Supplementary Table 1 - PDF file 57K, Supplementary Table 1. Details of platinum sensitivity and best response to olaparib and post-PARPi chemotherapy of the six patients whose tumor samples were analyzed by massively parallel sequencing. (NE: not evaluable)

Purpose Temsirolimus, a mTOR inhibitor, and AZD2171, a VEGFR inhibitor, have independently shown activity in patients with gynecological malignancies. Understanding the pivotal role of the PI3K/PTEN/AKT/mTOR pathway in regulating angiogenesis, a phase I study utilizing Temsirolimus and AZD2171 was initiated to study the safety of targeting the mTOR and VEGF pathway in patients with recurrent or refractory gynecological malignancies. Methods Patients with advanced gynecological cancers were enrolled in this phase 1 study with Temsirolimus and AZD2171. A traditional 3 + 3 design was followed. The primary objective was to determine the MTD of the combination. Secondary objectives included efficacy, progression free survival (PFS) and toxicity profile. An expansion phase was planned after the MTD was determined. Results The study enrolled 11 patients over 16 months. All patients were enrolled in dose level 1. Due to toxicity, the trial was halted at dose level 1. No MTD was determined. The most common grade 3/4 toxicities included hypertension, thrombocytopenia, thromboembolic events, and hypertriglyceridemia. Five patients were evaluable for best overall clinical response. The best overall clinical response was stable disease. Two patients died without documented progression of disease. The median PFS was 7.2 months. Conclusions Despite a conservative dose escalation, the toxicity data demonstrated that the combination of AZD2171 and Temsirolimus was not tolerable. Increased awareness of novel toxicities, pharmacological interactions, coupled with strict patient selection and early mitigation of side effects may enhance phase I clinical trial development.

BACKGROUND: The objective of this phase 1 and 2 trial was to identify the appropriate dose of combined carboplatin and pralatrexate for patients with recurrent, platinum-sensitive ovarian, fallopian tube, and primary peritoneal cancer. METHODS: In phase 1, patients received carboplatin (at an area under the curve of 5) and increasing doses of pralatrexate until the maximum-tolerated dose (MTD) of pralatrexate was achieved. The primary endpoint was the response rate. Additional endpoints were safety, response duration, progression-free survival, overall survival, and pharmacokinetics. RESULTS: Thirty patients were enrolled in phase 1, and 20 were enrolled in phase 2. Of all 50 patients, 49 completed the study. The mean patient age was 59 years, and patients completed a median of 6 cycles. The MTD for pralatrexate was 105 mg/m(2). The clinical benefit rate (complete responses plus partial responses plus stable disease) was 86%. Of 26 patients who received the MTD, 12 had a partial response, 11 had stable disease, and 2 had disease progression. The progression-free survival rate at 3 and 6 months was 87% and 79%, respectively; and the overall survival rate was 98% at 6 and 12 months and 66% at 24 months. Of 30 patients, 18 (60%) in phase 1 experienced an adverse event of any grade; and, of those, 4 patients (13%) had a grade 3 or greater adverse event. In phase 2, 12 patients (60%) had an adverse event of any grade, and 4 (20%) had grade 3 or greater toxicity. There was a significant reduction in the total body clearance of pralatrexate when it was received concurrently with carboplatin. CONCLUSIONS: Most patients responded to carboplatin-pralatrexate combination. This regimen is well tolerated and effective in this patient population. (C) 2016 American Cancer Society.

