Background: EP0057 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) of a cyclodextrin-based polymer backbone plus camptothecin, a topoisomerase-1 inhibitor. Prior studies showed efficacy in recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC). Methods: This phase Ib/2 trial assessed safety and efficacy of EP0057 Q2W plus weekly paclitaxel in patients with EOC. The recommended phase 2 dose (RP2D) was identified using a 3+3 design. The single-arm phase 2 assessed overall response (ORR) per RECIST 1.1 in patients previously treated with bevacizumab. Secondary objectives included progression free survival (PFS) and duration of response. Results: The RP2D was established as 15 mg/m2 EP0057 Q2W plus 80 mg/m2 paclitaxel administered 3 weeks on/1 week off. Nine patients enrolled on phase 1b, with no DLTs; 21 additional patients enrolled on phase 2. All completed >1 cycle. Median age was 62 (44-76) years, 57% ≥3 prior therapies. For the primary analysis, 6/19 patients with prior bevacizumab had confirmed responses (ORR=31.6% (95% CI: 15.4% to 54.0%)) including one complete response (CR). Median PFS was 5.4 months. Most common grade 3/4 adverse events attributed to treatment were decreased neutrophil count (13, 43%) and anemia (3, 10%). Conclusions: Although the observed ORR was not statistically better than the historical control rate, EP0057 remains an interesting option for treatment of recurrent EOC. EP0057 exhibits high plasma drug retention, slow clearance, and controlled slow release of CPT from the polymer when administered alone and with paclitaxel. (NCT02389985) 242 words

Preclinical studies have demonstrated synergistic antitumor activity for combinations of PARP inhibitors (PARPi) with PD-1/PD-L1 inhibitors (PD-1/PD-L1i) which is at least partly mediated by activation of the Stimulator of Interferon Genes (STING) pathway. Given that PD-1/PD-L1i exhibit only modest activity as monotherapy against MSS endometrial cancer (EC), we evaluated whether the combination of the PARPi talazoparib and the PD-L1i avelumab would demonstrate promising activity and acceptable toxicity in that setting. We conducted a single-arm phase 2 study to evaluate avelumab and talazoparib in recurrent MSS EC (MSS determined by IHC). Eligibility criteria included measurable disease, no limit on prior therapies, and all EC histologies including carcinosarcomas. Co-primary endpoints were objective response rate (ORR) by RECIST 1.1 and progression-free survival rate at 6 months (PFS6). Talazoparib 1mg PO daily and avelumab 10 mg/kg IV every 2 weeks were administered until progression or unacceptable toxicity. A two-stage design was employed to allow for early stopping for futility. In the 1st stage, 16 pts were enrolled; if there were ≥2 ORs or ≥2 PFS6 responses, accrual would continue to the 2nd stage with enrollment of 19 additional pts. Overall, if there were ≥4 ORs or ≥8 PFS6 responses, avelumab+talazoparib would be considered worthy of further study. As of June, 5th 2020, 35 pts initiated therapy. Three pts exhibited OR [3PRs, ORR 8.6% (95% CI 1.8%-23.1%)] and 8 exhibited PFS6 responses (PFS6 responses by histology: 3 endometrioid, 3 serous, 1 clear cell and 1 carcinosarcoma), 5 ongoing. PFS at 6 months was 25.8% (95% CI 12.4%-41.4%) and median PFS was 3.65 months (95% CI: 2.4-5.4 months). Most common G3+ treatment-related toxicities were anemia (n=16, 45.7%), thrombocytopenia (n=10, 28.6%) and neutropenia (n=4, 11.4%). Seven (20%) pts had dose reductions; no pt discontinued therapy because of toxicity. Avelumab and talazoparib met the predetermined PFS6 response criterion to be considered worthy of further evaluation in this pt population of recurrent MSS EC. Correlation with biomarkers of response to PARPi and PD-1/PD-L1i is ongoing.

