Introduction or Objective: Men with favorable-risk prostate cancer (PCa) on active surveillance may benefit from intervention strategies to slow or prevent disease progression and the need for definitive treatment. Pomegranate and its extracts have shown antiproliferative and proapoptotic effects in cell lines and animal models, but its effect on human prostate cancer as a target tissue remain unclear. Objectives of this trial include pomegranate's ability to alter serum and prostate tissue biomarkers and the ability of an active surveillance cohort to adhere to a chemoprevention trial for 1 year. Methods: Men with organ-confined, favorable-risk PCa on AS were randomly assigned to receive pomegranate fruit extract (PFE) 1000 mg (n = 15) or placebo (n = 15) once daily for twelve months. Prostate biopsies were performed at study entry and upon completion of the 1-year intervention. Plasma and urinary biomarkers were analyzed utilizing immunoassays and HPLC. Tissue proteins were assessed by immunohistochemistry (IHC) and measured by automated quantitation.
9cUAB30 is a synthetic analogue of 9-cis retinoic acid with chemoprevention activity in cell lines and animal models. The purpose of this phase I placebo-controlled, double-blinded, dose escalation study of 9cUAB30 was to evaluate its safety, pharmacokinetics, and determine a dose for future phase II studies. Participants received a single dose of study drug (placebo or 9cUAB30) on day 1 followed by a 6-day drug-free period and then 28 days of continuous daily dosing starting on day 8. Fifty-three healthy volunteers were enrolled into five dose cohorts (20, 40, 80, 160, and 240 mg). Participants were randomized within each dose level to receive either 9cUAB30 (n ¼ 8) or placebo (n ¼ 2). 9cUAB30 was well tolerated, with no dose limiting toxicities reported and no evidence of persistent elevations in serum triglycerides or cholesterol. Treatment-emergent grade 3 hypertension occurred in 1 of 8 participants at the 20 mg dose level and in 2 of 8 at the 240 mg dose level, all considered unlikely related to study agent; no other grade 3 adverse events were observed. The AUC increased, as expected, between day 1 (single dose) and day 36 (steady state). Pharmacokinetics were linear in dose escalation through 160 mg. 9cUAB30 administered by daily oral dosing has a favorable safety and pharmacokinetic profile. On the basis of the observed safety profile and lack of linearity in pharmacokinetics at doses greater than 160 mg, the recommended phase II dose with the current formulation is 160 mg once daily.
Background: Three proteins insulin like growth factor binding protein 2 (IGFBP2), human epidermal growth factor receptor 2 (HER2), and insulin like growth factor receptor-1 (IGF1R) are overexpressed in in pre-invasive and high risk breast lesions and are associated with progression to invasive breast cancer. These proteins are immunogenic and elicit both humoral and cellular immunity in breast cancer patients. It is hypothesized that immunization with a plasmid vaccine (WOKVAC) targeting antigens from these proteins will be safe and immunogenic. WOKVAC has been designed to include extended sequences of the immunizing antigens that are predominantly associated with eliciting Type I immune responses. Type I immunity results in immune cells called T-cells secreting high levels of inflammatory cytokines (called Th1) that stimulate tumor destruction as well as the generation of cytotoxic T-cells that can directly kill the tumors. Trial design: Phase I dose escalation study of 3 doses of WOKVAC admixed with 100mcg of GM-CSF. Patients will be assigned sequentially to one of three arms (10 patients/arm): Arm 1=150mcg, Arm 2=300mcg, Arm 3=600mcg. Each dose arm will have a staggered enrollment to assess toxicity. If the Arm 1 dose is determined to be safe, Arm 2 patients can be enrolled. If the Arm 2 dose is safe and immunologically more efficacious than Arm 1 then Arm 3 patients can be enrolled. Study treatment includes 3 monthly vaccines, two evaluations at 1 and 6 months post vaccine and a 5 year follow-up to collect reports from the patient's primary oncologist. Toxicity is assessed at baseline through the end of the study. Serial blood draws for immunologic monitoring is done. Eligibility criteria: Patients with non-metastatic, node positive, HER2 negative breast cancer that is in remission and defined as no evidence of disease. Patients must have a good performance status, be at least 28 days from last cytotoxic chemotherapy and/or radiotherapy and 28 days from any use of systemic steroids. Specific aims: (1) Determine safety of 3 escalating doses of WOKVAC, (2) Determine the most immunogenic dose, (3) Determine whether a WOKVAC Th1 polyepitope plasmid based vaccine elicits a persistent memory T-cell and (4) Determine whether WOKVAC vaccination modulates T regulatory cells and myeloid derived suppressor cells. Statistical methods: (1) Safety will be assessed per NCI CTCAE v. 4.0, (2) Immunogenicity will be defined by the magnitude of the Th1 IFN-gamma antigen specific immune response. Successful immunization is a protein specific IFN-g precursor frequency greater than 1:20,000 PBMC for each antigen or 2 fold increase if baseline immune response (3) The IGFBP2, HER2, and IGF1R specific IFN-g/IL-10 ratios by ELISPOT will be evaluated to determine that a predominantly Th1 immune response is stimulated, and (4) Humoral immune response will be measured by ELISA and serum antibody avidity for IGFBP2, HER2, and IGF1R to determine an avidity index (AI) before and after vaccination. Targeted Accrual: 30 patients Contact information: University of Washington: 866-392-8588/TrialTVG@uw.edu University of Wisconsin: 608-265-2493/prevention@uwcarbone.wisc.edu. Citation Format: Childs JS, Higgins DM, DeShong K, Heckman-Stoddard BM, Wojtowicz ME, Stanton SE, Bailey HH, Wisinski KB, Disis ML. A phase I trial of the safety and immunogenicity of a DNA plasmid based vaccine (WOKVAC) encoding epitopes derived from three breast cancer antigens (IGFBP2, HER2, and IGF1R) in patients with breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-01-03.
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