Abstract Background: In vivo synergy of the PI3-kinase inhibitor BKM120 with the PARP inhibitor olaparib has been observed using a mouse model of BRCA1-related breast cancer and sporadic TNBC (Juvekar et al and Ibrahim et al, Cancer Discovery 2012). In addition, olaparib has single agent activity in both HGSC and BRCA-associated breast cancer. The PI3kinase pathway is activated in both TNBC and HGSC (www.cancergenome.nih.gov). These preclinical and clinical data have served as the rationale for this phase I, multi-center study (NCT01623349) combining the oral PARP inhibitor olaparib with the oral PI3-kinase inhibitor BKM120 in patients with recurrent HGSC or recurrent TNBC. This study is being conducted through the Stand Up to Cancer (SU2C)'s Targeting PI3-kinase in Women's Cancers Dream Team. Study Design: This study has a 3 + 3 design, escalating if 0/3 or 1/6 participants have a dose limiting toxicity (DLT) during the first cycle of therapy (first 28 days). The study objectives are to determine the recommended phase II dose (RP2D) of daily continuous oral olaparib (using the tablet formulation) and BKM120, assess toxicities, safety, and preliminary activity of this combination, and determine pharmacokinetic profiles of both agents. In addition, there are several translational endpoints including elucidation of downstream signaling effects of the PI3-kinase pathway, examination of BRCA1 immunostaining, and assessment of BRCA1 promoter hypermethylation and somatic mutations in BRCA1 and BRCA2 using archived formalin fixed paraffin embedded (FFPE) tissue. Serial IL-8 and circulating DNA levels are also being monitored as well. Eligibility includes a diagnosis of recurrent TNBC or HGSC, PS 0 or 1, measurable or evaluable cancer, and normal lab values and organ function. Prior PARP inhibitor exposure is allowed. In addition, breast cancer or ovarian cancer patients with any histologic subtype are eligible if they have a known germline BRCA1 or BRCA2 mutation. At the RP2D, 10 pts each with a diagnosis of TNBC or HGSC will be enrolled to further determine safety and efficacy profiles in addition to more thoroughly studying translational endpoints. As of June 7, 2013, 16 patients have been enrolled into this study with a planned accrual of approximately 50 patients which may change based on number of dose levels tested during dose escalation. In addition, an amendment is pending that will add a second cohort studying the combination of olaparib and BYL719 based on robust pre-clinical activity observed in murine models which will increase our total accrual. Once this new cohort is open, both arms will enroll simultaneously. For further information, contact Ursula Matulonis at: umatulonis@partners.org. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-4-02.

Abstract Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated. Experimental Design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing. Results: Data were collected from 89 patients who received a median of 3 (range 1–11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13–21] and 34 weeks (95% CI, 26–42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15–29) and OS of 45 weeks (95% CI, 15–75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0–0.375)]. Conclusions: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC. Clin Cancer Res; 19(19); 5485–93. ©2013 AACR.

OBJECTIVE:Test the safety and efficacy of sequentially blocking angiogenesis by adding oral cyclophosphamide to bevacizumab following cancer progression on bevacizumab in patients with recurrent ovarian cancer. METHODS:Eligibility included ≤ 2 lines of treatment for recurrence and measurable cancer by RECIST 1.0. Patients received bevacizumab (15 mg/kg every 3 weeks IV) and upon RECIST progression, oral cyclophosphamide (50mg orally daily) was added. Objectives included safety, toxicities, 3- and 6-month PFS rates, response rate, PFS, and OS. RESULTS:20 patients were enrolled. Overall response rate was 10%, and 65% of patients had confirmed stable disease (SD). Thirteen of 20 patients received oral cyclophosphamide added to bevacizumab upon bevacizumab progression. Of these 13 patients, 1 patient subsequently achieved a PR (this patient had SD as best response during bevacizumab) and 3 patients had a confirmed SD. For all patients, median PFS was 8.41 months, 6 month PFS rate was 65%, duration of response (DOR) was 7.3 months, and median OS was 22.72 months. Median DOR for patients receiving both bevacizumab and cyclophosphamide was 8.4 months. Most toxicities were grades 1 and 2 and manageable. Grades 3 and grade 4 toxicities included 1 myocardial infarction, 1 gastrointestinal perforation (GIP), and 12/20 patients (60%) developed grade 3 HTN. CONCLUSIONS:Addition of oral cyclophosphamide to bevacizumab at the time of cancer progression on bevacizumab appears to have continued anti-cancer effects in a subgroup of patients and appears to be safe. Randomized trials testing combination versus sequential anti-angiogenic therapy for recurrent ovarian cancer are warranted.

Objective: The purpose of this study was to determine the response rate and progression-free survival of carboplatin/paclitaxel/bevacizumab (induction therapy) followed by either bevacizumab alone or bevacizumab+erlotinib (consolidation therapy) in patients with ovarian, fallopian tube or peritoneal cancer.

