Nancy Tait

Phase I clinical trial of all-trans-retinoic acid with correlation of its pharmacokinetics and pharmacodynamics

Abstract A phase I trial of all-trans-retinoic acid (ATRA) was conducted to establish the maximum tolerable dose (MTD) of ATRA given once daily to patients with solid tumors. Cancer patients for whom no standard therapy was available were treated with ATRA once daily. Doses were escalated in cohorts of at least three patients. The pharmacokinetics of ATRA were assessed on day 1 for all patients and weekly for 31 patients who received doses of ≥110 mg/m2 per day. Patients were followed for toxicity and response. Correlations of toxicity frequency and grade with pharmacokinetic parameters were sought. In addition, correlation of changes in ATRA pharmacokinetics with the concentration of ATRA metabolites in plasma were sought. A total of 49 patients received ATRA at doses ranging from 45 to 309 mg/m2 per day. Hypertriglyceridemia was dose-limiting at 269 mg/m2 per day. Other frequent toxicities included mucocutaneous dryness and headache. With chronic dosing, plasma ATRA concentrations fell in 59% of patients. Stable, low, or variable [ATRA] were seen in 16%, 6%, and 16% of patients respectively. Age, gender, smoking, or concurrent medication did not correlate with the pharmacokinetic pattern. Severe toxicities tended to occur with initial peak [ATRA] of ≥0.5 μg/ml (1.7 μM), and the toxicity frequency did not change if [ATRA] decreased with continued dosing. No consistent change in 4-oxo-ATRA or retinoid glucuronide concentrations was observed with decreases in plasma [ATRA]. The recommended once-daily ATRA dose is 215 mg/m2, although significant interpatient variability is observed in toxicity and plasma retinoid concentrations. Although not statistically significant, more frequent and severe toxicity tended to occur in patients with higher plasma peak ATRA concentrations. Other factors, such as responses at target tissues, may be at least as important as the plasma ATRA concentration in predicting toxicity and/or response.

Increased circulating Level of the survival Factor Gp88 (progranulin) in the serum of Breast cancer patients When compared to Healthy subjects

Introduction GP88 (PC-Cell Derived Growth Factor, progranulin) is a glycoprotein overexpressed in breast tumors and involved in their proliferation and survival. Since GP88 is secreted, an exploratory study was established to compare serum GP88 level between breast cancer patients (BC) and healthy volunteers (HV). Methods An IRB approved prospective study enrolled 189 stage 1–4 BC patients and 18 HV. GP88 serum concentration was determined by immunoassay. Results Serum GP88 level was 28.7+ 5.8 ng/ml in HV and increased to 40.7+ 16.0 ng/ml (P= 0.007) for stage 1-3 and 45.3 +23.3 ng/ml (P = 0.0007) for stage 4 BC patients. There was no correlation between the GP88 level and BC characteristics such as age, race, tumor grade, ER, PR and HER-2 expression. Conclusion These data suggest that serial testing of serum GP88 levels may have value as a circulating biomarker for detection, monitoring and follow up of BC.

Phase I study of docetaxel and topotecan in patients with solid tumors.

