Lana A. Vornik

Phase IB Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Women with Hormone Receptor–Negative Breast Cancer

Epidemiologic data support an inverse association between green tea intake and breast cancer risk, and numerous experimental studies have shown the antitumor effects of its main component, epigallocatechin gallate (EGCG). We conducted a phase IB dose escalation trial in women with a history of stage I to III hormone receptor–negative breast cancer of an oral green tea extract, polyphenon E (Poly E) 400, 600, 800 twice daily or matching placebo for 6 months. The primary endpoint was to determine the maximum tolerated dose (MTD), defined as the dose that causes 25% dose-limiting toxicity (DLT, grade ≥II). Assignment to dose level was based upon an adaptive design, the continual reassessment method. A mammogram and random core biopsy of the contralateral breast were obtained at baseline and 6 months and serial blood/urine collections every 2 months for biomarker analyses. Forty women were randomized: 10 to placebo, 30 to Poly E (16 at 400 mg, 11 at 600 mg, 3 at 800 mg). There was one DLT at 400 mg (grade III rectal bleeding), three DLTs at 600 mg (grade II weight gain, grade III indigestion and insomnia), and one DLT at 800 mg (grade III liver function abnormality). The DLT rate at 600 mg was 27% (3 of 11). Pharmacologic levels of total urinary tea polyphenols were achieved with all three dose levels of Poly E. Using a novel phase I trial design, we determined the MTD for Poly E to be 600 mg twice daily. This study highlights the importance of assessing toxicity for any chemopreventive agent being developed for chronic use in healthy individuals. Cancer Prev Res; 5(9); 1144–54. ©2012 AACR.

A Randomized Multicenter Phase II Study of Docosahexaenoic Acid in Patients with a History of Breast Cancer, Premalignant Lesions, or Benign Breast Disease

Obesity, a cause of subclinical inflammation, is a risk factor for the development of postmenopausal breast cancer and is associated with poorer cancer outcomes. Docosahexaenoic acid (DHA), an omega-3 fatty acid, possesses anti-inflammatory properties. We hypothesized that treatment with DHA would reduce the expression of proinflammatory genes and aromatase, the rate-limiting enzyme for estrogen biosynthesis, in benign breast tissue of overweight/obese women. A randomized, placebo-controlled, double-blind phase II study of DHA given for 12 weeks to overweight/obese women with a history of stage I–III breast cancer, DCIS/LCIS, Pagets disease, or proliferative benign breast disease was carried out. In this placebo controlled trial, the primary objective was to determine whether DHA (1,000 mg by mouth twice daily) reduced breast tissue levels of TNFα. Secondary objectives included evaluation of the effect of DHA on breast tissue levels of COX-2, IL1β, aromatase, white adipose tissue inflammation, and gene expression by RNA-seq. Red blood cell fatty acid levels were measured to assess compliance. From July 2013 to November 2015, 64 participants were randomized and treated on trial (32 women per arm). Increased levels of omega-3 fatty acids in red blood cells were detected following treatment with DHA (P < 0.001) but not placebo. Treatment with DHA did not alter levels of TNFα (P = 0.71), or other biomarkers including the transcriptome in breast samples. Treatment with DHA was overall well-tolerated. Although compliance was confirmed, we did not observe changes in the levels of prespecified biomarkers in the breast after treatment with DHA when compared with placebo. Cancer Prev Res; 11(4); 203–14. ©2018 AACR. See related editorial by Fabian and Kimler, p. 187

Abstract OT3-01-04: VADIS trial: Phase II trial of the nelipepimut-S peptide vaccine in women with DCIS of the breast