5083 Background: Ovarian cancer (ov ca) growth is driven by angiogenesis; drugs that block angiogenesis can result in anti-ov ca activity. This study sought to sequentially block angiogenesis by adding stepwise antiangiogenic agents targeting different aspects of the angiogenic cascade. Methods: Objectives were to assess the safety of sequential bevacizumab (bev) and oral low dose cyclophosphamide (Cy) and assess proportion of patients who remain on study at 3 months; others were toxicity, RR, and PFS. Eligibility: recurrent ov, tubal, or peritoneal ca, max of 2 lines of therapy for recurrent ca (biologic therapies included), platinum resistant or sensitive recurrence, ECOG PS of 0 or 1, measurable cancer by RECIST or CA125, no preexisting significant hypertension, and no evidence of SBO or impending SBO. Pts started on bev 15 mg/kg IV q21 days and were assessed radiographically every 2 cycles. If CR, PR, or SD and no significant toxicities occurred, patients continued on bev. If pts had PD and were clinically stable, Cy 50 mg PO daily was added to bev. Results: 20 patients were enrolled which was the target enrollment. 13 pts had ov, 2 had tubal, and 5 had peritoneal cancer. 14 pts had plat resistant cancer, and 6 had plat-sensitive. 7 pts had 2 prior lines for recurrence, 9 had 1 prior line, and 4 had no prior lines for recurrence. Grade 3 and 4 toxicities included 7 pts with grade 3 HTN, 1 pt with GIP, and 1 pt with acute MI. Of the 20 pts, 16 pts remained on study for at least 3 months or 4 cycles (80%). 2 pts had a PR, 16 pts had SD as their best response with bev, 1 pt is too early to evaluate, 1 pt had PD as their best response on bev and is now on PO Cy. 2 pts were removed during bev for toxicities (GIP after cycle 2 and MI following cycle 4), and 10 pts remain on single agent bev without progression. Cy has been started in 8 patients; of those 8, 4 pts attained SD, 3 pts had PD, and 1 pt is too early for evaluation. Conclusions: Bev as a single agent demonstrates biologic activity in recurrent ovarian cancer. Preliminary data suggests that the addition of PO Cy to bev following tumor progression on bev appears tolerable and can lead to stable disease. This observation may have implications in the design of future clinical trials using antiangiogenic agents for recurrent ovarian cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech

5111 Background: Circulating tumor cells (CTC's) can be used for detection of cancer recurrence and response to therapy. Epithelial ovarian cancer is diagnosed in an advanced stage in > 75% of patients, and despite high RR's of platinum- and taxane- based chemotherapy following diagnosis, most women will recur. The purpose of this study was to examine the utility of immunomagnetically-isolated CTC's, captured using the CellSearch System (Veridex) in predicting response to therapy in patients with known recurrent ovarian cancer. Methods: 50 consecutive patients with recurrent ovarian cancer (both platinum resistant and plat sensitive) were selected as part of an IRB-approved study at the Dana-Farber Cancer Institute. CTC's were isolated according to standard protocols for the Veridex CellSearch System. 7.5 mL of blood was collected in Cell Save Vacutainer tubes, samples were processed within 36 hrs of collection, and samples were immediately processed with the CellTracks Autoprep instrument using the Epithelial Cell Kit. Following processing, tumor cells were enumerated using the CellTracks Analyzer. Results: The mean age of the 50 patients was 56 years (range 37-81 yrs). CTC counts ranged from 0 to 8, with an average value of 7. No consistent trend was noted, as some patients' CTC counts increased through the study as others decreased, and these trends did not correlate with CA-125 levels or clinical/radiographic evidence of disease status. 24 pts patients underwent single agent chemotherapy (i.e., doxil, carboplatin, and topotecan), while 20 were placed on multiagent chemotherapy regimens; the remainder received biologic therapies. There was no correlation between CTC levels and the type of therapy, either single agent versus platinum doublet. Conclusions: The numbers of CTC's enumerated were quite low in all patients and failed to correlate with type or duration of chemotherapy. Additionally, the numbers of CTC's did not appear to correlate with CA-125 levels or with other modalities to measure treatment response in this patient population. Additional studies are needed to optimize the role for the enumeration of CTC's in monitoring patents with recurrent ovarian cancer. No significant financial relationships to disclose.

