PURPOSE:Selinexor inhibits exportin-1 (XPO1) resulting in nuclear accumulation of tumor suppressor proteins including p53 and has clinical activity in endometrial cancer (EC). The primary end point was to assess progression-free survival (PFS) with once-weekly oral selinexor in patients with advanced or recurrent EC. PATIENTS AND METHODS:ENGOT-EN5/GOG-3055/SIENDO was a randomized, prospective, multicenter, double-blind, placebo-controlled, phase III study at 107 sites in 10 countries. Patients 18 years or older with histologically confirmed EC were enrolled. All had completed a single line of at least 12 weeks of taxane-platinum combination chemotherapy and achieved partial or complete response. Patients were assigned to receive 80 mg oral selinexor once weekly or placebo with 2:1 random assignment (ClinicalTrials.gov identifier: NCT03555422). RESULTS:Between January 2018 and December 2021, 263 patients were randomly assigned, with 174 allocated to selinexor and 89 to placebo. The median PFS was 5.7 months (95% CI, 3.81 to 9.20) with selinexor versus 3.8 months (95% CI, 3.68 to 7.39) with placebo (hazard ratio [HR], 0.76 [95% CI, 0.54 to 1.08]; two-sided P = .126), which did not meet the criteria for statistical significance in the intent-to-treat population. Incorrect chemotherapy response stratification data for 7 (2.7%) patients were identified. In a prespecified exploratory analysis of PFS in audited stratification data, PFS for selinexor met the threshold for statistical significance (HR, 0.71; 95% CI, 0.499 to 0.996; two-sided P = .049). Furthermore, patients with the TP53 wild-type (wt) EC had a median PFS of 13.7 and 3.7 months with selinexor and placebo. The most common grade 3 treatment-related adverse events were nausea (9%), neutropenia (9%), and thrombocytopenia (7%). CONCLUSION:The significance level for PFS was only met in the audited analysis. However, a preliminary analysis of a prespecified exploratory subgroup of patients with TP53wt EC showed promising results with selinexor maintenance therapy.

Purpose The vascular disrupting agent fosbretabulin tromethamine selectively targets pre-existing tumor vasculature, which causes vascular shutdown and leads to cancer cell death and necrosis. Antiangiogenesis agents such as bevacizumab, a humanized antivascular endothelial growth factor monoclonal antibody, might prevent revascularization during and after treatment with a vascular disrupting agent. Patients and Methods Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to bevacizumab (15 mg/kg intravenously once every 3 weeks) or the combination of bevacizumab (15 mg/kg) plus fosbretabulin (60 mg/m2) intravenously once every 3 weeks until disease progression or toxicity. Randomization was stratified by disease status (measurable v nonmeasurable), prior bevacizumab, and platinum-free interval. The primary end point was progression-free survival (PFS). The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%. Results The study enrolled 107 patients. Median PFS was 4.8 months for bevacizumab and 7.3 months for bevacizumab plus fosbretabulin (hazard ratio, 0.69; 90% two-sided CI, 0.47 to 1.00; one-sided P = .05). The proportion responding (overall response rate) to bevacizumab was 28.2% among 39 patients with measurable disease and 35.7% among 42 patients treated with the combination. The relative probability of responding was 1.27 (90% CI, 0.74 to 2.17; one-sided P = .24). Adverse events greater than grade 3 were more common in the combination regimen than in bevacizumab only for hypertension (35% v 20%). There was one grade 3 thromboembolic event in the combination arm and one intestinal fistula in the bevacizumab only arm. Conclusion On the basis of the PFS, overall response rate, and tolerability of these two antivascular therapies, further evaluation is warranted for this chemotherapy-free regimen. Fosbretabulin in combination with bevacizumab increases the risk of hypertension.

