A Phase 2, Randomized, Open-Label Study of Irosustat Versus Megestrol Acetate in Advanced Endometrial Cancer.

OBJECTIVE: Advanced/metastatic or recurrent endometrial cancer has a poor prognosis. Malignant endometrial tissue has high steroid sulphatase (STS) activity. The aim of this study was to evaluate STS as a therapeutic target in patients with endometrial cancer. METHODS: This was a phase 2, multicenter, international, open-label, randomized (1:1), 2-arm study of the STS inhibitor oral irosustat 40 mg/d versus oral megestrol acetate 160 mg/d in women with advanced/metastatic or recurrent estrogen receptor-positive endometrial cancer. The primary end point was the proportion of patients without progression or death 6 months after start of treatment. Secondary end points included progression-free survival, time to progression, overall survival, and safety. RESULTS: Seventy-one patients were treated (36 with irosustat, 35 with megestrol acetate). The study was prematurely stopped after futility analysis. Overall, 36.1% and 54.1% of patients receiving irosustat or megestrol acetate had not progressed or died at 6 months, respectively. There were no statistically significant differences between irosustat and megestrol acetate in response and overall survival rates. Irosustat patients had a median progression-free survival of 16 weeks (90% confidence interval, 9.0-31.4) versus 40 weeks (90% confidence interval, 16.3-64.0) in megestrol acetate patients. Treatment-related adverse events occurred in 20 (55.6%) and 13 (37.1%) patients receiving irosustat or megestrol, respectively. Most adverse events in both groups were grade 1 or 2. CONCLUSIONS: Although irosustat monotherapy did not attain a level of activity sufficient for further development in patients with advanced/recurrent endometrial cancer, this study confirms the activity of hormonal treatment (megestrol acetate) for this indication.

Adverse Event Profile by Folate Receptor Status for Vintafolide and Pegylated Liposomal Doxorubicin in Combination, Versus Pegylated Liposomal Doxorubicin Alone, in Platinum-Resistant Ovarian Cancer: Exploratory Analysis of the Phase II PRECEDENT Trial.

OBJECTIVE: This exploratory analysis evaluated the incidence of adverse events (AEs) by folate receptor (FR) status in the randomized, multicenter, open-label PRECEDENT study in women with platinum-resistant ovarian cancer receiving pegylated liposomal doxorubicin (PLD) ± the small-molecule drug conjugate vintafolide. METHODS: Women 18 years or older with platinum-resistant ovarian cancer were randomized 2:1 to vintafolide (2.5 mg intravenously, 3 times per week, weeks 1 and 3, every 28 days) + PLD (50 mg/m intravenously, day 1, every 28 days) or PLD alone (same dose/schedule). The expression of functionally active FR was evaluated by single-photon emission computed tomography with etarfolatide. Patients were categorized according to FR positivity: patients with all target lesions positive for FR expression (FR 100%), patients with 1 or more but not all target lesions positive for FR expression (FR 10%-90%), and patients with all lesions negative for FR expression (FR 0%). RESULTS: Data on FR status were available for 94 patients: 38 were FR 100%, 36 were FR 10% to 90%, and 20 were FR 0%. Across all FR subgroups, the duration of treatment was longer, and the number of cycles was higher in combination-therapy arms than PLD-alone arms. Although the frequency of AEs was relatively consistent across subgroups, the FR 100% subgroup had a higher incidence of patients with at least 1 AE for combination therapy versus PLD alone. No surprising safety signals were shown according to FR status. The incidence of grade 3 or 4 treatment-emergent drug-related AEs was generally low across all FR subgroups and treatment arms. CONCLUSIONS: This exploratory analysis suggests that FR status does not influence the AE profile of vintafolide + PLD combination therapy or PLD alone in patients with platinum-resistant ovarian cancer. Future a priori analyses in larger populations are needed to confirm these findings.

Phase II study of MLN8237 (alisertib), an investigational Aurora A kinase inhibitor, in patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.