Background. Intraperitoneal (IP) chemotherapy can improve outcomes for women with optimally cytoreduced epithelial ovarian cancer but toxicities are a concern. We conducted 2 phase 2 trials of an IV/IP regimen using carboplatin and paclitaxel without (Trial A) and with bevacizumab (Trial B). Methods. Both trials consisted of carboplatin AUC 6 day 1, and paclitaxel 60 mg/m(2) on days 1,8, 15 of a 21-day cycle; in Trial B, patients received IV bevacizumab 15 mg/kg every cycle starting cycle 2. Chemotherapy was administered IV for cycle 1 and then IP for all subsequent cycles. Primary objectives included safety and tolerability, pathologic CR rate (Trial A), and the rate of completion of IP cycles of therapy (Trial B). Progression-free (PFS), overall survival (OS), and pharmacokinetic analysis were secondary endpoints. Results. 81 patients were treated on both trials (n = 40 and 41 in trials A and B, respectively). Median age for trials A and B was 59 (range, 36-76) and 55 (range, 19-69) years, respectively. 68% and 85% of patients, respectively for A and B, completed at least 4 cycles of treatment in both trials. Treatment with bevacizumab resulted in higher rates of grade 3 fatigue (37 versus 33%) and grade 3-4 diarrhea (22 versus 8%). Median PFS was 23.5 (95% CI 16.2-35.3) and 25 (95%CI 16.4-42.7) months, respectively; median OS was 68 (95%CI 49.5-NR) and 79.7 (95% CI 59.0-79.7) months, respectively for Trial A and B. Conclusions. Weekly administered IP carboplatin and IP paclitaxel is tolerable and safe with similar activity with and without concommittant bevacizumab in these 2 trials. (C) 2019 Published by Elsevier Inc.

Cerulean Pharma, Inc. is developing CRLX101, an investigational NDC with a camptothecin payload. CRLX101 has been investigated in more than 350 pts as monotherapy or in combination with bevacizumab in pts with renal cell carcinoma (Keefe, ASCO 2015, abstract #4543) and platinum-refractory OC (Krasner, ASCO 2014, abstract #5581). Preclinical and early clinical data suggest synergy between taxanes and topoisomerase 1 inhibitors. We started a Phase 1b trial for this combination in pts with platinum-resistant OC. Cohorts of 3 pts were accrued in this trial. Two dose levels of CRLX101 (every other week) in combination with weekly [wkly] paclitaxel 80 mg/m2 (3 wks on/1 wk off) were planned: dose level 1, CRLX101 12 mg/m2; dose level 2, CRLX101 15 mg/m2 . The primary objective was to determine the maximum tolerated dose of CRLX101 in combination with wkly paclitaxel. Secondary objectives included pharmacokinetics, safety, tolerability, and clinical activity. As of March 11, 2016, 9 pts have been enrolled and treated at dose levels 1 (n = 3) and 2 (n = 6); all pts were evaluable for safety and response. Median age was 61 years (range, 49–73); median number of previous regimens was 3 (range, 1–4). GOG score performance status was 0 (6 pts) or 1 (3 pts). No dose-limiting toxicities have been reported at either dose level, thus the RP2D is CRLX101 15 mg/m2 (every other week) and paclitaxel 80 mg/m2 (3 weeks on/1 week off). Treatment-related adverse events (AEs) included fatigue (6/9, 67%), neutrophil count decreased (4/9, 44%), nausea (4/9, 44%), vomiting, alopecia, headache, infusion-related reaction, and urinary tract infection (2/9, 22% for all). The only grade ≥3 treatment-related AE was neutropenia, which occurred in 2 pts (1 grade 3; 1 grade 4). Partial response and stable disease rates were 56% (5/9) and 11% (1/9), respectively. Moreover, CA125 responses (≥50% decline from baseline) were demonstrated in 33% (3/9) of pts. Two pts (at 15 mg/m2) are still receiving therapy. CRLX101 given every other wk in combination with wkly paclitaxel has demonstrated early signs of antitumor activity and has been generally well tolerated to date in pts with platinum-resistant OC.