Background Pegylated liposomal doxorubicin has activity in both breast and ovarian cancer. Preclinical data noted that ZD1839 acts synergistically with chemotherapy. Given the lack of cross-resistance between these two agents, a phase I trial was initiated examining the safety and efficacy of the combination of liposomal doxorubicin and ZD1839 in patients with recurrent gynecologic or metastatic breast cancer. Methods Dose-limiting toxicity (DLT) was defined within the first two cycles of treatment. Escalating doses of liposomal doxorubicin were administered every 4 weeks with ZD1839. Pharmacokinetic analysis and correlative studies were performed. Results Thirty-five patients were enrolled in this study: six in each cohort. One DLT (febrile neutropenia) was observed in cohort 2. Dose level 3 was determined to be the maximum tolerated dose (MTD), and an additional ten patients were accrued. Serious adverse events (SAEs) included one patient with mental status changes believed secondary to disease progression and two central nervous system (CNS) bleeds believed to be unrelated to the combination of study agents. Toxicities were generally mild except for skin and gastrointestinal toxicity. No cardiac toxicity was observed. The best response to therapy included four partial responses and 20 patients with stable disease. Conclusions Liposomal doxorubicin with ZD1839 is an active regimen but is associated with increased skin toxicity in patients with advanced breast and gynecologic cancer.

5590 Background: More than 50% of cases of ovarian cancer occur in the older patient population (>65), the only group with an increasing incidence. The elderly with ovarian cancer are thought to have a worse prognosis with possible causative factors being more aggressive biology, inability to tolerate aggressive debulking surgery and chemotherapy, and comorbidities. Carboplatin and paclitaxel remains the standard of care for newly diagnosed patients with suboptimally debulked epithelial ovarian cancer. Methods: The primary objective was to determine the completion rate of six cycles of carboplatin/paclitaxel in an elderly population, and evaluate clinical parameters that predict completion of treatment including VES-13 score, Charlson co-morbidity index, nutritional status, and pharmacokinetics of paclitaxel. Eligibility: Age 70 or older. Treatment: carboplatin AUC 5 IV and paclitaxel 175 mg/m2 IV over three hours, q21 days. Results: 12 patients were enrolled with a median age 82 (75–86), with ECOG performance score 0(n=2), 1(n=8), and 2(n=2). The study was formally audited when 3 of the patients died on study, and the study was closed. One 84-yo died of toxicity complicating PD after #1 with a combination of progression and toxicity with nausea and vomiting leading to dehydration and ARF, an 82-yo died suddenly #6 day 5 in CR, and a 75-yo died of aspiration after vomiting during #2. Grade 3/4 toxicity included cognitive disturbance, constipation, enteritis, fatigue (2), febrile neutropenia (2), obstipation, hypoxia, infection, and vomiting. Only 3 patients were able to complete treatment, one with cognitive impairment and only 2 without dose delays or reductions. Conclusions: Standard chemotherapy in vulnerable populations can be associated with unacceptable excess toxicity. Reported series with positive outcomes in geriatric populations likely reflect significant selection bias. Careful consideration should be given to initial treatment with reduced doses (Carboplatin AUC 4 and paclitaxel 135 mg/m2) and escalation as tolerated. No significant financial relationships to disclose.

OBJECTIVES:The primary objective was to determine the completion rate of 6 cycles of paclitaxel and carboplatin chemotherapy with no dose reductions in patients > or =70 years of age. METHODS:Phase II study of intravenous (IV) carboplatin Area Under the Curve (AUC) of 5 and paclitaxel 175 mg/m(2) given to patients > or =70 years of age, had any stage Müllerian cancer, and an ECOG performance status (PS) of 0-2. RESULTS:Twelve patients were enrolled (median age of 82 years, range 75 to 86 years). Six of 12 completed 6 cycles of chemotherapy with no dose reductions. Three patients died on study precipitating study closure; one with refractory cancer following cycle 1, one of aspiration pneumonia after cycle 1, and one with sudden death on day 5 of cycle 6. Patients undergoing upfront debulking surgery tolerated chemotherapy better compared to patients receiving neoadjuvant chemotherapy. Grade 3 or higher hematologic toxicities included 2 patients with febile neutropenia (17%). > or =Grade 3 non-hematologic toxicities included fatigue (8%), nausea (8%), constipation (8%), obstipation (8%), vomiting (8%), and hypoxia (8%). CONCLUSIONS:In this prospective trial of standard carboplatin and paclitaxel chemotherapy in a heterogeneous population of elderly patients, chemotherapy was well tolerated by patients who underwent upfront debulking surgery, had a PS of 0-1, and had few comorbidities. Patients not undergoing upfront debulking surgery because of either advanced cancer or poor surgical risk had excess morbidity/mortality. Prospective studies to identify risk factors for toxicity prediction are needed.