Purpose: Both docetaxel (DOC), a promoter and stabilizer of microtubule assembly, and topotecan (TOPO), a topoisomerase I inhibitor, have shown antitumor activity in a variety of solid tumor malignancies. This phase I trial was conducted to determine the overall and dose-limiting toxicities (DLT), the maximum tolerated dose (MTD) and the pharmacokinetics of the combination of DOC and TOPO in patients with advanced solid tumor malignancies. Methods: DOC was administered first at 60 mg/m2 without G-CSF and at 60, 70, and 80 mg/m2 with G-CSF by 1-h infusion on day 1 of the odd-numbered cycles (1, 3, 5, etc.) and on day 4 of the even-numbered cycles (2, 4, 6, etc.). TOPO 0.75 mg/m2 was administered as a 30-min infusion on days 1, 2, 3 and 4 of each cycle. G-CSF 300 μg was administered subcutaneously (s.c.) on days 5–14. Cycles were repeated every 21 days. All patients were premedicated with dexamethasone 8 mg orally every 12 h for a total of six doses starting on the day before DOC infusion. Results: A total of 22 patients were treated. Six patients were treated in cohort I with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, without G-CSF, and two patients developed DLT (febrile neutropenia). Four patients were treated in cohort II with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, with G-CSF, and no DLT was observed. Four patients were treated in cohort III with DOC and TOPO doses of 80 and 0.75 mg/m2, respectively, with G-CSF, and three developed DLT (febrile neutropenia). DOC was then de-escalated to 70 mg/m2 and delivered with TOPO 0.75 mg/m2 and G-CSF (cohort IV). Eight patients were treated at this dose level, and one DLT (febrile neutropenia) was observed. Two patients developed a severe hypersensitivity reaction shortly after the DOC infusion was started, one in cycle 1 and one in cycle 2. Both patients were removed from the study. Two patients developed severe dyspnea in the presence of progressive pulmonary metastases. Other nonhematological toxicities were mild. One patient with extensively pretreated ovarian carcinoma had a partial response, and eight patients with various solid tumor malignancies had stable disease with a median time to progression of 12 weeks (range 9–18 weeks). Administration of TOPO on days 1–4 and DOC on day 4 resulted in increased neutropenia. Conclusions: DOC 80 mg/m2 given first as a 1-h infusion on day 1 with TOPO 0.75 mg/m2 given as a 0.5-h infusion on days 1, 2, 3 and 4 with G-CSF was considered the MTD. The recommended phase II dose for DOC given on day 1 is 70 mg/m2 with TOPO 0.75 mg/m2 given on days 1, 2, 3 and 4 every 21 days with G-CSF 300 μg s.c. on days 5–14. The alternative schedule with DOC given on day 4 and TOPO on days 1–4 is not recommended.

Patient-reported Adherence to Adjuvant Aromatase Inhibitor Therapy Using the Morisky Medication Adherence Scale: An Evaluation of Predictors.

Objectives: Endocrine therapy is part of standard adjuvant therapy for patients with hormone receptor-positive breast cancer and has been shown to improve recurrence-free and overall survival. However, adherence to endocrine therapy is suboptimal and is difficult to measure. In this study we evaluate the feasibility of using the Morisky Medication Adherence Scale (MMAS) to assess patient adherence to aromatase inhibitor (AI) therapy. Methods: Patients with stage 1 to 3, hormone receptor-positive breast cancer receiving adjuvant AI therapy were prospectively enrolled on an Institutional Review Board approved protocol. The MMAS questionnaire was administered to each patient and adherence was measured. Information on duration of AI therapy, patient and tumor characteristics, and treatment was collected. A multivariable logit model approach was utilized to evaluate potential barriers to adherence. Results: Between 2011 and 2014, 100 patients were enrolled. The distribution of adherence levels was 13% low, 37% medium, and 50% high. High adherence was reported more frequently in white women (58%), patients with stage 2 and 3 disease (54%), and patients who did not receive chemotherapy (62%). Multivariable analysis demonstrated that higher adherence was more likely in white women compared with African American women (estimated odds ratio=2.8). Conclusions: Using the MMAS, only 50% of women with stage 1 to 3 breast cancer reported high adherence to AI therapy, consistent with other reports showing suboptimal adherence to adjuvant endocrine therapy. The MMAS allows for the rapid assessment of adherence to oral adjuvant endocrine therapy and is valuable in a busy clinical setting.