Background: Our group has been investigating vaccination strategies in breast cancer. Specifically, we have been evaluating HER2-derived peptide vaccines including nelipepimut-S+GM-CSF administered adjuvantly to breast cancer patients who have been rendered disease-free with standard of care therapy but are at high risk for recurrence. Early phase clinical trials showed an approximately 50% reduction in relative recurrence risk in vaccinated patients. Based on these data, nelipepimut-S+GM-CSF is being evaluated in a phase III registration trial. Having shown the vaccine to be safe, effective in stimulating an antigen-specific immune response and potentially having clinical efficacy in the setting of secondary prevention, the current study was initiated to evaluate vaccination in DCIS patients. This trial represents an initial step to move the vaccine into the primary prevention setting. Trial Design: Phase II, randomized, single-blind study. Patients will be randomized 2:1 to receive vaccine or GM-CSF alone. After enrollment, patients will receive 3 inoculations administered every other week preoperatively followed by surgery then completion of the vaccination series (3 additional inoculations) in the adjuvant setting. Eligibility: The trial will enroll pre- or post-menopausal women with a diagnosis of DCIS made by core biopsy. The area of radiographic abnormality must measure at least 1 cm. Because the vaccine is a MHC class I, CD8+ T cell-eliciting vaccine, it is HLA restricted, and patients must be HLA-A2+ to enroll. Participants must also have an ECOG performance status Specific Aims: The trial9s primary endpoint is to evaluate for nelipepimut-specific CD8+ T cells in the peripheral blood of vaccinated patients compared to patients receiving GM-CSF alone. Secondary endpoints include evaluating toxicity; determining the immune response in vivo by DTH, in vitro by evaluating for epitope spreading to other tumor antigens, and importantly in the tumor by assessing the degree of lymphocytic infiltration in surgically resected specimens. The extent of HER2 expression, Ki67 and cleaved caspase 3 in the resected specimen will also be assessed. Statistical Methods: A total of 108 DCIS patients will be consented and screened for eligibility. 48 (45%) are expected to be HLA-A2 positive. These 48 patienst will be randomized 2:1 to vaccine or GM-CSF alone groups. Accounting for 10% attrition rate and for an approximately 5% non-evaluable sample rate, we expect to have 40 evaluable patients, 27 in the vaccine group and 13 in the GM-CSF alone group, that have baseline, pre-surgery, and post-surgery measures of nelipepimut-S-specific CD8+ T cells. We will have 82% power to detect a significant increase in nelipepimut-S-specific CD8+ T cells in the vaccine group versus the GM-CSF alone group. Contact Info: The study is accruing at four sites to include Columbia University, Dana Farber Cancer Institute, MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center. Additional information can be obtained from the overall study PI, Dr. Elizabeth Mittendorf (eamitten@mdanderson.org). NCT0236582. Citation Format: Mittendorf EA, Plitas G, Garber J, Crew K, Heckman-Stoddard B, Wojtowicz M, Vornik L, Peoples GE, Brown PH. VADIS trial: Phase II trial of the nelipepimut-S peptide vaccine in women with DCIS of the breast [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 OT3-01-04.

