Roohi Ismail-Khan

Randomized Phase II, Double-Blind, Placebo-Controlled Study of Exemestane With or Without Entinostat in Postmenopausal Women With Locally Recurrent or Metastatic Estrogen Receptor-Positive Breast Cancer Progressing on Treatment With a Nonsteroidal Aromatase Inhibitor

PURPOSE Entinostat is an oral isoform selective histone deacetylase inhibitor that targets resistance to hormonal therapies in estrogen receptor-positive (ER+) breast cancer. This randomized, placebo-controlled, phase II study evaluated entinostat combined with the aromatase inhibitor exemestane versus exemestane alone. PATIENTS AND METHODS Postmenopausal women with ER+ advanced breast cancer progressing on a nonsteroidal aromatase inhibitor were randomly assigned to exemestane 25 mg daily plus entinostat 5 mg once per week (EE) or exemestane plus placebo (EP). The primary end point was progression-free survival (PFS). Blood was collected in a subset of patients for evaluation of protein lysine acetylation as a biomarker of entinostat activity. RESULTS One hundred thirty patients were randomly assigned (EE group, n = 64; EP group, n = 66). Based on intent-to-treat analysis, treatment with EE improved median PFS to 4.3 months versus 2.3 months with EP (hazard ratio [HR], 0.73; 95% CI, 0.50 to 1.07; one-sided P = .055; two-sided P = .11 [predefined significance level of .10, one-sided]). Median overall survival was an exploratory end point and improved to 28.1 months with EE versus 19.8 months with EP (HR, 0.59; 95% CI, 0.36 to 0.97; P = .036). Fatigue and neutropenia were the most frequent grade 3/4 toxicities. Treatment discontinuation because of adverse events was higher in the EE group versus the EP group (11% v 2%). Protein lysine hyperacetylation in the EE biomarker subset was associated with prolonged PFS. CONCLUSION Entinostat added to exemestane is generally well tolerated and demonstrated activity in patients with ER+ advanced breast cancer in this signal-finding phase II study. Acetylation changes may provide an opportunity to maximize clinical benefit with entinostat. Plans for a confirmatory study are underway.

Malignant Pleural Mesothelioma: A Comprehensive Review

BACKGROUND The incidence of malignant mesothelioma continues to increase, but the disease remains difficult to detect early and treat effectively. METHODS The authors review the pathogenesis, incidence, clinical presentation, diagnosis, pathology, and both standard and experimental treatments for mesothelioma. RESULTS When possible, surgery (video-assisted thoracoscopy, pleurectomy/decortication, or extrapleural pneumonectomy) is utilized. Effects on underlying structures limit application of radiation therapy, but some systemic agents are beginning to enhance survival. CONCLUSIONS The disease is expected to increase in incidence till 2020, so awareness of this entity as a possible diagnosis should be heightened. In patients with advanced disease, several newer antitumor agents are already showing a capability of extending survival so it is not unreasonable to expect further progress in this area.

Randomized Trial Using Gonadotropin-Releasing Hormone Agonist Triptorelin for the Preservation of Ovarian Function During (Neo)Adjuvant Chemotherapy for Breast Cancer

PURPOSE Chemotherapy-induced amenorrhea is a serious concern for women undergoing cancer therapy. This prospective randomized trial evaluated the use of gonadotropin-releasing hormone (GnRH) analog triptorelin to preserve ovarian function in women treated with chemotherapy for early-stage breast cancer. PATIENTS AND METHODS Premenopausal women age 44 years or younger were randomly assigned to receive either triptorelin or no triptorelin during (neo)adjuvant chemotherapy and were further stratified by age (< 35, 35 to 39, > 39 years), estrogen receptor status, and chemotherapy regimen. Objectives included the resumption of menses and serial monitoring of follicle-stimulating hormone (FSH) and inhibin A and B levels. RESULTS Targeted for 124 patients with a planned 5-year follow-up, the trial was stopped for futility after 49 patients were enrolled (median age, 39 years; range, 21 to 43 years); 47 patients were treated according to assigned groups with four cycles of adriamycin plus cyclophosphamide alone or followed by four cycles of paclitaxel or six cycles of fluorouracil, epirubicin, and cyclophosphamide. Menstruation resumed in 19 (90%) of 21 patients in the control group and in 23 (88%) of 26 in the triptorelin group (P= .36). Menses returned after a median of 5.8 months (range, 1 to 19 months) after completion of chemotherapy in the triptorelin versus 5.0 months (range, 0 to 28 months) in the control arm (P= .58). Two patients (age 26 and 35 years at random assignment) in the control group had spontaneous pregnancies with term deliveries. FSH and inhibin B levels correlated with menstrual status. CONCLUSION When stratified for age, estrogen receptor status, and treatment regimen, amenorrhea rates on triptorelin were comparable to those seen in the control group.

