AMG 386 combined with weekly paclitaxel was tolerable, with a manageable and distinct toxicity profile. The data suggest evidence of antitumor activity and a dose-response effect, warranting further studies in ovarian cancer.

Purpose Etirinotecan pegol (NKTR-102) is a unique, long-acting topoisomerase-I inhibitor with prolonged systemic exposure to SN38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan. This randomized phase II trial investigated two dosing schedules of etirinotecan pegol in patients with platinum-resistant/refractory ovarian carcinoma. Patients and Methods A total of 71 eligible patients were randomly assigned to receive etirinotecan pegol 145 mg/m2 every 14 or 21 days until progression or unacceptable adverse events (AEs). The primary end point was objective response rate (ORR) by RECIST (version 1.0). Secondary end points included response by Gynecologic Cancer Intergroup criteria, duration of ORR, progression-free survival (PFS), and overall survival (OS). Results The overall confirmed ORR was 20% (95% CI, 10% to 30%): 20% for once every 14 days, and 19% for once every 21 days. Median response duration was 4.1 months for once every 14 days and 4.0 months for once every 21 days. Median PFS for every 14 and every 21 days was 4.1 and 5.3 months, respectively, and median OS was 10.0 and 11.7 months, respectively. Etirinotecan pegol was well tolerated, with the most common grade 3 to 4 AEs being dehydration (24%) and diarrhea (23%). Diarrhea, dehydration, nausea, and neutropenia were less frequent with the schedule of once every 21 days than with that of once every 14 days. Conclusion Both schedules of etirinotecan pegol showed activity in patients with heavily pretreated ovarian cancer, with encouraging ORR and PFS rates. The schedule of once every 21 days was better tolerated and had slightly longer PFS and OS rates. The treatment schedule of etirinotecan pegol 145 mg/m2 once every 21 days was selected for the expanded phase II study and is preferred for future phase III studies. These findings provide support to directly compare etirinotecan pegol versus one of the approved drugs (eg, pegylated liposomal doxorubicin or topotecan) in platinum-resistant ovarian cancer.

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Objective. To examine the tolerability and antitumor activity of trebananib plus pegylated liposomal doxorubicin (PLD) or topotecan in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer.Methods. In this open-label phase 1b study, patients received trebananib 10 mg/kg or 15 mg/kg IV QW plus PLD 50 mg/m 2 (cohorts A1 and A3, respectively) or topotecan 4 mg/m 2 (cohorts B1 and B3, respectively). Endpoints were dose-limiting toxicity (DLT; primary); treatment-emergent adverse events (AEs), overall response rate, anti-trebananib antibodies, and pharmacokinetics (secondary).Results. 103 patients were enrolled. One patient in A1 and B1 had DLTs. Across all cohorts, the most common AEs were nausea, fatigue, and peripheral edema. Across both trebananib plus PLD cohorts (A1/A3), grade 4 AEs were pulmonary embolism, disease progression, and anemia. Two patients had grade 5 intestinal perforation (n = 1) and sudden death (n = 1). Across both trebananib plus topotecan cohorts (B1/B3), grade 4 AEs were neutropenia, hypokalemia, decreased granulocyte count, chest pain, dyspnea, decreased neutrophil count, and pulmonary embolism. Two patients had grade 5 disease progression. One patient had grade 5 pleural effusion associated with progressive disease. Confirmed objective response rates were 36.0% (A1), 34.8% (A3), 16.7% (B1), and 0.0% (B3). Median progression-free survival duration (months) was 7.4 (A1), 7.1 (A3), 3.5 (B1), and 3.1 (B3), respectively. No drug-drug interactions were apparent.

Ovarian Cancer Treatment Algorithm Ovarian Cancer 1st-line therapy Carboplatin/paclitaxel iv Platinum-sensitive (relapse > 12 mo) Platinum partiallysensitive (relapse 6-12 mo) Platinum-resistant / refractory (relapse < 6 mo / progression during) Evaluate surgery (prim or IDS) PLD/carbo, gemcitabine/carbo, paclitaxel/carbo progression during) PLD, topotecan, … Wkly carbo/paclitaxel Re-challenge: Platinum-based combination chemotherapy paclitaxel/carbo, PLD (MITO-8/ENGOT-ov1) trabectedin/PLD Wkly carbo/paclitaxel Experimental drugs Vergote I , 2009, adapted from the NICE Guidelines

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5560 Background: Volociximab (V), a chimeric monoclonal antibody with direct antitumor effects, blocks α5β1 binding to fibronectin and induces apoptosis in proliferating endothelial cells. A Phase I/II study was performed to evaluate PLD with/without V in patients (pts) with recurrent ovarian or primary peritoneal cancer that relapsed after platinum/taxane-based chemotherapy (maximum 2 prior lines). Methods: A 3-arm adaptive randomization design compared efficacy and safety of PLD (40 mg/m2 q4wk) + V (15 mg/kg q2wk or qwk) vs. PLD alone. Pts were stratified by platinum sensitivity and received treatment until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Pharmacokinetic (PK) and pharmacodynamic effects were also evaluated. Results: There were 6 iterations of adaptive randomization based on accumulating PFS data. 127 pts were randomized: 66 in Group A (PLD), 34 in Group B (PLD+V [q2wk]), and 27 in Group C (PLD+V [qwk]). The incidence of AEs was balanced across treatment groups. The most common Grade 3/4 AEs (≥5% in any group) were abdominal pain, intestinal obstruction, ascites, fatigue, hypoalbuminemia, and cytopenias. Based on preclinical data, therapeutic levels of V were maintained during treatment, and V did not appear to alter the PK of PLD. Response rates were comparable across groups. There were no CRs; PRs were 16%, 18%, and 19%. The median PFS estimates were 193, 164, and 221 days. Conclusions: The safety profile of V+PLD appeared similar to PLD alone. Preliminary analysis of PFS suggested that there was a low probability of detecting a statistically significant difference in favor of V+PLD, so the study was closed to enrollment. Analyses correlating PFS with platinum sensitivity and α5β1 tumor expression are ongoing. [Table: see text]

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