OBJECTIVE:To evaluate the efficacy and toxicity of erlotinib in the management of squamous cell carcinoma (SCC) of the vulva. METHODS:Patients with vulvar lesions amenable to surgery or chemoradiation (cohort 1) or those with metastatic measurable disease (cohort 2) received erlotinib 150 mg daily. Patients were monitored for toxicity. Responses were determined by digital photography or RECIST 1.1. Cohort 1 underwent pre and post treatment biopsies. EGFR immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH), and mutational analysis were performed. RESULTS:41 patients were enrolled: 17 in cohort 1 and 24 in cohort 2. Notable grade 3 or 4 toxicities included allergic reaction (1), diarrhea/electrolyte abnormalities (3), ischemic colitis (1), and renal failure (3) and electrolyte abnormalities (n=2). Mean number of cycles for cohort 2 was 3.3. Overall clinical benefit rate was 67.5% with 11 (27.5%) partial responses (PR), 16 (40.0%) stable disease (SD), and 7 (17.5%) progressive disease. Responses were of short duration. All pre and post treatment biopsies exhibited 2-3+ EGFR staining. 5 of 14 patients (35%) were found to have EGFR amplification (n=3) or high polysomy/trisomy (n=2). These five patients had either a PR (n=3) or SD (n=2). Gain of function mutations were not been identified. CONCLUSIONS:This is the first reported controlled trial evaluating erlotinib for the management of vulvar carcinoma. Toxicities were acceptable given the lack of treatment options for these patients. Given the observed clinical benefits erlotinib may represent one of the most active agents available to treat vulvar SCC.

5005 Background: Recurrent ovarian cancer following treatment of advanced disease with platinum-based therapy, such as GC, is associated with poor prognosis and 5-year survival. Addition of iniparib (BSI-201), an anticancer agent with poly (ADP-ribose) polymerase inhibitory activity, to GC potentiates the activity of GC alone, with low incremental toxicities, in patients with metastatic triple-negative breast cancer. (O’Shaughnessy et al. NEJM 2011). This study was designed to evaluate the efficacy and safety of iniparib in combination with GC in patients with platinum-resistant recurrent ovarian cancer. Methods: This multicenter, single-arm phase 2 study used a Simon two-stage design (Stage I n=25; total N=48). Eligible patients were ≥18 years with a histological diagnosis of epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma and had platinum-resistant disease, defined as relapse 2 to 6 months following primary treatment termination. Carboplatin (AUC 4; IV; days 1), gemcitabine (1000 mg/m2; IV; days 1 and 8), and iniparib (5.6 mg/kg; IV; days 1, 4, 8, and 11) were given on a 21-day cycle. The primary endpoint was overall response rate (ORR; RECIST 1.0); secondary endpoints were safety and progression-free survival (PFS). Results: Analysis from the first 19 patients demonstrated an ORR of 31.6%, consisting of 6 confirmed responses. Early analysis showed a median PFS of 5.9 months (95% CI, 3.0-NE). Safety profiles were consistent with those observed in previous clinical studies of iniparib + GC. Conclusions: Iniparib + GC demonstrated activity in patients with platinum-resistant recurrent ovarian cancer, with promising evidence of response (ORR=31.6%) and substantial increase in median PFS (5.9 months) compared with a previous study of pegylated lioposomal doxorubicin in platinum-resistant recurrent ovarian cancer (ORR=11.7%; median PFS=3.1 months; Mutch et al. JCO 2007). No unexpected toxicities have been reported. Data from all enrolled and dosed patients who have received at least one post-dose scan will be presented. (Clinicaltrials.gov number, NCT01033292).

5046 Background: Trabectedin (T) in combination with pegylated liposomal doxorubicin (PLD) was demonstrated to improve progression-free survival (PFS) and overall response rate (ORR) in comparison to PLD alone as a second-line treatment of recurrent ovarian cancer (J Clin Oncol 28:3107-14, 2010). We report the protocol defined final analysis of overall survival (OS). Methods: Women ≥18 years, stratified by performance status (0-1 vs 2) and platinum-free interval (PFI) <6 vs > 6 months(m), were randomly assigned to receive an IV infusion of PLD 30 mg/m2 followed by a 3-hour infusion of T 1.1 mg/m2 every 3 weeks or PLD 50 mg/m2 every 4 weeks. The primary endpoint was PFS by independent radiology assessment and secondary endpoints included OS and ORR. Results: The final OS analysis was performed on 12 Nov 2010. The median follow-up was 47.4m. Among the 672 randomized subjects, 522 (77.7%) deaths were observed (258 in the T+PLD arm and 264 in the PLD arm). The median OS for T+PLD and PLD arms was 22.2 and 18.9m, respectively (HR= 0.86; 95%CI: 0.72, 1.02; p=0.0835 [unstratified log-rank test]). There was an unanticipated imbalance in the PFI between the two arms favoring the PLD arm (mean PFI: PLD=13.3m, T+D=10.6m. To provide a better estimate of the true treatment effect of adding T to PLD, a multivariate analysis adjusted for key prognostic factors (including PFI) was performed which demonstrated a significant improvement in OS in subjects treated with the combination (HR=0.82; 95%CI: 0.69,0.98; p=0.0285). Consistent improvement in OS was seen across all PFI subgroups, which was more pronounced in 6-12PFI subgroup (Table). Conclusions: T+PLD combination showed an improvement in OS in recurrent ovarian cancer compared with PLD alone. Randomized trials of T+PLD versus platinum combinations are indicated. Subgroup analysis by PFI. Subgroup by PFI (m) Median PLD (m) Median T+PLD (m) HR (95%CI) 0-6 12.3 14.2 0.94 (0.71, 1.25) 6-12 16.4 22.4 0.64 (0.47, 0.86) >12 31.7 36.5 0.83 (0.59, 1.16)