Objective. This two-stage phase II study assessed activity of single agent dalantercept in patients with recurrent/persistent endometrial carcinoma (EMC).Methods. Eligible patients had persistent/recurrent EMC after 1-2 prior cytotoxic regimens, measurable disease (RECIST 1.1), and GOG performance <= 2. Dalantercept 1.2 mg/kg subcutaneous was administered once every 3 weeks until disease progression (PD)/development of prohibitory toxicity. Primary objectives were to estimate the proportion of patients with persistent/recurrent EMC, who survive progression-free without receiving non-protocol therapy (TPFS) for at least 6 months and to estimate the proportion having objective tumor response.Results. All 28 enrolled patients were eligible and evaluable. Median age: 62 years. Most common histologies: 32% Grade 1/2 endometrioid and 54% serous tumors. Prior treatment: 1 or 2 regimens in 82% and 18% of patients, respectively. Eighteen patients received prior radiation therapy. Patients received 1-12 cycles of dalantercept, and 46% of patients received cycles. The most common adverse events (AE) were fatigue, anemia, constipation and peripheral edema. Grade 3/4 AEs occurred in 39% and 4% of patients. One grade 5 gastric hemorrhage in a patient with a history of radiation fibrosis/small bowel obstruction was deemed possibly dalantercept-related. All patients are off study: 86% for PD. No ORs were observed; 57% had stable disease and 11% had TPFS > 6 mos. Median progression-free and overall survival: 2.1 months (90% Cl: 1.4-3.2) and 14.5 months (90% CI: 7.0-17.5), respectively.Conclusions. Dalantercept has insufficient single agent activity in recurrent EMC to warrant further investigation at this dose level and schedule. (C) 2015 Elsevier Inc. All rights reserved.

Objective This study aimed to determine surgical outcomes related to hand-assisted robotic surgery (HARS) for staging of ovarian cancer and uterine cancers with high risk of peritoneal spread and compare them to laparotomy and standard robotic-assisted surgery. Methods A retrospective cohort study of women undergoing staging for uterine and ovarian cancer between January 2011 and July 2013 at a major metropolitan teaching hospital was reviewed. Patients undergoing HARS were matched with patients undergoing staging laparotomy [exploratory laparotomy (XLAP)] for the same indications and with patients undergoing traditional robotic surgery (RS) for staging of endometrioid endometrial cancer. In HARS, a longer incision is used to allow palpation of the peritoneal surfaces, to exteriorize the small bowel, to examine the mesentery, and to perform omentectomy. Results One hundred five patients were analyzed (15 HARS, 45 RS, 45 XLAP). Compared with XLAP, HARS was associated with decreased blood loss (200 vs 400 mL, P = 0.011) and shorter hospital stay (1 vs 4 days, P < 0.001). Patients who had undergone HARS had fewer major complications, but those results did not reach statistical significance (0% vs 27%, P = 0.063). Hand-assisted robotic surgery was associated with higher blood loss and length of stay as compared to robotic staging of endometrioid endometrial cancer (RS). Minor wound complications were also more common (27% vs 2%, P = 0.012). Conclusions Hand-assisted robotic surgery allows for thorough visual and tactile assessment of peritoneal surfaces. It represents a safe alternative to laparotomy for staging of ovarian and uterine cancers with high risk of peritoneal spread. Long-term follow-up study is needed to determine oncologic adequacy of HARS.

PURPOSE:The vascular disrupting agent fosbretabulin tromethamine selectively targets pre-existing tumor vasculature, which causes vascular shutdown and leads to cancer cell death and necrosis. Antiangiogenesis agents such as bevacizumab, a humanized antivascular endothelial growth factor monoclonal antibody, might prevent revascularization during and after treatment with a vascular disrupting agent.PATIENTS AND METHODS:Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to bevacizumab (15 mg/kg intravenously once every 3 weeks) or the combination of bevacizumab (15 mg/kg) plus fosbretabulin (60 mg/m(2)) intravenously once every 3 weeks until disease progression or toxicity. Randomization was stratified by disease status (measurable v nonmeasurable), prior bevacizumab, and platinum-free interval. The primary end point was progression-free survival (PFS). The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%.RESULTS:The study enrolled 107 patients. Median PFS was 4.8 months for bevacizumab and 7.3 months for bevacizumab plus fosbretabulin (hazard ratio, 0.69; 90% two-sided CI, 0.47 to 1.00; one-sided P = .05). The proportion responding (overall response rate) to bevacizumab was 28.2% among 39 patients with measurable disease and 35.7% among 42 patients treated with the combination. The relative probability of responding was 1.27 (90% CI, 0.74 to 2.17; one-sided P = .24). Adverse events greater than grade 3 were more common in the combination regimen than in bevacizumab only for hypertension (35% v 20%). There was one grade 3 thromboembolic event in the combination arm and one intestinal fistula in the bevacizumab only arm.CONCLUSION:On the basis of the PFS, overall response rate, and tolerability of these two antivascular therapies, further evaluation is warranted for this chemotherapy-free regimen. Fosbretabulin in combination with bevacizumab increases the risk of hypertension.