Abstract LB-195: A double-blind randomized controlled multisite trial evaluating tissue effects of preoperative finasteride in clinically organ-confined prostate cancer: Pathologic outcomes.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: The Prostate Cancer Prevention Trial (PCPT) showed a relative reduction of 24.8% in cumulative incidence of prostate cancer (PC) in finasteride-treated men (18.4 v 24.4%; p<.001). However, high-grade cancers (Gleason score [GS] ≥7) were more commonly detected in men receiving finasteride than placebo (6.4 v 5.1%; p=.005), an effect of uncertain significance. We therefore undertook a study to determine differences between finasteride-exposed and -unexposed (placebo/control) cancers in the expression of a preselected molecular signature shown to distinguish Gleason grade (GG) 3 from GG 4 untreated tumors. Methods: This 4-site presurgical trial was in men with clinically organ-confined PC (cT1c/T2; GS 6 or 7; prostate-specific antigen [PSA] <10 ng/mL) randomly assigned to treatment with 5 mg finasteride or placebo daily for 4-6 wk prior to prostatectomy. At baseline and at surgery, PSA, testosterone (T), dihydrotestosterone (DHT), estrone (E1), and estradiol (E2) levels were measured in men who opted to donate blood for research. We used a standard method to handle radical prostatectomy (RP) specimens, including mapping of tumor foci to document relevant morphologic data. Results: In all, 210 patients consented, 204 were randomized, 183 were evaluable for detailed pathologic outcomes, and 163 were evaluable for PSA and hormone levels. Median age was 60 (45-73) yr. Median treatment time was 28 (10-43) days. Median prostate total tumor volume (TV) was 0.9 (0-10.4) cc, and peripheral zone TV, 0.6 (0-9.3) cc. Biopsy (Bx) GS, GS upgrade between Bx and RP, specimen GS/GG, total cancer foci, zonal origin of dominant cancer, and median total and PZ TV were similar in the 2 treatment arms (A v B). Post-treatment, median PSA was significantly lower (3.2 v 5.2 ng/mL; p<.001); testosterone, significantly higher (391 v 325 ng/dL; p=.021); and DHT, significantly lower (10 v 27 ng/dL; p<.001) in arm A than in arm B. No differences were noted in E1 and E2 levels. Biomarker analysis of a preselected molecular signature is under way; unblinding awaits completion of biomarker analysis. Conclusions: No significant difference in GS distribution was observed between the two groups after short-term exposure to finasteride or placebo. Modulation of PSA, T, and DHT levels occurred in a statistically significant uneven distribution by study arm. Molecular signature characterization has been completed, and the planned analysis of associations is under way. The findings are expected to provide insight into the reported grade effect attributed to finasteride. (This work was supported in part by NCI contract N01-CN-35159.) Citation Format: Jeri Kim, John W. Davis, Eric A. Klein, Cristina Magi-Galluzzi, Yair Lotan, John F. Ward, Louis L. Pisters, Joseph W. Basler, Curtis A. Pettaway, Elsa M. Li Ning Tapia, Xuemei Wang, Kim-Anh Do, Jack Lee, Lana A. Vornik, Joe Tangrea, Howard L. Parnes, Scott M. Lippman, Ian M. Thompson, Powel H. Brown, Patricia Troncoso, Christopher J. Logothetis. A double-blind randomized controlled multisite trial evaluating tissue effects of preoperative finasteride in clinically organ-confined prostate cancer: Pathologic outcomes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-195. doi:10.1158/1538-7445.AM2013-LB-195

Abstract C52: A phase Ib biomarker trial of naproxen in patients at risk for DNA mismatch repair deficient colorectal cancer

Rationale: Approximately 15% of colorectal cancers (CRC) display Microsatellite Instability (MSI). The DNA mismatch repair (MMR) system is deficient in this tumor subtype secondary to a germline mutation in one of the MMR system genes (MLH1, MSH2, MSH6, PMS2) or to the presence of hypermethylation MLH1. Therefore, MSI tumors can have a genetic origin (Lynch syndrome) or a sporadic origin (hypermethylated MSI tumors). Patients and families diagnosed with Lynch Syndrome have an up to 70-80% lifetime risk of CRC. Therefore, this high-risk population may benefit from effective chemopreventive strategies. Results from the CAPP-II trial suggest that aspirin use is associated with reduction of risk for CRC and other tumors in Lynch syndrome; however the large doses needed and potential side effects present barriers to adoption. Other non-steroidal anti-inflammatory drugs (NSAID) with stronger efficacy and better tolerability may be reasonable alternatives for CRC chemoprevention. Naproxen is a NSAID that is widely used in the community with an excellent safety profile. Recent pre-clinical data sponsored by the Division of Cancer Prevention of the National Cancer Institute using a conditional mouse model of Lynch Syndrome (VC-MSH2-LoxP) have shown that Naproxen is the most effective agent from a panel of NSAIDs preventing CRC. Therefore, this clinical trial was designed to confirm the activity of Naproxen observed in vivo in patients diagnosed with Lynch Syndrome. Because NSAIDs exert their therapeutic effects through the inhibition of COX-1/-2 which in turn leads to a reduction in prostaglandin production, tissue level of prostaglandin E2 (PGE2) is a robust biomarker for the effect of NSAIDs. We wish to report herein the background and schema of this early-phase (Ib) cancer prevention trial to introduce the concept of NSAID chemoprevention strategy in this specialized and genetically well-defined patient population, and thus to also facilitate the identification of additional collaborators for potential further larger trials initiatives. Design: Eligible patients include individuals harboring a pathogenic mutation in one of the MMR genes and individuals who have been diagnosed with non-sporadic MSI-high tumors (i.e. no evidence of MLH1 hypermethylation or BRAF mutation). The primary endpoints are to test whether Naproxen at a once-daily 220 mg (low-) or 440 mg (high-) dose, administered for 6 months, reduces the concentration of PGE2 levels in normal colorectal mucosa, when compared to placebo; and to determine the safety profile and tolerability of Naproxen. A total of 60 participants will be randomized to achieve an evaluable sample size of 45 participants. Under the assumption of an effect size of 1.25, we will have 80% power for pairwise comparisons by the two-sample t-test among the three groups with 15 evaluable participants per group. Response to treatment will be defined as having a 30% reduction in the PGE2 level post-treatment. Secondary endpoints include the determination of Naproxen concentrations in plasma and in normal colorectal mucosa after 6 months of treatment, and levels of PGE2 in urine after 6 months of treatment, all measured by validated biomarker assays. The study will be conducted at three clinical sites (The University of Texas MD Anderson Cancer Center, The University of Michigan Comprehensive Cancer Center and Dana Farber Cancer Institute). Screening and accrual are expected to begin in the latter part of 2013. Supported by NCI, DCP Contract HHSN261201200034I to the UT MD Anderson Cancer Prevention Agent Development Program: Early Phase Clinical Research Consortium. Citation Format: Eduardo Vilar, Y. Nancy You, Lana A. Vornik, Elena M. Stoffel, Ramona M. Lim, Steven M. Lipkin, Marjorie Perloff, Powel H. Brown. A phase Ib biomarker trial of naproxen in patients at risk for DNA mismatch repair deficient colorectal cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr C52.