A phase I study of indoximod in patients with advanced malignancies

Purpose Indoximod is an oral inhibitor of the indoleamine 2,3-dioxygenase pathway, which causes tumor-mediated immunosuppression. Primary endpoints were maximum tolerated dose (MTD) and toxicity for indoximod in patients with advanced solid tumors. Secondary endpoints included response rates, pharmacokinetics, and immune correlates. Experimental Design Our 3+3 phase I trial comprised 10 dose levels (200, 300, 400, 600, and 800 mg once/day; 600, 800, 1200, 1600, and 2000 mg twice/day). Inclusion criteria were measurable metastatic solid malignancy, age ≥18 years, and adequate organ/marrow function. Exclusion criteria were chemotherapy ≤ 3 weeks prior, untreated brain metastases, autoimmune disease, or malabsorption. Results In 48 patients, MTD was not reached at 2000 mg twice/day. At 200 mg once/day, 3 patients previously treated with checkpoint inhibitors developed hypophysitis. Five patients showed stable disease >6 months. Indoximod plasma AUC and Cmax plateaued above 1200mg. Cmax (∼12 μM at 2000 mg twice/day) occurred at 2.9 hours, and half-life was 10.5 hours. C reactive protein (CRP) levels increased across multiple dose levels. Conclusions Indoximod was safe at doses up to 2000 mg orally twice/day. Best response was stable disease >6 months in 5 patients. Induction of hypophysitis, increased tumor antigen autoantibodies and CRP levels were observed.

Phase 2 trial of docetaxel and gefitinib in the first‐line treatment of patients with advanced nonsmall‐cell lung cancer (NSCLC) who are 70 years of age or older

This is a phase 2 study of chemotherapy‐naive patients, 70 years of age or older, with nonsmall‐cell lung cancer (NSCLC) who were treated with docetaxel and gefitinib. The primary endpoint was response rate (RR). Secondary endpoints were overall survival (OS) and progression‐free survival (PFS).

Abstract P3-14-01: Phase Ib/II study of ribociclib and alpelisib and letrozole in ER+, HER2– breast cancer: Safety, preliminary efficacy and molecular analysis