Elevated serum levels of the growth factor GP88 are found in breast cancer patients when compared to healthy individuals.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #2006 Background: GP88 is an autocrine growth factor that plays a critical role in breast tumorigenesis. GP88 is expressed in human BC tumors in a positive correlation with their tumorigenicity. Increased GP88 expression is associated with resistance to anti-estrogen therapy in ER + cells and with herceptin resistance in Her-2 overexpressing breast tumors. Inhibition of GP88 expression in human breast adenocarcinoma inhibited tumor incidence and growth in nude mice. Immunohistochemical studies have shown that GP88 was expressed in invasive ductal carcinomas in correlation with the expression of poor prognosis markers whereas normal tissues and benign lesions were negative. High GP88 expression in tumor biopsies was accompanied by decreased disease-free survival. Since GP88 can be secreted, we have hypothesized that GP88 could be secreted in the circulation and found in serum. We examined whether GP88 could be found in the circulation and whether GP88 could be elevated in the sera of breast cancer patients when compared to healthy individuals. Methods: An IRB approved blood sampling study was conducted at the University of Maryland Breast Clinic to determine the serum level of GP88 in healthy volunteers (HV) and breast cancer patients (BC pts). Serum GP88 concentration was determined in triplicate by quantitative enzyme immunoassay. 189 BC pts were accrued. In addition, sera from 18 HV were obtained to establish a GP88 baseline in healthy volunteers. BC patient characteristics: Race: Caucasian- 91, African American-92, Asian-6; median age, 51 (range 29-86), stage I – 48, II - 52, III – 26, IV - 63. Results: Circulating GP88 was measurable in the serum. Median level of GP88 was 28.7 ng/ml (range 16.6-38.2) in HV; 40.7 ng/ml (range 6.4-100) in early stage (stage 1 –3) BC pts (p- value = 0.007) and 45.3 ng/ml (range 9.8 to 158.4) in stage 4 metastatic BC patients (p-value= 0.0007). Statistically significant increase in circulating GP88 level was found in early stages as well as in metastatic disease. Correlation studies with BC prognostic factors such as stage, tumor size, lymph node involvement, tumor grade and presence of ER and HER-2 will be presented. Conclusion: GP88 can be detected in the sera of HV and BC pts. Comparison between the two groups of subjects indicates that GP88 level is significantly higher in the sera of BC pts. These studies are important as they identify as a measurable circulating biomarker GP88 that is also a therapeutic target of malignant transformation or malignant progression of breast carcinoma (BC). Future studies will examine whether there is any correlation between the serum level of GP88 and therapeutic response to systemic therapy in breast cancer patients. This study was supported by grant from MIPS, the Avon Foundation and 1R43 CA 124179-01A1 from the National Institutes of Health. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2006.

Nutritional Concerns in Cancer Patients

One of the prime nutritional concerns in cancer patients is cachexia and deteriorating nutritional status. Cachexia can occur as a result of either treatment or the tumor itself. The progressive malnutrition ultimately affects performance status and organ function. Tolerance to treatment may thus be decreased, which, in turn, may adversely affect toxicity and response. In addition, the deleterious effects of malnutrition on the immune system can increase susceptibility to infection. The weakness and fatigue related to muscle wasting and changes in metabolism affect physical appearance, leading to a loss of self-esteem. Thus, the vicious cycle of cachexia severely impacts on every aspect of daily life. Providing nutritional support and effective treatment may reverse the cachexia. Studies involving caloric supplements alone have not been encouraging. Conversely, studies using megestrol acetate have shown that cancer patients gain weight and that their sense of well-being improves. However, the mechanisms of weight gain remain unknown, and further studies are needed to determine the mechanisms by which appetite is stimulated or catabolism is inhibited or both. Nursing interventions to stimulate appetite and promote greater food intake, coupled with the use of agents that alter metabolism, such as megestrol acetate, may reverse the trend of cachexia and thus provide an increased sense of well-being and improved quality of life.

Abstract 3918: Circulating progranulin (GP88/PGRN) level correlates with survival in metastatic breast cancer patients

Current monitoring of therapy response in metastatic breast cancer (MBC) patients is dependent on expensive and time consuming imaging methods that have limited sensitivity to detect disease response in a timely manner. Understanding of real-time biological processes through measurement of circulating disease associated biomarkers may provide a clearer understanding of the disease state and thus aid real-time clinical management of MBC patients. Current biomarkers used in MBC include CA15-3, CA27.29 and CEA. While useful, they have limitations in providing clinicians with a reliable insight into real-time monitoring of disease processes. Thus, addition of new circulating biomarkers may improve the management of MBC patients. We characterized a target biomarker, the 88kDa glycoprotein Progranulin (GP88) expressed in tumor tissue and secreted in the circulation of BC patients. Biological studies have established GP88 as one of the critical drivers for tumor cell proliferation, survival, invasiveness and drug resistance. Clinical studies have demonstrated that elevated GP88 tissue levels are prognostic for poor outcome and that breast cancer patients have a statistically elevated GP88 serum level than healthy individuals. Using tissue and serum tests to detect and quantify GP88 could provide an ideal target for monitoring disease progression in BC patients undergoing therapy. In the present study, we examined whether GP88 serum levels were elevated in MBC patients and whether GP88 serum levels were correlated to patient survival. Under an IRB approved protocol, 92 MBC patients that met the inclusion criteria and were undergoing therapy at the UMGCC Breast Clinic were consented. Clinical and disease characteristics along with serum CA15-3 values were collected as part of the study. Serum samples were collected from each patient during therapy and subsequently the patients were monitored. The serum was stored at -80C until tested for GP88. The validated GP88 assay (AG 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3918.