OBJECTIVES: Aurora A kinase (AAK), a key mitotic regulator, is implicated in the pathogenesis of several tumors, including ovarian cancer. This single-arm phase II study assessed single-agent efficacy and safety of the investigational AAK inhibitor MLN8237 (alisertib), in patients with platinum-refractory or -resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. METHODS: Adult women with malignant, platinum-treated disease received MLN8237 50mg orally twice daily for 7 days plus 14 days' rest (21-day cycles). The primary endpoint was combined objective tumor response rate per Response Evaluation Criteria in Solid Tumors (RECIST) and/or CA-125 criteria. Secondary endpoints included response duration, clinical benefit rate, progression-free survival (PFS), time-to-progression (TTP), and safety. RESULTS: Thirty-one patients with epithelial ovarian (n=25), primary peritoneal (n=5), and fallopian tube carcinomas (n=1) were enrolled. Responses of 6.9-11.1 month duration were observed in 3 (10%) patients with platinum-resistant ovarian cancer. Sixteen (52%) patients achieved stable disease with a mean duration of response of 2.86 months and which was durable for ≥3 months in 6 (19%). Median PFS and TTP were 1.9 months. Most common drug-related grade≥3 adverse events were neutropenia (42%), leukopenia (23%), stomatitis, and thrombocytopenia (each 19%); 6% reported febrile neutropenia. CONCLUSIONS: These data suggest that MLN8237 has modest single-agent antitumor activity and may produce responses and durable disease control in some patients with platinum-resistant ovarian cancer. MLN8237 is currently undergoing evaluation in a phase I/II trial with paclitaxel in recurrent ovarian cancer.

The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial.

Malignant ascites is a common manifestation of advanced cancers, and treatment options are limited. The trifunctional antibody catumaxomab (anti-epithelial cell-adhesion molecule x anti-CD3) represents a targeted immunotherapy for the intraperitoneal (i.p.) treatment of malignant ascites secondary to epithelial cancers. In this phase II/III trial (EudraCT 2004-000723-15; NCT00836654), cancer patients (n = 258) with recurrent symptomatic malignant ascites resistant to conventional chemotherapy were randomized to paracentesis plus catumaxomab (catumaxomab) or paracentesis alone (control) and stratified by cancer type (129 ovarian and 129 nonovarian). Catumaxomab was administered as an i.p. infusion on Days 0, 3, 7 and 10 at doses of 10, 20, 50 and 150 mug, respectively. The primary efficacy endpoint was puncture-free survival. Secondary efficacy parameters included time to next paracentesis, ascites signs and symptoms and overall survival (OS). Puncture-free survival was significantly longer in the catumaxomab group (median 46 days) than the control group (median 11 days) (hazard ratio = 0.254: p < 0.0001) as was median time to next paracentesis (77 versus 13 days; p < 0.0001). In addition, catumaxomab patients had fewer signs and symptoms of ascites than control patients. OS showed a positive trend for the catumaxomab group and, in a prospectively planned analysis, was significantly prolonged in patients with gastric cancer (n = 66; 71 versus 44 days; p = 0.0313). Although adverse events associated with catumaxomab were frequent, they were manageable, generally reversible and mainly related to its immunologic mode of action. Catumaxomab showed a clear clinical benefit in patients with malignant ascites secondary to epithelial cancers, especially gastric cancer, with an acceptable safety profile.

Retrospective Analysis of Intravaginal Brachytherapy in Adjuvant Treatment of Early Endometrial Cancer.

The aim of this study was to determine the role of adjuvant endovaginal brachytherapy HDR (High Dose Rate) or observation, as well as identification of risk factors of tumor recurrence. The study included 178 women after radical hysterectomy. All patients belonged to the group of low- and medium-risk stage I FIGO. Analysis consisted of 3-, 5-, and 10-year OS, DFS, and LRFS in both groups. Follow-up was more than 6.5 years. The 5-OS, 5-DFS, and 5-LRFS were 93%, 96%, and 98% in the treated group and 95%, 94%, and 96% in the observed group, respectively. These differences were not statistically significant. There was a statistically significant difference in 5-OS in the treated group, between low- and medium-risk subgroups (100% versus 87.55%, p = 0.018). There was a better prognosis among the patients with FIGO IA compared to FIGO IB (5-DFS, 97 versus 86%, p = 0.047). Among the risk factors, there were only statistically significant differences in the 5-OS, between the ages of ≤ 70 years and >70 years. Use of brachytherapy may affect the reduction in the number of local recurrences at the vaginal stump (6% versus 2%). This is particularly noticeable in the low-risk subgroup (9% versus 0%).