Purpose The doublet gemcitabine and carboplatin is effective for the treatment of recurrent ovarian cancer, while multi-agent chemotherapy with bevacizumab may add additional benefit. This phase II study tested the efficacy and safety of a biweekly gemcitabine, carboplatin, and bevacizumab combination in patients with platinum-sensitive recurrent ovarian, peritoneal, or tubal cancer (ROC). Patients and methods Eligible patients received concurrent gemcitabine 1000 mg/m2, carboplatin area under the curve 3, and bevacizumab 10 mg/kg administered intravenously on days 1 and 15 every 28 days for six cycles or up to 24 cycles if clinical benefit occurred. The primary end points were progression-free survival (PFS) by RECIST, and safety; the secondary end points were objective response rates and overall survival. Results Overall, 45 patients were enrolled. The median PFS was 13.3 months (95% CI, 11.3 to 15.3). The objective response rate was 69%. Grade 4 hematologic toxicities included neutropenia (27%) and thrombocytopenia (2%). Grades 3 and 4 non-hematologic toxicities included fatigue (18%), pain (9%), and nausea/vomiting (4%). There were 2 episodes of cerebrovascular accidents, 2 noted DVTs, and no episodes of bowel perforation. Median OS was 36.1 months (95% CI, 26.7 to 45.5). Conclusion Biweekly gemcitabine, carboplatin, and bevacizumab were an effective regimen in recurrent ovarian cancer, with comparable toxicity to recently reported day 1 gemcitabine, carboplatin, bevacizumab, and day 8 gemcitabine. Response rate and PFS are improved from reported outcomes of the gemcitabine carboplatin doublet. The degree to which biweekly dosing may present a more rationale schedule for this triplet should be evaluated further.

5594 Background: Angiogenesis has a role in endometrial cancer (EC) progression and prognosis. Single agent bevacizumab had a response rate (RR) of 13% and 6 month progression-free survival of 40% in recurrent EC with 1-2 prior cytotoxics. ALK1 is selectively expressed on activated endothelial cells unlike constitutively expressed VEGFR2. ALK1 pathway is essential for vascular morphogenesis and the formation of functional capillary networks in developing vasculature. EC vasculature has variable ALK1 expression. Dalantercept (Dal), a first-in-class ALK1 receptor fusion protein, binds to BMP9/BMP10 and prevents ALK1 pathway activation. Methods: A 2-stage design was used to estimate number of pts with persistent/recurrent EC who survived progression-free without receiving non-protocol therapy (TPFS) for at least 6 mos and number of pts who had objective tumor response (ORR) and determine toxicity of Dal 1.2 mg/kg SC Q3W. Recurrent/persistent epithelial EC, measurable disease, and 1- 2 prior chemotherapy lines were required. Biologic adjuvant therapy was permitted. Results: 28 pts ages 47-79 years were enrolled. G1/2 Endometrioid (n=9, 32%) and serous (n=15, 54%) tumors were most common. 82% of pts had 1 prior regimen. Pts received 1-12 cycles of Dal; 13 pts (46%) received ≤2 cycles. Most common adverse events (AE) regardless of attribution were fatigue, anemia, constipation, and limb edema. Grade (G) 3 and 4 AEs occurred in 39% and 4% of pts. There was 1 G 5 AE possibly Dal associated: gastric hemorrhage in pt with history of radiation fibrosis/small bowel obstruction. All pts are off study treatment: 24 for disease progression (PD), 1 consent withdrawal, 2 for toxicity, 1 for death. By RECIST 1.1: ORR was 0%; stable disease 57%, PD 39%, and indeterminate 4%. 11% of pts had TPFS > 6 mos; median PFS 2.1 mos (90% CI: 1.4-3.2) and median OS 9.4 mos (90% CI: 8.9-11.7). Conclusions: Dal has insufficient single agent activity in recurrent EC to warrant further investigation at this dose/schedule. Studies of IHC expression of VEGF, FGF, PDGF, TGF-β, ALK1, CD105, ALK1 gene expression, plasma concentration of VEGF, BMP9, BMP10, and ALK1 via ELISA are ongoing. Clinical trial information: NCT01642082.

