant adverse events were attributed to the experimental regimen, confirming that enbrel can be safely administered along with oncolytic virotherapy. Two of the three patients in cohort 3 had detectable viral DNA at days 3 and 8 post-ONYX-015 infusion. Their detectable circulating viral DNA was markedly higher during cycle 1 (with enbrel coadministration) as compared with cycle 2 (without enbrel) at the same time points. Area under the curve determinations indicate a marked higher level of TNF- induction and accelerated clearance at cycle 2 in the absence of enbrel. Further assessment is recommended.