Abstract C49: A randomized phase II trial of low-dose aspirin versus placebo in high-risk individuals with CT screen-detected subsolid lung nodules

Lung cancer screening by spiral low-dose CT scan (ld-CT) is a noninvasive test with low radiation exposure and no contrast medium and offers the opportunity to serially examine the peripheral lung for the first time, albeit with the limitation that small lesions cannot be biopsied, leaving their identity unknown. However, the incidence of undetermined nodules detected with ld-CT is more than 50% in high-risk individuals. The nature of these nodules remains uncertain but some of them could represent precancerous lesions. Particularly, ground glass opacities (GGO), compared with solid nodules, can represent localized bronchioloalveolar carcinoma without foci of active fibroblastic proliferation or atypical adenomatous hyperplasia, a putative adenocarcinoma precursor lesion. Two screening programs with annual ld-CT in current and former smokers are run at the EIO and they may represent suitable cohorts of at-risk subjects to be enrolled in a chemopreventive study. Aspirin, the first nonsteroidal anti-inflammatory drug (NSAID) identified, may have anti-cancer properties, especially for diseases whose etiology implicates chronic inflammation including lung cancer. The anti-inflammatory effect of NSAIDs operates through inhibition of prostaglandins via suppression of cyclooxygenase-1 (COX-1) and COX-2. Evidence of this effect is derived from several recently published meta-analyses of aspirin in the prevention of cardiovascular events showing that daily aspirin reduced the incidence of several cancers and reduced metastases. In 2011, Rothwell et al. pooled data from 8 double-blind randomized controlled trials of daily aspirin and analyzed the effect of aspirin on cancer mortality as secondary endpoints. The 20-year risk of death due to all cancers was lower in the aspirin than in the control group and the benefit increased with treatment duration. Lung cancer-specific mortality rates were reduced by 29% (95% CI, 11-42) in the aspirin group in the 20-year period after the trial commenced. No trend with dose (above 75 mg/day) was observed, but the effect on all cancers was more evident in adenocarcinomas and was present in both smokers and nonsmokers. Several further observational studies have been published confirming a lower lung cancer risk in aspirin users. Based on the growing evidence on the potential preventive effect of Aspirin on lung cancer, we will conduct a monoinstitutional, double-blind, placebo-controlled phase IIb study in which 128 participants enrolled in a ld-CT annual screening program will be randomized to receive either low dose Aspirin (100 mg/day) or placebo for 12 month. The primary endpoint will be the shrinkage of GGO and partially solid nodules after one-year treatment in a per-lesion and per-subject analysis. Secondary endpoints will be the modulation of biological markers and their potential correlation with modification of lung nodules shrinkage. In particular, we will evaluate the effect of Aspirin on a signature of serum miRNA correlated to subsolid nodules. Other secondary endpoints will be the evaluation of lung nodule density before and after treatment and the number and size of non-target lesions. Additional circulating biomarkers will include the modulation of hs-CRP as a marker of inflammation, the evaluation of urinary cotinine as marker of tobacco exposure and investigation of the potential effect of aspirin according to its concentration, the measurement of urinary prostaglandin metabolites (PGEM) and urine LTE4. Tolerability of low dose Aspirin will be also evaluated. The study is expected to start by December 2013. Supported by NCI, DCP Contract HHSN261201200034I to the UT MD Anderson Cancer Prevention Agent Development Program: Early Phase Clinical Research Citation Format: Aliana Guerrieri-Gonzaga, Giulia Veronesi, Pier Paolo Di Fiore, Matteo Lazzeroni, Massimo Bellomi, Eva Szabo, Lana A. Vornik, Powel H. Brown, Bernardo Bonanni. A randomized phase II trial of low-dose aspirin versus placebo in high-risk individuals with CT screen-detected subsolid lung nodules. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr C49.