5037 Background: GOG172 demonstrated improved survival for patients (pts) with ovarian cancer treated with intraperitoneal (IP) chemotherapy, as compared with standard IV dosing. Two ongoing phase III trials have added bevacizumab (bev) to upfront treatment and the next planned GOG study has been designed to include bev in conjunction with multiple IP regimens. A pilot trial done in collaboration between Ovarian SPORE sites was undertaken to evaluate the safety, tolerability and pharmacokinetics of such a regimen. Methods: Carboplatin AUC 6 on day 1 and paclitaxel 60 mg/m2 on days 1, 8, 15 was given, IV in cycle 1 and IP in the 5 subsequent 21-day cycles. The initial IV cycle was designed to allow for intra-patient IV vs. IP pk comparison. Pts received bev 15 mg/kg IV on day 8 in cycle 2 and day 1 in cycles 3-6. Results: Trial is complete with40 evaluable pts. Pts were able to complete most of the planned treatment, with 34 pts completing all 6 cycles. There was no progressive disease on trial. Toxicity was mild with no febrile neutropenia, no grade 3-4 neuropathy, hypertension, proteinuria or renal complications. There was no delayed wound healing or bowel perforation, and a single port-related problem. Significant grade 3-4 toxicity includes: abdominal pain (5), fatigue (6), neutropenia (10), thrombocytopenia (5), nausea (4). There were 2 pulmonary emboli. The PK of paclitaxel and carboplatin have been characterized to assess the effect of Avastin on systemic drug exposure. Conclusions: This regimen appears safe. PK results confirm no negative interaction with bev. Updated results will be available. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech

5085 Background: Advanced ovarian cancer has a poor prognosis, with a 5-year survival of 25%-30%. Few studies have examined whether age influences advanced ovarian cancer patients' prognostic understanding or quality of life at the time of diagnosis. Methods: Women with advanced epithelial ovarian cancer, primary peritoneal or fallopian tube cancer were interviewed using validated measures, including: EORTC QLQ-30 (overall QOL), QLQ-V28 (ovarian cancer specific QOL), MHI-17 (anxiety, depression and global well-being), trust in physician, and fear of recurrence. Associations between patients' age, defined by the sample median, and quality of life, mental health, hopelessness, and prognostic understanding were examined. Results: Sixty-four women, age 40 to 83 were interviewed within 12 weeks of diagnosis. The median age at diagnosis was 61.3 years. There were no differences between older and younger women's self-reported QOL, overall health, anxiety, depression, or trust in their physicians. However, older women were more likely to report that they were cured (66.7% vs. 33.3%, p = 0.04), compared to younger women. Conclusions: Older women with advanced ovarian cancer are less likely to understand that their disease may be incurable. Future studies should investigate how age influences physicians' communication behaviors and patients' understanding of what is communicated. No significant financial relationships to disclose.