Background: The interaction between the PI3K/AKT/mTOR and cyclin D–CDK4/6–INK4–Rb pathways has been reported to play a critical role in ER-driven breast cancer (BC). Furthermore, in preclinical ER+ BC models, the combination of ribociclib (LEE011; LEE), alpelisib (BYL719; BYL), and letrozole (LET) has recently shown enhanced activity vs each agent alone. A Phase Ib/II, 3-arm study is investigating the combination of LEE, BYL, and LET in pts with ER+ advanced (a)BC (CLEE011X2107; NCT01872260). Here, we report on safety, preliminary efficacy, and molecular analysis focusing on Arm (A)3 (LEE + BYL + LET) of Phase Ib. Methods: Postmenopausal women with ER+, HER2– aBC received a fixed dose of 2.5 mg LET QD (continuous) with escalating doses of either oral LEE QD (3-wks-on/1-wk-off) or BYL QD (continuous), or both, in 28-day cycles. The primary objective is to determine the MTD and/or RP2D of each combination by assessing DLTs in Cycle 1 using an adaptive Bayesian Logistic Regression Model with overdose control principle. Secondary objectives include safety, PK, and preliminary efficacy assessments. Potential biomarkers predictive of response were assessed by next-generation sequencing in all patients, and immunohistochemistry in available tumor samples. Results: As of Mar 2, 2015, 41 pts received LEE + LET (A1), 21 pts received BYL + LET (A2), and 36 pts received LEE (300–500 mg) + BYL (200–250 mg) + LET (A3). Here, we present results from A3. The number of prior endocrine regimens for advanced disease was: 0 (14 pts); 1–2 (14 pts); 3–4 (7 pts); ≥5 (1 pt); 33% of pts had previously received PI3K/AKT/mTOR inhibitors for aBC. Fifteen pts discontinued treatment: 7 (19%) due to PD and 8 (22%) due to AEs. The most frequent study drug-related AEs (all grade >35%) were: nausea (all grade, 44%; G3/4, 6%), hyperglycemia (44%; 17%), neutropenia (42%; 22%), and fatigue (36%; 11%). The median duration of exposure was 8 weeks; 9 (25%) pts received treatment for ≥4 cycles. Of 27 evaluable pts, 2 (7%) pts had PR, 4 (15%) pts had unconfirmed PR, 6 (22%) pts had SD, 6 (22%) pts had non-CR non-PD (NCRNPD), and 5 (19%) pts had PD as best overall response. One pt with PR was treated for 9 cycles, had 5 lines of prior therapy including a PI3K/AKT/mTOR inhibitor, and had alterations in PIK3R1 and CDK4. The other pt with PR was treated for >9 cycles, had 3 lines of prior therapy, and had alterations in PIK3CA and CCND1. In A1, an increase from baseline to C1D15 in pAKT and pS6(235) was observed in 5 and 3 pts, respectively; importantly, there was a more consistent reduction in Ki67 in A3 vs A1 or A2. Conclusions: LET + LEE + BYL (A3) has an acceptable safety profile and demonstrates preliminary clinical activity in heavily pretreated pts with ER+, HER2– aBC. Preliminary data suggest CDK4/6 pathway activation is associated with improved response to triplet therapy. Importantly, the pathway analysis reported is supportive of a mechanistic combination effect whereby inhibition of the three pathways provides a sustained downregulation of Ki67, potentially preventing a feedback mechanism and hence delaying progression through therapy. Future randomized studies will compare LET + LEE or BYL with LET + LEE + BYL. Citation Format: Juric D, Ismail-Khan R, Campone M, Garcia-Estevez L, Becerra C, De Boer R, Hamilton E, Mayer IA, Hui R, Lathrop KI, Pagani O, Asano S, Bhansali SG, Zhang V, Hewes B, Munster P. Phase Ib/II study of ribociclib and alpelisib and letrozole in ER+, HER2– breast cancer: Safety, preliminary efficacy and molecular analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-01.

PD01-04: Entinostat, a Novel Histone Deacetylase Inhibitor, Added to Exemestane Improves PFS in Advanced Breast Cancer in a Randomized, Phase II, Double-Blind Study.

Background: Entinostat is a novel, oral, class I-selective histone deacetylase inhibitor (HDACi) that has been shown pre-clinically to inhibit mechanisms of aromatase inhibitor (AI) resistance through epigenetically driven down-regulation of activated growth factor signaling pathways and normalization of estrogen receptor levels. This provided a strong rationale for the entinostat breast cancer (BC) program, which was designed to evaluate entinostat9s ability to increase and/or restore sensitivity to treatment with an AI. Methods: Postmenopausal women with ER+ advanced BC who had ≤ 1 prior chemotherapy and had progressed on a non-steroidal AI were randomized 1:1 to exemestane 25 mg daily + entinostat 5 mg or placebo weekly. Progression free survival (PFS) was the primary endpoint; objective response rate and clinical benefit rate were secondary endpoints and overall survival (OS) was an exploratory endpoint. Prospectively defined subsets of interest included patients with “AI-sensitive and AI-resistant disease”. AI-sensitive was defined as having had a PR, CR or SD for ≥6 months (mos) in the metastatic setting or having completed and remained disease free for ≥12 months post adjuvant therapy. All others were considered AI-resistant. Treatment continued until disease progression or unacceptable toxicity. Response assessments were performed every 8 weeks. Results: 130 women were enrolled (64 exemestane+entinostat [E+E]; 66 exemestane+placebo [E+P]. All but 1 patient had Stage IV disease. 82% had measurable disease, of which 60% had visceral involvement. 42% had 1 prior line of hormonal therapy; 58% had >1. Analysis of the intent-to-treat (ITT) population showed significantly (defined prospectively as p Conclusions: Adding entinostat to exemestane resulted in improved PFS, the study9s primary endpoint. At a median follow-up of 18 mos, the exploratory endpoint of OS was also increased in the E+E arm. Importantly for a phase II study, the PFS benefit in all subsets evaluated was consistent with the overall improvement seen in the ITT. These data demonstrate that the addition of entinostat to AI therapy may prolong the duration of AI therapy, thereby delaying the initiation of subsequent therapies such as chemotherapy, a goal for many breast cancer patients. A phase III study is planned. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD01-04.

