In the last year, we published the results of three clinical trials discussed in the 2014-2015 Annual Report: 1. Docetaxel +/- PANVAC in metastatic breast cancer, 2. Phase 1 trial of yeast-brachyury vaccine, and 3. Quadramet +/- PROSTVAC in metastatic castration resistant prostate cancer after docetaxel chemotherapy. We have completed enrollment of the following studies and expect publication in the next 6 months. MVA BRACHYURY TRICOM PHASE 1: MVA brachyury TRICOM is a novel vector-based vaccine, created on the TRICOM platform (transgene for target antigen and three costimulatory molecules encoded within poxviral vectors) (NCT02179515). Patients with advanced cancer (n=25) or chordoma (n=13) enrolled. Dose escalation was performed following 3+3 design in 3 dose levels (DL1=2x108, DL2=4x108, DL3=8x108 plaque forming units, with vaccine administered every 4 weeks x 3 doses). After safety was established, expansion cohorts were enrolled at DL2 and DL3 to compare brachyury-specific-T-cell responses. Peripheral blood mononuclear cells from pre- and post-vaccination (day 29, 57, 85, and 176) were stimulated with brachyury or human leukocyte antigen (HLA) (negative control) 15-mer peptide pools and analyzed for brachyury-specific T-cell responses by intracellular staining of CD4 and CD8 T-lymphocytes for the cytokines IFNg, TNF, and IL2, and the degranulation marker CD107a. In total, 3 patients enrolled on DL1, 17 on DL2, and 18 on DL3. On DL2 and DL3, 1 and 2 patients, respectively, were not evaluable for safety or immune responses and replaced. MVA-brachyury was well tolerated with no dose limiting toxicities. The maximal tolerated dose was not reached. No serious adverse event (AE) was related to vaccine. AEs occurring in 2 unique patients included diarrhea (7.9%), fever (18%), flu-like symptoms (34%), and injection site reaction (74%). One grade 3 AE, diarrhea, was related to vaccine, and resolved without intervention after 48 hours. All other AEs related to vaccine were grade 1 or 2 with short duration. Immune responses were analyzed in 29 patients. Brachyury-specific T-cell responses were observed at each dose level: 66% (2/3) of patients at DL1, 80% (12/15) at DL2, and 90% (10/11) at DL3. At DL2 and DL3, 80% of the patients that developed brachyury-specific T-cells demonstrated responses in both CD4 and CD8 T-lymphocytes. These findings demonstrate the safety and immunogenicity of this vaccine and provide adequate rationale for further exploration in phase 2 studies. The manuscript for this trial is currently in preparation. ANTI-PD-L1 (AVELUMAB) PHASE 1: Avelumab (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. Reported here is the pharmacokinetic (PK) profile of avelumab and receptor occupancy (RO) from a phase I dose escalation trial (NCT01772004). In this study, dose escalation (3+3 design) was performed for 4 dose levels (DL 1, 3, 10, and 20 mg/kg). The dose limiting toxicity (DLT) evaluation period was 3 weeks. After DL safety was determined, accrual of additional patients (pts) was allowed for the purpose of generating additional safety, PK, and RO data. 50 patients with advanced solid tumors were enrolled and treated with avelumab, Q2W. Four, 13, 13, and 20 patients were accrued to DL 1 to 4, respectively. Median patient age was 59 years (range 29 to 77); 19 had an ECOG PS of 0, and 29 had an ECOG PS of 1 (2 unknown). The median number of prior lines of therapy was 3 (range 1 to greater than 4). Data from 45 patients were evaluable for PK analysis. Cmax and AUC increased linearly with dose. Half-lives were 66, 86, 92, and 115h for DL 1, 2, 3 and 4, respectively, with no statistically significant differences between the 3 higher DLs. Trough levels at 10 mg/kg, but not at 1 and 3 mg/kg, were sufficient for 95% RO at all dosing occasions. Population PK analysis showed that a two-compartment model with linear elimination best described the data. There was no significant change in absolute lymphocyte count or in additional multiple immune cell subsets evaluated. The PK and RO data indicate the 10 mg/kg dose of avelumab achieves excellent RO with a predictable PK profile. Based on these data and the safety profile reported separately, the 10 mg/kg dose is being tested in ongoing phase II trials. The manuscript for this study is in final stages of preparation for submission. The following studies are ongoing. NHS-IL12: NHS-IL12 is an antibody-cytokine conjugate. The NHS antibody delivers IL12 to the tumor microenvironment by binding areas of exposed double stranded DNA at histone binding sites (areas of necrosis), which should only be present in tumor. A 3+3 dose-escalation study in solid tumors evaluated the safety of NHS-IL12 in single subcutaneous doses, and its pharmacokinetic (PK) and pharmacodynamic (PD) effects. After establishing the safety of single doses, an amendment allowed repeat dosing every 28 days. Dose level (DL) 1 was 0.1 mcg/kg, with a planned maximum DL9 (21.8 mcg/kg). With the first 2 doses, patients were admitted for PK/PD draws and observed for 48 hours. An expansion cohort of 10-15 patients was enrolled at the maximum tolerated dose (MTD) for further PK/PD analysis. 59 patients were enrolled in DLs 1-9. Median age was 62.1 (33.8-85.0). 22 patients were enrolled in single-dose cohorts. One died of progressive disease; all others completed the 28-day evaluation period. 37 patients were enrolled in multiple-dose cohorts. Dose-limiting toxicities occurred in 1/6 patients on and 2/6 patients in DL9, making the MTD DL8 (16.8 mcg/kg). 11 patients were enrolled in an expansion of DL8. The most common adverse events (AEs) in the first 16 patients treated in DL8 were decreased lymphocyte count (81.3%), increased AST (81.3%), decreased WBC count (75%), increased ALT (75%), and fever (62.5%). Most AEs were well controlled with NSAIDs or acetaminophen and resolved within 10 days post-dosing. Laboratory abnormalities were self-limited and resolved without steroids. AEs were apparently related to peak serum IFN-g levels. PK measurements varied greatly. Median time to Cmax: 24 to 48 hours post-injection; mean t1/2: 2 to 10 days; mean apparent volume of distribution: 1200 to 1800 mL/kg. Increasing DLs from 0.5 to 21.8 mcg/kg led to dose-proportional increases in Cmax and AUC. NHSIL12 administration resulted in time- and dose dependent increases in IFNg, IL10, and TNFa. IFNg values peaked 24 to 96 hours post-injection, returning to baseline by day 8. ANTI-IL8 (HuMax): A fully-human monoclonal antibody designed to bind to free IL-8 has been evaluated in a first-in-human phase 1 clinical trial. In that study, 4 dose levels were evaluated in a 3+3 design. Dose levels 1 to 4 (4, 8, 16, and 32 mg/kg) enrolled 3, 3, 3, and 6 patients, respectively. There were no dose limiting toxicities and the maximally tolerated dose was not exceeded. Further pharmacokinetic and pharmacodynamic evaluation will be performed to determine the optimal biologic dose. To determine this, more patients at some dose levels may be enrolled to increase sample numbers. It is expected that this agent will be useful to modify the stem-like characteristics induced by IL-8 signaling, which can improve T cell mediated killing, as supported by our preclinical work. PHASE 2 RANDOMIZED DOUBLE BLIND STUDY OF RADIATION ALONE VERSUS IN COMBINATION WITH YEAST BRACHYURY VACCINE IN LOCALLY ADVANCED CHORDOMA: This study has opened for enrollment in this rare population We have seen initial evidence of clinical benefit.
Showing the most recent 10 out of 15 publications