Abstract OT2-1-03: A pilot and phase II study of entinostat and anastrozole/tamoxifen in women with triple negative breast cancer (TNBC) to evaluate biomarkers and surrogates for response

Background: Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that lack ER, PR, and HER2. TNBC is inherently resistant to endocrine therapy (ET) such as aromatase inhibitor (AI) and tamoxifen. Previous studies suggested that the loss of ER/PR expression in TNBC is due to epigenetic silencing. We have demonstrated histone deacetylase inhibitor (HDACi), entinostat, can induce expression of functional ER and render TNBC sensitive to ET both in vitro and in vivo (Sabnis et al. Cancer Research 2011). Furthermore, the combination of entinostat and AI can induce prolonged tumor regression and significantly reduce lung metastasis in vivo. Trial Design: This is a single arm phase I/II study of entinostat in combination with ET. There are 2 cohorts in this study: cohort 1 – operable stage I-II TNBC, cohort 2 – metastatic and unresectable locally advanced TNBC. For ET, anastrozole will be used in postmenopausal women and tamoxifen in premenopausal women. The treatment regimen is: entinostat started on day 1 followed by ET on day 4. In cohort 1, paraffin embedded tissue from core needle biopsy and surgical specimens will be collected. In cohort 2, biopsies before and after 15-29 days of treatment are required. Eligibility Criteria: Female age ≥ 18 with ECOG PS ≤ 2 and TNBC defined as ER and PR Specific Aims: To determine ER expression as well as the percentage change in proliferation index (Ki67) after treatment. Moreover, safety and tolerability of the combination given either in neoadjuvant or metastatic setting will be evaluated. Response is defined as ≥ 50% reduction in Ki67 AND ≥ 1% ER-positivity OR pathologic complete response in the post-treatment surgical specimens. Statistical Methods: For the pilot phase, a 3+3 cohort design is employed. The Simon’s two-stage design is used in the phase II. The total sample size for the phase II is 32 with 12 and 20 pts in the first and second stage respectively. The study will be terminated if there is no response among the first 12 pts. If ≥ 1 response in these 12 pts is observed, then 20 more pts will be accrued. The combination will be considered promising, if ≥ 4 out of 32 pts have a response. This design yields 87% power. The probability of early stopping and declaring that this combination has no sufficient activity is 0.54, if the true success rate is 5% and 0.07 if the true response rate is 20%. If the true proportion of pts with Ki67 reduction combined with ER up-regulation is 0.20, the probability of concluding that the drug has sufficient activity is 0.87 and 0.07 if the true proportion is 0.05. To allow about 10% inevaluability, the phase II trial will accrue 35 eligible pts. Therefore, the total target accrual is 41 pts. To date, there are a total of 7 pts enrolled. Accrual is currently ongoing. Please contact ntait@umm.edu for further information. Citation Format: Saranya Chumsri, Gauri Sabnis, Nancy Tait, Jane Lewis, Emily Bellavance, Susan Kesmodel, Steven Feigenberg, Katherine RH Tkaczuk, Peter Ordentlich, Martin J Edelman, Angela H Brodie. A pilot and phase II study of entinostat and anastrozole/tamoxifen in women with triple negative breast cancer (TNBC) to evaluate biomarkers and surrogates for response [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-03.