Between 30% and 50% of women who have high‐grade uterine leiomyosarcoma (uLMS) limited to the uterus at diagnosis remain progression‐free at 2 years. Adjuvant pelvic radiation does not improve outcome. The objective of the current study was to determine the 2‐year and 3‐year progression‐free survival (PFS) among a prospective cohort of women who received adjuvant gemcitabine plus docetaxel followed by doxorubicin.

Objective: Recent evidence suggests that many high-grade “ovarian” serous carcinomas (HGSC) are associated with epithelial precursors in the fallopian tube (FT). Such tubal intraepithelial carcinomas are observed in salpingectomy specimens obtained at risk-reducing surgery in BRCA-positive women. The purpose of this study was to evaluate the cytomorphology of cells obtained from the FT.

On page 540 in the section titled Clinical activity, there is a sentence which states, “Stable disease was observed in 14 patients (32%) and 10 are alive with (7) or without (3) disease progression.” This is a correct statement. However, Fig. 1. has a legend that indicates that 16 patients are alive with (10) or without (6) disease progression. The updated figure is qualitatively similar and does not alter the conclusions. The discrepancy resulted from including an earlier figure based strictly on clinical outcome data. A phase II evaluation of aflibercept in the treatment of recurrent or persistent endometrial cancer: A Gynecologic Oncology Group studyGynecologic OncologyVol. 127Issue 3PreviewAflibercept targets vascular endothelial growth factor and placental growth factor. We evaluated activity and toxicity of aflibercept in recurrent/persistent endometrial cancer patients. Biomarkers and association with clinical characteristics and outcome were explored. Full-Text PDF

Sarcomas comprise approximately 5–6% of the 49,560 cases of uterine cancer occurring in the United States in 2013 [ [1] Siegel R. Naishadham M.A. Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013; 63: 11-30 Crossref PubMed Scopus (11389) Google Scholar ]; the contribution of these cases to the projected 8190 annual deaths, however, approaches 30% [ [2] Nordal R. Tjorsen S. Uterine sarcomas in Norway 1956-1992: incidence, survival, and mortality. Eur J Cancer. 1997; 33: 907-911 Abstract Full Text PDF PubMed Scopus (178) Google Scholar ]. Although there is an extensive classification of these tumors, this review is limited to carcinosarcomas, leiomyosarcomas, endometrial stromal sarcomas, and mullerian adenosarcomas. Carcinosarcomas probably represent dedifferentiated endometrial adenocarcinomas, but they will be included.

Objectives. Aflibercept targets vascular endothelial growth factor and placental growth factor. We evaluated activity and toxicity of aflibercept in recurrent/persistent endometrial cancer patients. Biomarkers and association with clinical characteristics and outcome were explored.Methods. Eligible patients had measurable disease; 1-2 prior cytotoxic regimens; performance status 0-2. Aflibercept 4 mg/kg IV q14 days (28-day cycles) was administered until disease progression or prohibitive toxicity. Primary endpoints were the proportion of patients with progression-free survival at 6 months (PFS6) and tumor response rate. A flexible two-stage group sequential design to detect 20% increases in the proportion of patients responding or enduring PFS6 with 90% power (alpha=10%) was employed.Results. Forty-nine patients were enrolled; five were excluded: wrong primary (2), second primary (1), wrong cell type (1); and never treated (1). Median age was 64 (range 48-83). Eighteen patients (41%) had two prior regimens; 27 (61%) had prior radiation. The PFS6 rate was 41%; three patients (7%, 90% Cl: 2-17) had partial response. Of note, 10 patients (23%) met the PFS6 endpoint without starting a subsequent therapy; the remaining eight patients discontinued therapy for toxicity and started another therapy before 6 months elapsed. Median PFS and overall survival were 2.9 months and 14.6 months, respectively. Significant grade 3/4 toxicities were: cardiovascular (23%/5%), constitutional (7%/0), hemorrhage (2%/5%), metabolic (7%/2%), and pain (18%/0). Two treatment-related deaths were recorded: GI perforation (1), and arterial rupture (1). FGF1 expression was associated with response.Conclusions. Aflibercept met pretrial activity parameters, but was associated with significant toxicity at this dose and schedule in this population. (C) 2012 Elsevier Inc. All rights reserved.