Cyclin A correlates with YB1, progression and resistance to chemotherapy in human epithelial ovarian cancer.

BACKGROUND: Cyclin A is a cell-cycle regulatory gene and its overexpression promotes tumor cell growth. Y-Box-binding protein 1 (YB1) is a transcription/translation factor involved in tumor growth, invasion, and drug resistance. We investigated whether an association exists between protein products of these genes in epithelial ovarian cancer (EOC) specimens and clinicopathological parameters, patient response and EOC sensitivity to platinum-based first-line chemotherapy. PATIENTS AND METHODS: Cyclin A and YB1 expression were analyzed by immunohistochemistry in 54 human primary EOC tissues. Immunolabeling of both proteins was graded according to their staining intensity (scale 0-3) and the proportion of immunostained cancer cells (scale 0-4) to obtain a staining index (SI; value=0-12). RESULTS: Significantly higher cyclin A immunostaining (SI≥4) in EOC specimens was discovered in patients with advanced (International Federation of Gynaecology and Obstetrics (FIGO) III and IV, p=0.003), poorly differentiated (G3, p<0.001) tumors, and tumors of those with residual disease>1 cm (p=0.001). YB1 immunostaining was significantly higher in EOCs from patients with suboptimal debulking (p=0.025). Over-expression of cyclin A (SI≥9) in EOCs was significantly linked with poorer patient response (p=0.001) and higher resistance of tumors to platinum-based first-line chemotherapy (p=0.007), while immunolabeling of YB1 in EOCs was not significantly associated with either of these variables (p>0.05). Cyclin A expression was significantly and positively correlated with that of YB1 (R=0.588, p<0.001). CONCLUSION: Increased cyclin A expression in EOC is related to a more aggressive tumor behavior and predicts the response of patients to first-line platinum-based chemotherapy.

PRECEDENT: a randomized phase II trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in patients with platinum-resistant ovarian cancer.

PURPOSE: Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. This randomized phase II trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined. PATIENTS AND METHODS: Women with recurrent platinum-resistant ovarian cancer who had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1 ratio to PLD (50 mg/m(2) intravenously [IV] once every 28 days) with or without vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide scanning was optional. The primary objective was to compare progression-free survival (PFS) between the groups. RESULTS: The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio [HR], 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806). CONCLUSION: Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to benefit from vintafolide.

Randomized, open-label, phase III study comparing patupilone (EPO906) with pegylated liposomal doxorubicin in platinum-refractory or -resistant patients with recurrent epithelial ovarian, primary fallopian tube, or primary peritoneal cancer.

PURPOSE: This study compared the efficacy and safety of patupilone with those of pegylated liposomal doxorubicin (PLD) in patients with platinum-refractory or -resistant epithelial ovarian, primary fallopian tube, or primary peritoneal cancer. PATIENTS AND METHODS: Patients with three or fewer prior regimens were eligible if they had received first-line taxane/platinum-based combination chemotherapy and were platinum refractory or resistant. Patients were randomly assigned to receive patupilone (10 mg/m(2) intravenously every 3 weeks) or PLD (50 mg/m(2) intravenously every 4 weeks). RESULTS: A total of 829 patients were randomly assigned (patupilone, n = 412; PLD, n = 417). There was no statistically significant difference in overall survival (OS), the primary end point, between the patupilone and PLD arms (P = .195; hazard ratio, 0.93; 95% CI, 0.79 to 1.09), with median OS rates of 13.2 and 12.7 months, respectively. Median progression-free survival was 3.7 months for both arms. The overall response rate (all partial responses) was higher in the patupilone arm than in the PLD arm (15.5% v 7.9%; odds ratio, 2.11; 95% CI, 1.36 to 3.29), although disease control rates were similar (59.5% v 56.3%, respectively). Frequently observed adverse events (AEs) of any grade included diarrhea (85.3%) and peripheral neuropathy (39.3%) in the patupilone arm and mucositis/stomatitis (43%) and hand-foot syndrome (41.8%) in the PLD arm. CONCLUSION: Patupilone did not demonstrate significant improvement in OS compared with the active control, PLD. No new or unexpected serious AEs were identified.