DOCETAXEL +/- PANVAC IN METASTATIC BREAST CANCER: Previous Phase I and II trials of PANVAC, a poxviral-based cancer vaccine, suggested clinical efficacy in some patients with breast, ovarian, and colorectal cancer, and evidence of immunologic activity. Preclinical data showed docetaxel can modify tumor phenotype, making tumor cells more amenable to T-cell-mediated killing. This open-label randomized Phase II, dual-center trial was designed to enroll 48 patients with metastatic breast cancer to receive docetaxel with PANVAC (arm A) or docetaxel alone (arm B). Participants were patients with metastatic breast cancer, all subtypes, no limitations on prior lines of therapy. The primary endpoint was progression-free survival (PFS), using a Phase 2.5 statistical design, with the intent of identifying a trend toward benefit (defined as 1-sided p 0.10) to guide a larger trial design. Secondary endpoints included safety and immunologic studies. Forty-eight subjects were enrolled (arm A, n=25; arm B, n=23). No patient remained on study at the time of the final analysis. Patient and tumor characteristics were well matched. Analysis of adverse events on both arms demonstrated very little difference between the two groups. Final data analysis indicates median PFS is 7.9 vs. 3.9 months in A vs. B (one-sided p=0.09, hazard ratio (HR = 0.65 (95% CI: 0.34 - 1.14)). This study was hypothesis generating and provides both rationale and statistical assumptions for a larger definitive randomized study. PHASE 1 TRIAL OF YEAST-BRACHYURY VACCINE: The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinoma as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown a recombinant Saccharomyces cerevisiae (yeast) vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A Phase I dose escalation (3+3 design) trial enrolled 34 patients at 4 dose levels. Expansion cohorts were enrolled at 40 and 80 YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events were observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising carcinoembryonic antigen (CEA), remains on study for greater than 1 year with stable disease and evidence of decreased tumor density and decreased serum CEA. This study is the first-in-human to demonstrate the safety and immunogenicity of this therapeutic cancer vaccine and provides rationale for exploration in Phase II studies. A randomized Phase II chordoma study is enrolling. 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 pox viral vectors). A phase 1 trial to demonstrate safety and immunogenicity began in July 2014 and completed enrollment in February 2015 (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 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 IL-2, 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. Two deaths occurred on study, both due to complications of rapid disease progression, unrelated to vaccine. Two other serious adverse events (AEs) occurred, a hip fracture after a fall and a colonic obstruction due to disease progression. No serious adverse event 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 adverse event, diarrhea, was related to vaccine, and resolved without intervention after 48 hours. All other adverse events 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. 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 1-4, respectively. Median patient age was 59 years (range 29-77); 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- 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. 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. The phase 1 dose escalation study (3+3 design) of NHS-IL12 is ongoing. Forty-eight patients have been enrolled over 9 dose levels. There have been DLTs at the 2 highest dose levels (8 and 9), but the MTD has not yet been determined. Ongoing analysis includes serum cytokine and peripheral blood immune subset analysis pre- and post-treatment.
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