19524 Background: CIM is a significant toxicity that is treated with cytokine growth factors, dose reductions and/or delays. Preliminary uncontrolled Chinese studies suggest that acupuncture lessens CIM. Methods: Patients (pts) with newly diagnosed or recurrent gyn cancers receiving chemotherapy were eligible. Trial design was a double blinded, randomized trial of active acupuncture or sham for 5 weeks (administered 3x per week). Primary endpoints were first nadir WBC and ANC levels at chemo cycle 2; other endpoints were recovering counts following the cycle 2 nadir, QOL, G-CSF levels, and feasibility. Results: >460 patients were screened. 21 pts were randomized to either active acupuncture (n=11) or sham control (n=10). Median age of the pts was 55 yrs (range: 28–81). 15 pts have completed the acupuncture treatment to provide the baseline and nadir WBC and ANC. Toxicities related to either sham or active acupuncture were minimal. The active pts group showed higher baseline WBC (median: 3,600 vs. 2,600, NS) and ANC (median: 2,269 vs. 1,922, NS) values. The nadir WBC was higher in the pts receiving acupuncture (median 3,600 vs. 2,300) but the difference was not statistically significant after adjusting for the baseline difference (p=0.16). Nadir ANC was higher among the pts receiving acupuncture (median: 2,424 vs. 1,274) but the difference was not statistically significant after adjusting for the baseline difference (p=0.1107). Recovering WBC in the pts receiving acupuncture was higher (median: 8,600 vs. 4,400) after adjusting for the baseline difference (p=0.045). The recovering ANC in the pts receiving acupuncture was higher (median: 6,530 vs. 4,038) but this difference was not statistically significant after adjusting for the baseline difference (p=0.0919). QOL and G-CSF data will be presented at ASCO. Conclusions: Although a larger randomized trial is necessary to determine the effects of acupuncture on CIM, there were consistent trends, and recovering WBC counts were significantly higher in patients receiving acupuncture. Formal evaluation of CAM is vital to confirm potentially clinically meaningful benefits. No significant financial relationships to disclose.

OBJECTIVES:To evaluate the toxicity and efficacy of cisplatin and gemcitabine in women with recurrent cervical cancer.METHODS:A multi-institutional phase I/II dose finding study of cisplatin and gemcitabine delivered to women with recurrent previously radiated cervical carcinoma.RESULTS:Twenty eight patients were enrolled. The mean and median age of patients was 51 years (age range 35 to 70 years). Chemotherapy was given on a 28-day cycle; cisplatin was administered at a fixed dose of 50 mg/m(2), day 1 and gemcitabine, days 1, 8, and 15. Gemcitabine doses started at 600 mg/m(2) (dose level 1) and were escalated by 100 mg/m(2)/dose level until 1000 mg/m(2) (dose level 5). Twenty seven patients were evaluable for toxicity and disease response, and 75 cycles of chemotherapy were administered. Toxicities were predominantly hematological; 18% of patients experienced grade 3 anemia, 37% grade 3 and 11% grade 4 leukopenia, 41% grade 3 neutropenia, and 26% grade 3 thrombocytopenia. The maximally tolerated dose (MTD) was not reached. One patient experienced a dose-limiting toxicity on dose level 2 (febrile neutropenia). One patient had a CR and 3 patients had a PR to therapy (15% response rate), 41% of patients had SD, and 44% had progression of cancer. Median survival was 11.9 months.CONCLUSION:Although this 28-day gemcitabine and cisplatin regimen in recurrent cervix cancer has tolerable toxicity, 21-day regimens are recommended because of improved practicality, higher dose intensity, and higher response rates.