5060 Background: A pooled analysis of efficacy with Tr as second/third line in 295 ROC pts demonstrated a median time to progression (TTP) of 4.6 months (mo) (McMeekin, ASCO 2007). Pts sensitive to platinum with a PFI > 6 m (PS), reached a TTP of 6.0 mo, and an overall response rate (ORR) of 36.4% (45.5% in pts with ≥ 2 prior lines). This subanalysis is focused in ROC pts with partially platinum sensitive (PPS) disease, i.e. relapsing between 6-12 m after the end of last prior platinum regimen (PFI:6-12 mo). Methods: Of the 295 pts, 103 were PPS). Three Tr schedules were studied: weekly (0.58 mg/m2 3-h ×3 q4w), and two every 3 weeks (1.3 mg/m2 3-h and 1.5 mg/m2 24-h), that were administered to 41%, 34% and 25% patients, respectively. Efficacy and safety in these patients are reported. Results: Baseline characteristics: median age 58 years (35-80), ECOG PS 0/1: 72%/27%; papillary/serous histology 76%; histology grade 1-2/3: 28%/58%; liver involvement 35%. Treatment with Tr induced 4% complete responses (CR), 26% partial responses (PR), and 40% stable disease (SD); median response duration (RD:PR+CR) 5.2 mo.(95%CI: 3.9-5.8). Median TTP was 5.3 mo (95%CI: 3.8-6.2); 44% pts were progression free at 6 mo (95%CI: 34%-54%). In pts with liver metastases CR+PR was 36% with median TTP 5.3 mo (95%CI: 3.7-6.5). The most common adverse events were neutropenia and transaminase elevations, which were manageable and without serious clinical consequences. Conclusions: Tr monotherapy is active in patients with ROC, including patients with PPS disease (PFI 6-12 mo), with a 30% ORR plus 40% SD, with a median TTP of 5.3 mo. Activity was retained in pts with liver metastasis, with 36% ORR and identical TTP. These single-agent results support the findings of the randomized phase III trial OVA-301 where trabectedin + PLD demonstrated superior clinical benefit over PLD alone in the overall population with particularly pronounced efficacy in the PPS cohort. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson, PharmaMar Ortho Biotech, PharmaMar Janssen-Ortho, Zeltia-PharmaMar Ortho Biotech, PharmaMar

5015 Background: While most patients with advanced ovarian cancer respond to standard chemotherapy following surgery, relapses are common. In previous studies in patients with malignant ascites the trifunctional antibody catumaxomab demonstrated the ability to destroy EpCAM-positive tumor cells in the peritoneal cavity. This study was conducted primarily to evaluate the safety and tolerability of intraperitoneal (IP) catumaxomab in the consolidation setting for patients with minimal residual disease. Methods: 47 patients with advanced ovarian cancer (FIGO stage IIb-IV) with a complete response to standard chemotherapy were included in this single-arm study. For each patient a four-dose series of IP catumaxomab infusions was attempted, consisting of 10, 20, 50, and 150 μ g, respectively, by constant-rate 3-hour infusion. The primary objective was to assess the safety and tolerability of administering the planned catumaxomab therapy within a 21-day period. Patients were followed for safety for 90 days after treatment and then for 24 months post-study. Results: 32 patients (68.1%) received all 4 infusions, and 29 (61.7%) completed the four-dose series of catumaxomab infusions within 21 days. Among the 37 patients (78.7%) who received more than one infusion, 32 (86.5%) received all of the planned infusions. At sites where more than 2 patients were treated, 30 of 40 patients (75%) received all infusions within 21 days. All patients experienced at least 1 treatment-emergent adverse event (AE) assessed as related to study drug (731 total events). Most common AEs were nausea, pyrexia, vomiting and abdominal pain. AEs decreased with subsequent infusions; only 1 patient had a grade ≥ 3 AE after the fourth infusion. Kaplan-Meier estimates of PFS and OS at 24 months post treatment were 26.3% and 80.3%, respectively. Conclusions: IP catumaxomab appears tolerable as a consolidation regimen, with results reflecting data from other studies of this drug in early and late-stage ovarian cancer. While AEs were more frequent in this study, they were similar in nature to those in previous studies of this drug. Tolerability of the four-dose regimen was higher at sites where more patients were treated. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Fresenius Biotech, Fresenius Biotech GmbH AstraZeneca, Lilly Fresenius Biotech

e16507 Background: To estimate the anti-tumor activity of pemetrexed in patients with advanced or recurrent carcinoma of the endometrium that failed on higher priority treatment protocols and to determine the nature and degree of toxicity. Methods: A multicenter phase II trial was conducted by the Gynecologic Oncology Group (GOG). Patients must have had advanced or recurrent measurable carcinoma of the endometrium and failed one prior chemotherapy regimen. Pemetrexed at a dose of 900 mg/m2 was to be administered as an IV infusion over 10 minutes every 21 days. Results: From May 1, 2006 to July 31, 2007, 27 patients were entered by ten member institutions of the GOG. A total of 101 cycles were administered with 27% of patients receiving five or more cycles. The treatment was well tolerated overall. More serious toxicities (grade 3 and 4) included anemia in 19%, leukopenia in 38%, neutropenia in 46%, and constitutional in 19%. No treatment related deaths were reported. One patient (4%) had a partial response. Twelve patients (46%) had stable disease and eleven (46%) patients had increasing disease. Median progression-free survival (PFS) was 2.7 months and overall survival (OS) was 9.4 months. Conclusions: Pemetrexed has minimal activity in the treatment of recurrent or persistent endometrial carcinoma at the dose and schedule tested. [Table: see text]