PURPOSETwo cases of successful desensitization to docetaxel after severe hypersensitivity reactions are reported.SUMMARYTwo patients with gynecological malignancies (uterine leiomyosarcoma and ovarian adenocarcinoma) experienced severe hypersensitivity reactions with docetaxel, including flushing, numbness, sharp radiating pain, severe nausea and vomiting, apnea, and unresponsiveness. Both patients received ondansetron before docetaxel. One patient received dexamethasone, diphenhydramine, and famotidine premedication before docetaxel, as she had previously reacted to paclitaxel. Docetaxel infusions were stopped, and the reactions were treated with diphenhydramine and dexamethasone (one patient also received famotidine). After resolution of symptoms, the docetaxel was not reinitiated due to the nature of the reactions. For the next cycle, both patients received a graded drug challenge or desensitization. Both were pre-medicated with dexamethasone, diphenhydramine, and famotidine. The docetaxel was given as infusions of 0.1%, 1%, and 10% of the dose, with each infusion given over one hour. After this, the remainder of the dose was infused over one hour. Both patients tolerated this desensitization well and completed a total of three and four cycles each. The first patient to receive the desensitization did complain of chest pain during the first desensitization, and the infusion rate was decreased to administer the drug over two hours. After she tolerated two cycles of two-hour infusions, the infusion rate was increased to administer each docetaxel infusion over one hour.CONCLUSIONTwo patients who had severe hypersensitivity reactions to docetaxel successfully received further docetaxel doses via a desensitization procedure that involved the sequential administration of solutions containing increasing concentrations of the drug.

Primary squamous cell carcinoma of the endometrium (PSCCE) is a rare entity, with fewer than 100 cases reported in the literature. We report two cases of PSCCE and review the literature regarding associated markers and treatment outcomes. Many different markers have been tested for association with PSCCE, with mixed results. Thus, it is likely that several etiologic factors are responsible for the development of PSCCE. Further, due to the rarity of the condition, the optimal postoperative management of patients with PSCCE remains to be defined. Diagn. Cytopathol. 2013;41:817–820. © 2012 Wiley Periodicals, Inc.

Objective: The optimal treatment of high‐risk cancers of the endometrium is yet to be determined. Evidence shows a benefit to both chemotherapy and radiotherapy, and "sandwich" therapy (chemotherapy-radiotherapy-chemotherapy) has shown promise. We conducted a cohort study of women in our practice undergoing sandwich therapy to evaluate its toxicity, safety, and short-term survival. Additionally, we assessed the feasibility of using sandwich therapy in a community setting.