Abstract P5-19-05: Combination vorinostat and lapatinib reverses epithelial-mesenchymal transition, inhibits the cancer stem cell population of HER2+ breast cancer cells and is effective in heavily pretreated advanced tumors

Although strides have been made in the treatment of breast cancer, patients often relapse due to recurrence or metastasis. The targeting of these cellular processes has become essential in the quest for a cancer cure. Previously, we have demonstrated the efficacy of histone deacetylase inhibitors (HDACi) in inducing differentiation and inhibiting metastasis in triple negative breast cancer cells. In addition, we have shown that HER2 regulates the cancer stem cell (CSC) population in AI resistant cells. Based on these previous results, we hypothesize that the combination of both HDACi and HER2 inhibition may be synergistic and further reduce CSC. In this study, we treated a panel of HER2+ breast cancer cell lines with the combination of 1µM vorinostat (HDACi) and 1µM lapatinib (a dual EGFR/HER2 inhibitor) for 72 hours and examined its effects on cell number, mesenchymal and epithelial markers, migratory potential, and cancer stem cell characteristics. The combination reduced cell number when compared to either agent alone (p Citation Format: Amanda J Schech, Saranya Chumsri, Preeti Shah, Stephen L Yu, Nancy S Tait, Kenneth S Bauer, Jane C Lewis, Ting Bao, Martin J Edelman, Katherine H Tkaczuk, Angela H Brodie. Combination vorinostat and lapatinib reverses epithelial-mesenchymal transition, inhibits the cancer stem cell population of HER2+ breast cancer cells and is effective in heavily pretreated advanced tumors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-05.

Abstract OT3-1-09: Acupuncture to prevent chemotherapy dose reduction due to chemotherapy-induced peripheral neuropathy in breast cancer patients

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting side effect of neurotoxic chemotherapy for breast cancer patients. CIPN develops within weeks or months after chemotherapy is initiated and affects 30-40% of breast cancer patients. As a result of severe CIPN, about 8% of breast cancer patients require their chemotherapy dose to be reduced or discontinued, which could detrimentally impact breast cancer related outcomes. Acupuncture is a Traditional Chinese Medicine technique that involves inserting filiform stainless steel needles into pre-defined points on the skin. Previous clinical trials suggest that acupuncture may be an effective treatment to reduce CIPN symptoms with minimal interactions with chemotherapy. Methods: We are conducting a pilot, randomized, standard care and placebo controlled clinical trial (N = 60) assessing the effects of acupuncture to prevent chemotherapy dose reduction due to CIPN. Breast cancer patients receiving taxane based chemotherapy in the neoadjuvant or adjuvant setting will be screened for development of Grade 2 CIPN by completing a weekly Functional Assessment of Cancer Therapy-Neurotoxicity (FACT-Ntx) questionnaire. If patients develop Grade 2 CIPN during chemotherapy they will be randomized to one of three groups: real acupuncture (N = 20), sham acupuncture (N = 20) or standard of care (N = 20). Patients and investigators will be blinded to the treatment assignments. All patients will complete FACT-Ntx and Neuropathy Pain Scale questionnaires weekly. Patients in the real or sham acupuncture groups will receive weekly real or sham acupuncture treatments. Use of pain medications and acupuncture-related adverse events will be self recorded daily in patient diaries. We will explore changes in serum nerve growth factor and other neurotrophic factors such: as brain-derived neurotrophic factor, neurotrophin-3, insulin-like growth factors, and vascular endothelial growth factor. Blood (4 ml) will be drawn before each real or sham acupuncture treatment, at the end of chemotherapy, and at a 4 week follow up visit. Statistics: We expect that acupuncture will significantly decrease the number of patients who require dose reduction during a course of chemotherapy, and increase chemotherapy cumulative relative dose intensity. When a sample size in each cohort is 20, a three group Chi-square test with a 0.05 Type I error will have an adequate 85% power to distinguish between these groups of patients when the proportions are characterized by effect size, of 0.187. We expect the following proportions of patients who would require dose reduction in the acupuncture, sham acupuncture and standard care arms to be 0.05, 0.2, and 0.5, respectively. Statistical analysis will be conducted on-intent-to treat basis. Our specific aims are: to determine the effect of acupuncture on chemotherapy dose reduction, to determine the effect of acupuncture on CIPN during chemotherapy and to explore the mechanisms of acupuncture in treating CIPN. Nine subjects have been consented for screening and one has been randomized. Recruitment is ongoing. Please contact rkirk@umm.edu if interested in the trial. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-09.