5526 Background: In an open-label, multicenter, randomized phase III study comparing the combination of trabectedin and PLD to PLD alone in patients with relapsed ovarian cancer, the combination demonstrated significantly improved progression free survival and response rates, manageable non-cumulative toxicity, and fewer PLD-associated adverse events. We studied the impact of the combination of trabectedin with PLD on the quality of life (QoL)/patient-reported outcomes (PRO) evaluated as part of the trial. Methods: QoL/PRO questionnaires, EORTC-QLQ C30, OV28, and EQ-5D were completed by patients at screening and on Day 1 of every other treatment cycle starting with Cycle 1, and at the end-of-treatment visit. Global health status/QoL, fatigue, rain subscales from QLQ C30, and abdominal pain/GI symptoms scale from OV28 were chosen a priori for primary analyses. Other scales of the three questionnaires were analyzed on a supportive basis. Results: A total of 672 patients were randomized. 663 (98%) completed at least the baseline questionnaires. Median cycles of treatment was 6 (131 days) for the combination arm and 5 (143 days) for the monotherapy arm. Mixed effects models (using a covariance structure of AR[1]) predicting the score at baseline and follow-up scores as a function of treatment, days after baseline, and interaction between treatment and days after baseline showed no significant differences between the treatment arms for any of the prespecified scales. Similar analyses of other scales, including EQ-5D Health Index scores and Health State on the Visual Analog Scale, support the findings. Conclusions: The addition of trabectedin to PLD results in superior efficacy in patients with relapsed ovarian cancer, with no added decrement to overall health status as assessed by PRO. [Table: see text]

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.

5524 Objective: To estimate the anti-tumor activity of pemetrexed (LY231514) in patients with persistent or recurrent platinum-resistant epithelial ovarian or primary peritoneal cancer who have failed on higher priority treatment protocols and to determine the nature and degree of toxicity of pemetrexed in this cohort of patients. Methods: A multicenter cooperative group Phase II Trial was conducted by the Gynecologic Oncology Group (GOG). Patients must have had recurrent or persistent epithelial ovarian or primary peritoneal cancer and failed one prior chemotherapy regimen. Pemetrexed at a dose of 900 mg/m2 was to be administered as an IV infusion over 10 minutes every 21 days. Response was assessed by RECIST criteria. Dose adjustment was permitted for toxicity. Treatment was continued until disease progression or unacceptable adverse effects. Results: From July 6, 2004 to August 23, 2006, 51 patients were entered by 15 member institutions of the GOG. Two patients were ineligible (wrong primary, low creatinine clearance) and one did not receive treatment. A total of 259 cycles (median: 4; range 1 to 19) of pemetrexed were administered with 40% of patients receiving 6 or more cycles. Overall, the treatment was well tolerated. More serious toxicities (grade 3 and 4) included neutropenia in 42%, leukopenia in 25%, anemia in 15%, and constitutional in 15%. No treatment-related deaths were reported. One patient (2%) had a complete and nine patients (19%) had partial responses with a median duration response of 6.8 months. Seventeen patients (35%) had stable disease for a median of 4.1 months. Eighteen patients (38%) had increasing disease. Three patients (6%) were inevaluable. Median progression-free survival (PFS) was 3.0+ months and overall survival (OS) was 11.4+ months. Conclusion: Pemetrexed has demonstrated activity in the treatment of recurrent platinum resistant ovarian carcinoma at the dose and schedule tested. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Lilly Oncology Lilly Oncology

