A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcoma of the uterus, an NRG Oncology/Gynecologic Oncology Group study.

BACKGROUND: The primary objectives were to determine the objective response rate (ORR) and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS. METHODS: Patients had measurable disease; up to two prior chemotherapeutic regimens were allowed, but must have included a taxane. Women received ixabepilone 40mg/m2 as a 3hour IV infusion on day 1 of a 21daycycle. Treatment was continued until disease progression or unacceptable toxicity occurred. RESULTS: Forty-two women were enrolled, with 34 eligible and evaluable. Median age was 68years. ECOG performance status was 0 in 56% of women, 38% had received radiation, and 15% had received 2 lines of chemotherapy. Overall ORR was 11.8% (4/34, 90% CI 4.2-25.1%); all were partial responses. Stable disease for at least 8weeks was achieved in 8 patients (23.5%). Median PFS and OS were 1.7mo and 7.7mo, respectively, with a median follow-up of 37mo. Six month PFS was 20.6%. Major grade≥3 toxicities were neutropenia (47%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 peripheral neuropathy was reported in 18%. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS. CONCLUSION: In this cohort of women, single agent ixabepilone showed modest but insufficient clinical activity.

Venous Thromboembolism in Patients Receiving Extended Pharmacologic Prophylaxis After Robotic Surgery for Endometrial Cancer.

OBJECTIVE: This study aims to determine the rate of postoperative venous thromboembolism (VTE) in endometrial cancer patients undergoing robotic hysterectomy with or without extended pharmacologic VTE prophylaxis. METHODS/MATERIALS: A retrospective chart review of women undergoing robotic hysterectomy with or without other procedures for endometrial cancer from January 2010 to February 2015 was conducted at 2 institutions. Charts were manually abstracted, and rates of VTE within 30 and 60 days after surgery were determined. Patients were then stratified by those who did and did not receive extended VTE prophylaxis. RESULTS: A total of 403 patients were included, of which 367 patients (91%) received extended pharmacologic prophylaxis and 36 patients (9%) did not. Low molecular weight heparin prescriptions ranged from 7 to 30 days. Patients receiving extended prophylaxis (EP) were older (63 ± 11 vs 57 ± 12; P = 0.004), more frequently underwent lymphadenectomy (67% vs 34%; P < 0.001), and had higher-grade tumors compared with patients not receiving EP. Overall 30-day and 60-day VTE rates were 0.7% and 1.2%, respectively. There were no significant differences in 30-day and 60-day VTE rates among patients that did and did not receive EP, although a trend toward lower VTE rates in the EP group was observed (30-day rates 0.5% vs 2.8% respectively, P = 0.25; 60-day rates 0.8% vs 5.6%, P = 0.07). CONCLUSIONS: In this study, 30-day and 60-day VTE rates after minimally invasive surgery for endometrial cancer were low. Rates were also similar to those of previous reports in this setting in which the majority of patients did not receive extended VTE prophylaxis. Given the consistent finding that postoperative VTE in this population is rare regardless of prophylaxis use and the variability in practice patterns for VTE prophylaxis, the development of best practice guidelines for EP use specific to this setting is warranted.

A phase I trial of pegylated liposomal doxorubicin (PLD), carboplatin, bevacizumab and veliparib in recurrent, platinum-sensitive ovarian, primary peritoneal, and fallopian tube cancer: An NRG Oncology/Gynecologic Oncology Group study.

OBJECTIVE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of veliparib combined with PLD and carboplatin (CD) in patients with recurrent, platinum-sensitive epithelial ovarian cancer. To determine the tolerability at the MTD combined with bevacizumab. METHODS: Patients received PLD (30mg/m(2), IV) and carboplatin (AUC 5, IV) on day 1 with veliparib on days 1-7 (intermittent) or days 1-28 (continuous). Standard 3+3 design was used in the dose escalation phase with DLTs based on the first cycle. Once the MTDs were determined, cohorts of 6 patients were enrolled to each regimen with bevacizumab (10mg/kg on days 1 and 15) to assess feasibility. DLTs were based on the first 4cycles of treatment in the bevacizumab cohorts. RESULTS: In the dose-escalation phase, 27 patients were treated at 3 dose levels with DLTs noted in 6 patients including grade 4 thrombocytopenia (n=4), and prolonged neutropenia >7days (n=3). At the MTD of veliparib (80mg p.o. b.i.d. for both dosing arms), myelosuppression was the DLT. At MTD, 12 additional patients were treated with bevacizumab with 9 patients experiencing DLTs including grade 4 thrombocytopenia (n=4), prolonged neutropenia >7days (n=1), grade 3 hypertension (n=5), and grade 5 sepsis (n=1). CONCLUSIONS: The MTD of veliparib combined with CD is 80mg p.o. b.i.d. in women with recurrent, platinum-sensitive ovarian cancer. With bevacizumab, DLTs were noted in 9 out of 12 patients. Lower doses of veliparib will need to be considered when given in combination with platinum-based therapies.