Abstract CN06-02: Phase IB randomized, double-blinded, placebo-controlled, dose escalation study of Polyphenon E in women with a history of hormone receptor-negative breast cancer

Background : Priorities in breast cancer chemoprevention include developing safe and tolerable agents for potential chronic use that are effective against hormone receptor (HR)-negative breast cancer and validating intermediate biomarkers which correlate with breast cancer risk. Various epidemiologic studies have demonstrated an inverse association between green tea consumption and breast cancer risk. The primary polyphenol of green tea, epigallocatechin gallate (EGCG), is a potent antioxidant that acts on multiple stages of carcinogenesis. The primary objective of this phase IB trial was to demonstrate the safety of using an oral green tea extract, Polyphenon E (Poly E), over a 6-month period in patients with a history of HR-negative breast cancer. Secondary exploratory objectives were to investigate the dose-related biologic effects of Poly E on breast tissue, radiographic, serum and urine-based biomarkers. Methods : Forty women with stage I-III HR-negative breast cancer who completed adjuvant treatment were randomized to oral Poly E: (1) 400mg, (2) 600mg, or (3) 800mg (2–4 capsules) bid or matching placebo for 6 months. The primary endpoint of this dose escalation study was to determine the maximum tolerated dose (MTD) of Poly E in this patient population, defined as the dose that causes 25% dose limiting toxicity (DLT, grade 2 or higher). Assignment to dose level was based upon an adaptive clinical trial design called the time-to-event continual reassessment method, such that more participants were assigned to the MTD. Safety was assessed by monitoring clinical and laboratory parameters during monthly visits. At baseline and 6 months, a mammogram and random core biopsy of the contralateral breast and serial blood and urine collections were obtained for biomarker analyses. Secondary exploratory endpoints included breast tissue-based biomarkers (Ki-67, ER), mammographic density, serum hormone metabolites (estradiol, testosterone, IGF-I, IGFBP-3, SHBG), inflammatory and oxidative stress biomarkers (serum CRP, urine PGE-M, 8-OHdG, isoprostane). Results : From July 2007 to Sept 2009, 40 women were enrolled from 4 sites. Baseline characteristics included median age: 55 (39–65); pre/postmenopausal: 10/30; White/Hispanic/Black/Asian: 23/9/7/1; stage I/II/III: 16/15/9; median time since diagnosis: 33 months (10–170). Eighteen participants were each assigned to dose levels 1 and 2, four participants to dose level 3. There was 1 DLT at dose level 1 (grade 3 rectal bleeding), 3 DLTs at dose level 2 (grade 2 weight gain and indigestion, grade 3 insomnia), and 1 DLT at dose level 3 (grade 3 liver function abnormality). As a result, 600mg bid was found to be the MTD for Poly E. Biomarker analyses are currently ongoing. Conclusions : Using a novel clinical trial design for phase I testing which evaluates long-term toxicity, we determined the MTD for Poly E that will serve as the upper safety limit in future breast cancer chemoprevention trials. We also obtained preliminary data on the biological effects of Poly E on biomarkers of breast cancer risk, which can elucidate potential mechanisms of action and possibly serve as surrogate endpoints in future clinical efficacy trials. Citation Information: Cancer Prev Res 2011;4(10 Suppl):CN06-02.