5593 Background: Platinum remains the single most effective drug for the treatment of epithelial ovarian cancer; however with relapse and re-treatment most patients eventually become resistant to these drugs. Response rates to salvage chemotherapy in this population is 10–20%, with PFS typically < 8 weeks in 4th line. One mechanism of platinum resistance is thought to be mediated by changes in the cellular redox potential. Oxidized glutathione (GSSG), the active component of NOV-002, regulates the intracellular redox state via the glutathione (GSH) pathway. This study aims to determine tolerabilty, response rate and PFS to NOV-002 with carboplatin in women with platinum resistant ovarian, tubal or peritoneal cancer. Methods: NOV-002 is given by IV bolus on lead-in day -1 at cycle 1, and on day 1 at subsequent cycles, followed by Carboplatin AUC 5. NOV-002 is then continued via daily SC injection, with 28 day cycles. Patients must be platinum refractory/resistant, with measurable disease and ≤ 3 prior lines. Fifteen patients are accrued in the first stage of the trial; if ≥ 2 responses, 10 additional patients will be accrued. Results: Stage I accrual is complete. Patients were heavily pretreated with 11/15 having received 3 prior lines. Toxicity was mild-moderate with no grade 4 toxicity. There was no febrile neutropenia. The most common toxicities were nausea and fatigue, as well as abdominal pain and bowel obstruction thought to be related to underlying disease. To date, there is 1 PR, 7 SD and 5 PD, with 1 patient off-trial for patient discretion. PFS is 14 weeks. Treatment and evaluation are ongoing, with the possibility of accrual to the second stage if another PR is seen. Conclusions: Patients tolerated this regimen extremely well, with most toxicity attributable to carboplatin alone. The PFS was longer than expected, with a significant proportion of these platinum resistant patients achieving clinical benefit with prolonged stable disease. Updated results will be available. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novelos

5523 Background: More efficacious, less toxic combinations are needed to treat platinum-sensitive recurrent ovarian cancer. Pemetrexed (Pem) is a multitargeted antifolate that has a manageable toxicity profile and has been combined with carboplatin in other cancers. Methods: Phase II study of carboplatin AUC 5 with Pem 500 mg/m2 both administered IV on day 1, with Decadron, B12, and folate premedication, and given every 21 d for six cycles with the possibility of receiving 8 if benefit derived. Eligibility included platinum sensitive (>6 mos without progression after last platinum regimen), measurable (by RECIST) recurrent ovarian, peritoneal, or fallopian tube cancer, PS ≤ 2, ≤ 2 prior regimens for recurrence, and normal bone marrow, liver/renal function. Primary objective was response rate. Other endpoints included toxicities, time to progression (TTP), and survival. A RR of ≥ 31% was considered worthy of further phase III testing. Results: 45 patients have been enrolled, and accrual is complete. 1 pt was ineligible. 3 pts withdrew before 2 cycles were completed because of grade 3 fatigue/weakness, grade 3 diarrhea and a carboplatin reaction, respectively and were not evaluated for response. 27 pts completed at least 6 cycles. No dose reductions (DR’s) were required because of toxicities in 28 of 41 pts who received at least 2 cycles. 13 pts had DR’s as a result of myelosuppression or GI toxicity; 11 had one DR and 2 had two DR’s. 44 pts are evaluable for toxicities. Grade 3 and 4 toxicities are as follows: neutropenia (19 pts), platelets (11 pts), leukopenia (7 pts), anemia (4 pts), fatigue (4 pts), nausea (2 pts), diarrhea (2 pts), dizziness (2 pts), and 1 pt each experienced hypokalemia, vomiting, constipation, anorexia, memory impairment, pulmonary embolism. 14 pts had a carboplatin allergy. No significant rashes nor mucositis occurred. 41 pts were evaluable for RR, TTP, and survival. Overall RR was 61%; 1CR (2%), 24 PR’s (59%), 14 SD (34%), and 2 PD (5%). Median TTP was 4.6 months (95% CI 3.2 -5.9) while median PFS was 7.7 months (95% CI 6.7 - 10.1). Conclusions: Carboplatin/Pem is a well-tolerated regimen with significant activity in platinum-sensitive recurrent ovarian cancer. Further testing of this regimen in this population is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Lilly Oncology