Statin Use Significantly Improves Overall Survival in High-Grade Endometrial Cancer.

OBJECTIVE: Preclinical data and recent epidemiological studies suggest that statins have antiproliferative and antimetastatic effects in various cancer cells, and reduce cancer mortality and recurrence. We study the effect of statin use on survival outcomes and recurrence rates in patients with endometrial cancer with high-risk histology. MATERIALS AND METHODS: All patients receiving definitive therapy for high-risk endometrial cancer from 1995 to 2014 were retrospectively reviewed. Health characteristics at baseline were collected, and statin use was determined from medical records. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards regression models were used for univariate and multivariate analysis to determine independent factors associated with OS and PFS. RESULTS: A total of 199 patients were included in the study, of which 76 were hyperlipidemic and 50 used statins. The median follow-up time was 31 months from time of diagnosis. Hyperlipidemic patients who used statins had improved OS compared with hyperlipidemic patients not using statins (hazard ratio, 0.42; 95% confidence interval, 0.20-0.87; P = 0.02). Statin use was also associated with improved PFS (hazard ratio, 0.47; 95% confidence interval, 0.23-0.95; P = 0.04) on multivariate analysis. Hyperlipidemic patients who used statins had borderline improved freedom from local failure compared with hyperlipidemic cases not using statins (P = 0.08, log-rank test). Statin use was not found to be associated with improved cancer-specific mortality. CONCLUSIONS: Statin use is independently associated with significant improvements in PFS for the overall group and PFS and OS in the hyperlipidemic group.

A phase II trial of trebananib (AMG 386; IND#111071), a selective angiopoietin 1/2 neutralizing peptibody, in patients with persistent/recurrent carcinoma of the endometrium: An NRG/Gynecologic Oncology Group trial.

OBJECTIVES: Ang1 & 2 (angiopoietin-1; -2) interact with Tie2 receptors on endothelial cells to mediate vascular remodeling in an angiogenesis signaling pathway distinct from the VEGF axis. Trebananib is a peptide Fc fusion protein that binds Ang1 and 2 and prevents interaction with Tie2. The efficacy of trebananib in recurrent/persistent endometrial cancer (EC) was studied. METHODS: The primary objective was to determine the frequency of patients with objective tumor responses (ORR) and event-free survival for ≥6months (6-month EFS) and determine toxicity of trebananib at a dose and schedule of 15mg/kg, IV QW. Recurrent/persistent EC, measurable disease, and ≤2 prior chemotherapy lines were required. RESULTS: Thirty-two patients were eligible and treated. The most common histologies were G1/2 endometrioid (31%), G3 endometrioid (28%) and serous (31.3%). 78% of patients had 1 prior regimen. Patients received 1-9+ cycles of trebananib; 24 patients (75%) received ≤2cycles. One patient had a partial response (3.1%); 8 patients had stable disease (25%) and 5 patients (15.6%) had 6 month EFS. Median progression-free survival and overall-survival were 1.97 months (90% CI 1.77-2.1) and 6.6 months (90% CI 4.01-14.75), respectively. Most common adverse events (AEs) were fatigue, anemia, and GI issues. Grade 3 and 4 AEs were: GI 31 and 0%; vascular 22 and 0%; metabolism/nutrition 19 and 3%; and general (including edema) 16 and 0%. CONCLUSIONS: Trebananib has insufficient single agent activity in recurrent EC to warrant further investigation at this dose/schedule.

Patterns and utility of routine surveillance in high grade endometrial cancer.