Urinary symptoms in breast cancer: a systematic review.

A large body of research has documented the prevalence and severity of menopausal symptoms, especially vasomotor symptoms, in breast cancer survivors and their impact on quality of life. However, urinary symptoms as part of the constellation of menopausal symptoms have received relatively little attention. Thus, less is known about the prevalence and severity of urinary symptoms in breast cancer survivors. The authors of this report conducted a systematic review of studies published between 1990 and 2010 to describe the prevalence and severity of urinary symptoms in breast cancer survivors. In total, 16 eligible studies that involved >2500 women were identified. The studies varied with respect to purpose, design, and nature of the samples included; the majority used the same definition and assessment approach for urinary symptoms. Prevalence rates for symptoms ranged from 12% of women reporting burning or pain on micturition to 58% reporting difficulty with bladder control. Although, in many studies, the largest percentage of women rated symptoms as mild, 23% reported severe symptoms. Symptoms appeared to adversely affect womens quality of life. The authors concluded that there is a need for additional research assessing the natural history of urinary symptoms using consensus definitions and validated measures in diverse populations. Nevertheless, this review suggested that clinicians should screen for urinary symptoms in breast cancer survivors and should offer treatment recommendations or make referrals as appropriate. Cancer 2012;.

Comparison of breast magnetic resonance imaging clinical tumor size with pathologic tumor size in patients status post-neoadjuvant chemotherapy

BACKGROUND Neoadjuvant chemotherapy (NACT) is used in breast cancer to evaluate the response to treatment. We examined the usefulness of breast magnetic resonance imaging (MRI) in the evaluation of tumor response after NACT. METHODS Breast MRIs of 87 women with MRI after NACT were reviewed. The Spearman coefficient was used for estimating the correlation between MRI and pathologic tumor sizes (ypTs). RESULTS The median age was 50 years (range 25 to 83 years). The median MRI size was 1.25 cm (range 0 to 10 cm). The median ypT was 1.20 cm (range 0 to 10.4 cm). The Spearman coefficient between MRI and ypT was .78 (95% confidence interval, .67 to .85; P < .0001). MRI was found to have a positive predictive value of 92% and a negative predictive value of 64% for residual in-breast disease. The sensitivity and specificity of MRI were 86% and 77%, respectively. CONCLUSIONS MRI correlates well with the final pathology and can be a useful modality to predict residual disease after NACT and aid in surgical planning.

Developing a comprehensive Cardio-Oncology Program at a Cancer Institute: the Moffitt Cancer Center experience

Cardio-oncology is a multidisciplinary field focusing on the management and prevention of cardiovascular complications in cancer patients and survivors. While the initial focus of this specialty was on heart failure associated with anthracycline use, novel anticancer agents are increasingly utilized and are associated with many other cardiotoxicities including hypertension, arrhythmias and vascular disease. Since its inception, the field has developed at a rapid pace with the establishment of programs at many major academic institutions and community practices. Given the complexities of this patient population, it is important for providers to possess knowledge of not only cardiovascular disease but also cancer subtypes and their specific therapeutics. Developing a cardio-oncology program at a stand-alone cancer center can present unique opportunities and challenges when compared to those affiliated with other institutions including resource allocation, cardiovascular testing availability and provider education. In this review, we present our experiences establishing the cardio-oncology program at Moffitt Cancer Center and provide guidance to those individuals interested in developing a program at a similar independent cancer institution.