5501 Background: Angiogenesis is important for ovarian cancer growth; blocking angiogenesis can lead to ovarian cancer regression. Cediranib (AZD2171) is a highly selective and potent oral tyrosine kinase inhibitor (TKI) of VEGFR1, VEGFR2, VEGFR3, and c-Kit. Methods: CTEP-sponsored phase II study of single agent Cediranib for recurrent ovarian, peritoneal, or tubal cancer. Eligibility: up to 2 prior lines of chemotherapy for recurrence, ECOG PS of 0 or 1, and normal organ function. Primary endpoint is response rate measured either by RECIST or modified GCIG CA125 criteria; other endpoints are PFS, toxicity, and pharmacodynamic endpoints. Results: 29 patients (pts) have been enrolled thus far; 27 are evaluable. 1 pt never started. 24 pts have ovarian cancer; 5 with peritoneal cancer. Of the 28 pts receiving drug, 12 pts had plat-sensitive and 16 had plat-resistant cancer. Starting phase II dose was 45 mg PO, but because of toxicities seen in the first 11 pts, the dose was lowered to 30 mg for subsequent pts. Thus far, grade 3 toxicities include: HTN (n=13; 5 pts on 45 mg and 8 pts on 30 mg), fatigue (n=5), diarrhea (n=3), vomiting (n=2), hyponatremia (n=2), oral cavity pain (n=2), and nausea, constipation, abdominal pain, headache, and hypothyroidism (all n=1). Gr 4 toxicities include: CNS hemorrhage (1 pt., 45 mg dose), lipase (1 pt) and hypertriglyceridemia (1 pt). No cardiac toxicities, bowel perforations, fistulas have been reported. Grade 1 or 2 abnormalities of thyroid function tests were reported in 10 pts and responded to thyroxine replacement therapy. 2 pts had grade 1 thyrotoxicosis. Tumor responses: 5 pts have had confirmed PR's (2 pts with plat-sens and 3 plat-resis) lasting 8, 11, 11, 12, and 25 weeks (overall RR of 18.5%), and 3 SD lasting 30, 27+, and 24 weeks. Of the remaining 19 pts, 2 pts had 28% decrease (lasting <16 weeks) and 27% decrease in disease after 2 cycles, 1 too early, 9 were removed for toxicities, and 7 had PD. Conclusions: Cediranib is an active drug in recurrent ovarian cancer; cediranib has predictable toxicities observed with other TKI's and warrants further study. No significant financial relationships to disclose.

5517 Background: Bevacizumab is a recombinant humanized monoclonal antibody that neutralizes VEGF, but is associated with arterial complications and GI perforations in patients with advanced ovarian cancer. Maintenance antiangiogenic therapy is an attractive strategy for patients after first line therapy. However, no data exist on the safety of maintenance bevacizumab in this setting. Methods: An open label phase II clinical trial of carboplatin, paclitaxel and bevacizumab (CPB) in newly diagnosed patients =ECOG 2, with chemotherapy naïve, stage =IC, epithelial müllerian tumors. Patients receive carboplatin AUC 5 IV, paclitaxel 175 mg/m2 IV, and bevacizumab 15 mg/kg IV for 6–8 cycles D1 Q21. Bevacizumab is omitted in the first cycle, and continued as single agent for one year. Results: 58 patients are evaluable. Median age is 58 (18–77), and 39(67%) were ECOG 1. 43(74%) have ovarian, 8(14%) uterine papillary serous (UPSC) tumors, 4(7%) peritoneal, and 3(5%) fallopian tube cancers. 38(65%) were serous, 8(14%) MMMT, 4(7%) clear cell, and 3(5%) endometrioid cancers (5(9%) mixed/other). 36(62%) were stage III and 11(19%) stage IV. Surgery was optimal in 45(80%) patients. 50 patients have completed chemotherapy, associated with 2 PEs, and 2 GI perforations, all occurring during the induction chemotherapy phase of treatment. 43 patients have received 360 cycles of maintenance therapy with mild toxicity. 6(14%) have come off for PD, 4(9%) for toxicity (inc. 1 nasal perforation), 4 withdrew consent, and 3 patients asymptomatic, continue despite a rising CA125. During maintenance there has been no grade IV toxicity, and 13 grade III toxicities (musculoskeletal pain (5), dyspnea, hyperglycemia, hypertension (1 grade III, 4 grade II), infection, lymphopenia, thrombocytopenia, proteinuria, syncope). Radiographic responses were documented in 21 of 28 (75%: CR 11, PR 10). Median PFS is 11(1–21) months at 13 months median FU. Conclusion: Maintenance bevacizumab is feasible and well tolerated with mild myalgias, and hypertension common but treatable side effects. No significant financial relationships to disclose.