This trial determined the efficacy and tolerability of sorafenib and weekly topotecan in patients with platinum-resistant ovarian cancer (OC) or primary peritoneal carcinomatosis (PPC).Primary endpoints were maximum tolerated dose of sorafenib with weekly topotecan (phase I) and response rate (phase II). Secondary endpoints were progression free survival (PFS), overall survival (OS), toxicity, and rate of clinical benefit. Eligibility included recurrent platinum-resistant OC or PPC, <3 prior regimens, normal end-organ function. 3+3 dose escalation was used for phase I, sorafenib being tested at 400mg and 800 mg orally daily. Topotecan dose was reduced from 4 mg/m(2) to 3.5mg/m(2) IV weekly. The phase II regimen was sorafenib 400mg daily and topotecan 3.5mg/m(2) weekly on days 1, 8, 15 of a 28 days cycle.16 patients were enrolled in phase I and 14 patients in phase II. Median age was 52.5 years (range 35-79), 27 patients had OC, and 3 PPC. Median number of cycles administered was 2.5 (0-15). There were 5 partial responses (PR) (16.7%), and 14 patients (46.7%) with stable disease (SD). Four PRs were recorded during phase I and 1 during phase II. One of those PRs occurred in a patient with platinum-sensitive disease. Grade 3/4 toxicities included leukopenia/neutropenia (23%), thrombocytopenia (17%), anemia (10%), fatigue, nausea, vomiting (7% each). One case of grade 3 hand-foot syndrome was recorded.The combination of sorafenib and topotecan causes significant toxicity, precluding administration of full doses and resulting in modest clinical efficacy in platinum resistant OC or PPC.

Purpose The Gynecologic Oncology Group (GOG) conducted a phase II trial to assess the efficacy and tolerability of the anti-EGFR antibody cetuximab, in persistent or recurrent carcinoma of the cervix. Patients and methods Eligible patients had cervical cancer, measurable disease, and GOG performance status ≤2. Treatment consisted of cetuximab 400 mg/m2 initial dose followed by 250 mg/m2 weekly until disease progression or prohibitive toxicity. The primary endpoints were progression-free survival (PFS) at 6 months and response. The study used a 2-stage group sequential design. Results Thirty-eight patients were entered with 3 exclusions, leaving 35 evaluable for analysis. Thirty-one patients (88.6%) received prior radiation as well as either 1 (n=25, 71.4%) or 2 (n=10) prior cytotoxic regimens. Twenty-four patients (68.6%) had a squamous cell carcinoma. Grade 3 adverse events possibly related to cetuximab included dermatologic (n=5), GI (n=4), anemia (n=2), constitutional (n=3), infection (n=2), vascular (n=2), pain (n=2), and pulmonary, neurological, vomiting and metabolic (n=1 each). No clinical responses were detected. Five patients (14.3%; two-sided 90% CI, 5.8% to 30%) survived without progression for at least 6 months. The median PFS and overall survival (OS) times were 1.97 and 6.7 months, respectively. In this study, all patients with PFS at 6 months harbored tumors with squamous cell histology. Conclusion Cetuximab is well tolerated but has limited activity in this population. Cetuximab activity may be limited to patients with squamous cell histology.

10021 Background: Only 30-50% of women with high-grade, uterine leiomyosarcoma (uLMS) limited to the uterus at diagnosis remain progression free at 2 years. Adjuvant pelvic radiation has not improved outcomes. Fixed-dose rate GT, and D, each have achieved objective responses in 25-53% of patients with metastatic uLMS. We sought to determine whether adjuvant treatment of uLMS with GT, followed by D, would result in ≥50% of women remaining progression-free at 2 years. Methods: Women with FIGO stage I, II, or serosa-positive-only III, high-grade uLMS and adequate organ function were eligible. Pts were required to initiate treatment within 12 weeks of complete resection and have no evidence of disease. Treatment: 4 cycles of every 3-week G 900mg/m2 over 90 minutes days 1 and 8, T 75 mg/m2 day 8 with granulocyte stimulating factor support. If disease-free by CT after cycle 4, then: 4 cycles of every 3-week D 60 mg/m2. CT performed 6 weeks after D, then every 3 months for 2 years, then every 6 months for 3 year...