5159 Background: Symptoms of bowel obstruction and intermittent chronic obstruction are common complications in patients (pts) with recurrent ovarian cancer. Mechanisms of bowel obstructions include intraabdominal carcinomatosis, drug-induced intestinal immobility, and intraluminal obstruction. Octreotide inhibits gastrointestinal hormonal secretion and decreases splanchnic blood flow. Sandostatin LARDepot (LAR) is a long-acting depot form of octreotide given intramuscularly (IM) once per month. Methods: The objectives of this trial were to assess efficacy and toxicities of LAR in ovarian cancer pts with chronic or intermittent bowel obstruction. Pts must have recurrent ovarian or primary peritoneal cancer, symptoms related to a non-surgically amenable bowel obstruction, and a life expectancy of >2 months. Following a test dose of short-acting octreotide to rule out a hypersensitivity reaction, subcutaneous (SQ) octreotide was started at a dose of 100 mcg 3x/day for 2 weeks (in order to quickly achieve therapeutic serum levels) along with LAR 30 mg IM qmonth. IM LAR was given until symptom progression or toxicity. Results: Since the study began in 9/02, 15 pts have been enrolled, and the study is now completed. The mean age of pts is 57 years of age. One enrolled pt never received any study drug, and data is available on 14 pts. Of the 15 pts enrolled, 13 have died from cancer progression. 3 pts received a successful test dose and one LAR injection, but were taken off study per their request. Of the 9 pts who received >2 months of LAR, the duration of LAR ranged from 2 to >12 months with a median of 4 months. No grade 3 or 4 toxicities related to LAR were seen, and LAR was well tolerated. 2 pts had skin reactions, and 1 of these 2 pts was taken off study. QOL data was collected and will be presented at ASCO. Conclusions: LAR is well tolerated following successful administration of a test dose of SQ octreotide. In this ovarian cancer population with inoperable bowel obstruction, LAR has activity in the management of symptoms of bowel obstruction and can be used safely in this population without apparent cumulative toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis

5063 Background: Both the selective aromatase inhibitor, anastrazole, (Arimidex) and Gefitinib (Iressa), an oral epidermal growth factor receptor tyrosine kinase inhibitor have demonstrated modest single agent activity in the treatment of women with ovarian cancer. Preclinical studies studies demonstrate that interruption of both pathways simultaneously may be an effective therapeutic strategy. Methods: Open label phase II study performed in patients with recurrent Mullerian malignancy including ovarian, peritoneal or fallopian tube carcinoma. Eligible patients had tumors that were IHC + for expression of the estrogen and/or progesterone receptor. Additionally, patients must asymptomatic without an indication for immediate systemic chemotherapy, ECOG PS of = 1. Patients could have either measurable or evaluable disease or a rising CA-125, defined as a single value > 35 U/ml or 2 successively rising values with the most recent 3 times patient's nadir value. Archived tumor samples were also sent for quantitative EGFR expression, but this was not an eligibility requirement. Treatment consisted of anastrazole 1mg po qd and Iressa 250mg po qd. Monthly follow-up included interim history, physical exam and CA-125, with radiologic evaluation q 3 months. Results: Thirty five women with a median age of 60 (range 40–79 years) were enrolled. Included were 30, 4, and 1 women with ovary, primary peritoneal and fallopian tube cancers, respectively. To date 23 women are evaluable for response and 7 patients remain on study. Best overall response of patients who have completed the study includes 1 CR, 0 PR, 14 SD. Median TTT was 68 days (range 19–261), with 8, 2, 1 patients with stable disease at = 3, = 6, and = 9 months, respectively. An additional two patients remain on study with SD > 9 months. Toxicity was tolerable, including mild fatigue, nausea, hot flashes, skin rash (gr 1:17 pts, gr 2:5 pts, gr 3:1 pt), stomatitis (gr 1:4pts), and diarrhea (gr 1:15 pts, gr 2:5pts, gr 3:1 pt). Conclusions: Anastrazole in combination with Iressa is a well-tolerated oral regimen with modest activity in women with recurrent/persistent Mullerian cancers. Exploratory analysis regarding EGFR expression, EGFR mutations and response are underway. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca

Symptoms of malignant bowel obstruction in patients with recurrent ovarian cancer lead to a poor quality of life. Sandostatin LAR® Depot (LAR) (Novartis Pharmaceuticals Corp., East Hanover, NJ) is an intramuscular, monthly administered, long-acting form of octreotide. LAR's safety and utility were evaluated in a pilot study enrolling 15 advanced ovarian cancer patients with bowel dysfunction. Once safety with subcutaneous (SQ) octreotide was assessed, patients were given 30mg LAR on Day 1 and octreotide SQ for 2 weeks. Of 13 evaluable patients, three patients had a major response to LAR treatment with reduction in bowel obstruction symptoms, two had a minor response, four had no response, and four had progressive symptoms. Three patients remained on LAR for more than 9 months. No significant toxicities were attributable to octreotide or LAR. Because three patients received nine or more monthly injections of LAR, possible direct antitumor effects of LAR or synergy with chemotherapy needs to be explored.

Background. Topotecan and pegylated liposomal doxorubicin (Doxil) interact with topoisomerase I and II (topo I and II), respectively, with schedule dependent, and potentially synergistic cytotoxicity.Objectives. Define dose-limiting toxicity (DLT) and determine the maximum tolerated dose (MTD) of topotecan delivered by 72-h infusion administered immediately after Doxil delivered at a fixed dose (30 mg/m(2)) in a cohort of women with recurrent mullerian malignancies.Methods. Topotecan dose was escalated from 0.5 mg/m(2)/day for 3 days in 0.2 mg/m(2)/day increments with treatment repeated every 21 days. Eligibility criteria required ECOG less than or equal to 2 and no more than four prior lines of chemotherapy. No dose reductions were allowed in the first two cycles to allow evaluation of cutaneous toxicity.Results. Between November 2000 and August 2002, 18 patients were enrolled. Median age 59 (40-71) years. Patients received a median 1 (1-6) cycles of chemotherapy, with 39 cycles of treatment delivered at DL 1. All patients were evaluable for toxicity and 12 for response. At dose level 2, dose-limiting toxicity consisted of nausea and vomiting, mucositis, cutaneous toxicity, and neutropenia. There was no clinically significant cardiac toxicity. There were no radiologically confirmed partial responses.Conclusions. Doxil 30 mg/m(2) and topotecan 0.5 mg/m(2)/day by 72-h infusion (total dose 1.5 mg/m), although a rational combination of cytotoxic therapies, have limited clinical activity. (C) 2004 Elsevier Inc. All rights reserved.

Objective To determine the activity and tolerability of weekly docetaxel in patients with platinum-resistant mullerian origin tumors. Methods Patients with persistent disease, or those recurring less than 6 months after receiving platinum-containing therapy, were eligible for this phase II study. Docetaxel was initially administered at a dose of 40 mg/m2 on days 1, 8, and 15, with a cycle length of 28 days. This starting dose was subsequently reduced to 30 mg/m2 due to toxicity. Dexamethasone prophylaxis was administered at a dose of 4 mg PO every 12 hours for 3 doses, starting 12 hours before each dose of docetaxel. Results Thirty-two patients were enrolled, with a median age of 59 years. The majority of patients received a median of 3 prior regimens, with 45% of the study group having received 4 or more prior regimens. The overall response rate in 29 evaluable patients was 6.9%, with no complete responses. Seventeen percent of patients experienced stable disease. Dose reduction or delay was required in 10 of the first 22 patients enrolled, prompting a reduction in the starting dose to 30 mg/m2. Hematologic toxicity was generally tolerable, and no patient experienced febrile neutropenia. Non-hematologic toxicity was generally grade 1 in nature, although a combination of multiple low grade toxicities occurring in an individual patient oftentimes mandated dose reduction. Conclusions Weekly docetaxel demonstrated modest activity in a heavily pre-treated, platinum-resistant population. A starting docetaxel dose of 30 mg/m2 would be reasonable for future studies exploring the utility of weekly dosing in less heavily pre-treated patients.