OBJECTIVE: To evaluate surveillance methods and their utility in detecting recurrence of disease in a high grade endometrial cancer population. METHODS: We performed a multi-institutional retrospective chart review of women diagnosed with high grade endometrial cancer between the years 2000 and 2011. Surveillance data was abstracted and analyzed. Surveillance method leading to detection of recurrence was identified and compared by stage of disease and site of recurrence. RESULTS: Two hundred and fifty-four patients met the criteria for inclusion. Vaginal cytology was performed in the majority of early stage patients, but was utilized less in advanced stage patients. CA-125 and CT imaging were used more frequently in advanced stage patients compared to early stage. Thirty-six percent of patients experienced a recurrence and the majority of initial recurrences (76%) had a distant component. Modalities that detected cancer recurrences were: symptoms (56%), physical exam (18%), surveillance CT (15%), CA-125 (10%), and vaginal cytology (1%). All local recurrences were detected by symptoms or physical exam findings. While the majority of loco-regional and distant recurrences (68%) were detected by symptoms or physical exam, 28% were detected by surveillance CT scan or CA 125. One loco-regional recurrence was identified by vaginal cytology but no recurrences with a distant component detected by this modality. CONCLUSIONS: Symptoms and physical examination identify the majority of high grade endometrial cancer recurrences, while vaginal cytology is the least likely surveillance modality to identify a recurrence. The role of CT and CA-125 surveillance outside of a clinical trial needs to be further reviewed.

Tubal ligation frequency in Oklahoma women with cervical cancer.

OBJECTIVE: Infrequent Pap screening is an important risk factor for cervical cancer. We studied the association between contraceptive methods, screening frequency, and cancer. METHODS: Women (n=2004) enrolled in the cross-sectional Study to Understand Cervical Cancer Endpoints and Determinants (SUCCEED) underwent colposcopy to evaluate an abnormal Pap test. Questionnaire data were compared between those with cervical intraepithelial neoplasia (CIN) 3/adenocarcinoma in situ (AIS) and those with invasive cancer to identify factors associated with cancer. Logistic regression was used to calculate age-stratified measures of association between contraceptive method and Pap frequency as well as tubal ligation (TL) and cancer risk. RESULTS: In all age groups, women with TL were more likely to have had no Pap screening in the previous 5 years compared to women using other contraception: 26-35 years (OR 4.6, 95% CI 2.4-8.6; p<0.001), 36-45 years (OR 3.8, 95% CI 2.1-7.0; p<0.001), and 46-55 years (OR 2.2, 95% CI 1.0-4.9; p=0.050). Subjects with cancer (n=163) were more likely to have had a TL (41% vs. 21%, p<0.001) than those with CIN 3/AIS (n=370). Age-stratified analyses showed increased odds of tubal ligation in women with cancer versus those with CIN 3/AIS between 25 and 45 years, with a significant increase in women 26 to 35 years old (OR 3.3, 95% CI 1.4-8.1; p=0.009). Adjusting for Pap frequency changed the effect only slightly, suggesting that increased risk was not fully mediated by lack of screening. CONCLUSION: Contraceptive type is associated with Pap screening. Women with TLs obtain less frequent Pap testing and may be at an increased risk for cervical cancer.

Phase I study of BNC105P, carboplatin and gemcitabine in partially platinum-sensitive ovarian cancer patients in first or second relapse (ANZGOG-1103).

PURPOSE: The primary objective of this study was to determine the recommended dose of the vascular disrupting agent, BNC105P, in combination with gemcitabine and carboplatin in patients with ovarian cancer in first or second relapse with a minimum 4 month progression-free interval after last platinum. METHODS: Patients received carboplatin AUC4 on day 1 in combination with escalating doses of 800 or 1000 mg/m2 gemcitabine on days 1 and 8 and escalating doses of 12 or 16 mg/m2 BNC105P on days 2 and 9 every 21 days for a maximum for six cycles. Maintenance treatment with 16 mg/m2 BNC105P treatment continued for a maximum of six additional cycles. Patients were followed for safety and anti-tumor activity. RESULTS: Fifteen patients were enrolled in the study. Adverse events were most commonly of hematological origin. Dose-limiting toxicities (thrombocytopenia and neutropenia) occurred in two patients at the dose level of 800 mg/m2 gemcitabine, carboplatin AUC4 and 16 mg/m2 BNC105P. No dose-limiting toxicities were observed at a dose level of gemcitabine 1000 mg/m2, carboplatin AUC4 and BNC105P 12 mg/m2. BNC105P as a single agent was well tolerated at a dose of 16 mg/m2 in maintenance treatment. Ten patients (67%) achieved a complete or partial response according to CA125 and/or RECIST response criteria, four of 13 (31%) responded by RECIST alone. The median progression-free survival was 5.9 months. CONCLUSIONS: We have established that BNC105P 12 mg/m2 with gemcitabine 1000 mg/m2 and carboplatin AUC4 is the recommended dose level and has an acceptable toxicity profile. Further exploration of BNC105P in the ovarian cancer setting is planned.