5108 Background: Recent data showed that the multikinase inhibitor sorafenib (S) is active in ovarian cancer (OC). The scope of this trial was to determine efficacy and tolerability of S in combination with topotecan (T), an FDA-approved agent for platinum resistant OC. Methods: This multi-institutional phase I/II study was designed to determine the maximum-tolerated dose (phase I) and the response rate (phase II) to the regimen S+T in platinum resistant OC. Secondary endpoints were to measure PFS, toxicities, and rate of clinical benefit. Eligible patients had measurable or detectable recurrent OC, up to three prior cytotoxic treatments, ECOG PS of 0-1 and normal end-organ function. S was administered orally daily and T was given IV weekly at a fixed dose of 4 mg/m2, 3 weeks on and 1 week off during a 28 day cycle. For the phase I trial a 3 + 3 dose escalation design was used, testing two S dose levels: 400 mg daily (level 1) and 800 mg daily (level 2). The T dose was reduced to 3.5 mg/m2 weekly. The regimen tested during phase II was S at 400 mg daily and T at 3.5 mg/m2 weekly. Results: 16 pts were enrolled in phase I and 14 pts in phase II; all 30 were evaluable. Median age was 52.5 years (range 35-79), 27 pts had OC, and 3 pts had PPC. Nine pts were platinum refractory, 18 platinum-resistant, and 3 had platinum allergy. Median number of cycles administered was 2.5 (0-15). There were 5 PRs (16.7%), and 12 pts (40%) with stable disease (SD). Four PRs were recorded during phase I and 1 PR during phase II. Of these, 2 PRs occurred in pts receiving T at 4 mg/m2 and 1 PR in a pt receiving S at 800 mg/day. Median SD duration was 4.2 months (95% CI, 3.7-4.9). The most common treatment related all grade toxicities were nausea (53%), anemia (53%), thrombocytopenia (40%), neutropenia (50%), fatigue (37%), vomiting (23%), hand-foot syndrome (HFSR), and anorexia (20% each). Grade 3/4 toxicities included neutropenia (23%), thrombocytopenia (17%), anemia (10%), and fatigue, nausea, vomiting (6.7% each). One case of grade 3 HFSR was recorded. Conclusions: S can be safely combined with T in OC patients, but requires reduction of T to 3.5 mg/m2 weekly. The combination has clinical activity, however most responses were registered in pts receiving the higher doses of S or T. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Bayer Bayer

Abstract Background: The objectives of the study were to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities (DLTs) and objective response rate to combination therapy with sorafenib and topotecan in patients with platinum resistant epithelial ovarian cancer (EOC). Methods: This multi-institutional phase I trial used a fixed dose of weekly topotecan and escalating doses of sorafenib. Eligible patients had recurrent platinum-resistant EOC, measurable or detectable disease, and up to three prior cytotoxic treatments. Prior anti-angiogenic therapy was not allowed. Sorafenib was administered orally daily and topotecan was given iv weekly at a fixed dose of 4 mg/m2, 3 weeks on and 1 week off. Each treatment cycle was 28 days. A standard 3 + 3 dose escalation design was used, testing two sorafenib dose levels: 400 mg daily (level 1) and 800 mg daily (level 2). The topotecan dose was de-escalated to dose level −1 (3.5mg/m2 weekly). The primary endpoints of the phase I study were to determine the MTD and the toxicity profile of this combination. Results: 16 patients were enrolled between 12/12/07 and 11/13/08. Median number of prior regimens was 2 (range 1–7), median age was 52.5 (range 41–66), and all 16 patients had EOC. Distribution of patients per dose level and DLTs encountered are summarized in the table below. Five patients were inevaluable because of intercurrent illness or withdrawal of consent. Grade 3–4 toxicities during cycle 1 included: thrombocytopenia (3), neutropenia (2), febrile neutropenia (1), nausea and vomiting (2), rash (2), abdominal pain (1) and abnormal liver function tests (1). Grade 3–4 toxicities occurring after cycle 1 included: neutropenia (2), thrombocytopenia (1), anemia (2), nausea and vomiting (1), anorexia (1), and insomnia (1). Clinical activity was an exploratory endpoint. There was 1 partial response by RECIST lasting for over 12 months, but no complete responses. Six patients had stable disease. Conclusions: Sorafenib can be safely combined with topotecan in EOC patients. The dose recommended for phase II investigation is sorafenib 400mg daily with topotecan 3.5 mg/m2 weekly. Toxicities during dose escalation Topotecan dose (mg/m2) Sorafenic dose (mg) No patients No patients DLT/Decision DLT/Decision 4 400 6 2; not tolerated 3.5 400 4 0, tolerated, phase 2 3.5 800 6 2, not tolerated Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B273.