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Randomized Phase II Trial of Seribantumab in Combination With Paclitaxel in Patients With Advanced Platinum-Resistant or -Refractory Ovarian Cancer.

ABSTRACT: Purpose Seribantumab is a fully human immunoglobulin G2 monoclonal antibody that binds to human epidermal growth factor receptor (HER) 3 (ErbB3), blocking heregulin (HRG) -mediated ErbB3 signaling and inducing ErbB3 receptor downregulation. This open-label randomized phase II study evaluated progression-free survival (PFS) with seribantumab in combination with once-per-week paclitaxel compared with paclitaxel alone in patients with platinum-resistant or -refractory ovarian cancer. A key secondary objective was to determine if any of five prespecified biomarkers predicted benefit from seribantumab. Patients and Methods Patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned at a ratio of two to one to receive seribantumab plus paclitaxel or paclitaxel alone. Patients underwent pretreatment core needle biopsy; archival tumor samples were also obtained to support biomarker analyses. Results A total of 223 patients were randomly assigned (seribantumab plus paclitaxel, n = 140; paclitaxel alone, n = 83). Median PFS in the unselected intent-to-treat population was 3.75 months with seribantumab plus paclitaxel compared with 3.68 months with paclitaxel alone (hazard ratio [HR], 1.027; 95% CI, 0.741 to 1.425; P = .864). Among patients whose tumors had detectable HRG mRNA and low HER2 (n = 57 [38%] of 151 with available biomarker data), increased treatment benefit was observed in those receiving seribantumab plus paclitaxel compared with paclitaxel alone (PFS HR, 0.37; 95% CI, 0.18 to 0.76; P = .007). The HR in patients not meeting these criteria was 1.80 (95% CI, 1.08 to 2.98; P = .023). Conclusion The addition of seribantumab to paclitaxel did not result in improved PFS in unselected patients. Exploratory analyses suggest that detectable HRG and low HER2, biomarkers that link directly to the mechanism of action of seribantumab, identified patients who might benefit from this combination. Future clinical trials are needed to validate this finding and should preselect for HRG expression and focus on cancers with low HER2 levels.

SUBMITTER: Liu JF

PROVIDER: S-EPMC5562430 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Randomized Phase II Trial of Seribantumab in Combination With Paclitaxel in Patients With Advanced Platinum-Resistant or -Refractory Ovarian Cancer.

Liu Joyce F JF Ray-Coquard Isabelle I Selle Frederic F Poveda Andrés M AM Cibula David D Hirte Hal H Hilpert Felix F Raspagliesi Francesco F Gladieff Laurence L Harter Philipp P Siena Salvatore S Del Campo Josep Maria JM Tabah-Fisch Isabelle I Pearlberg Joseph J Moyo Victor V Riahi Kaveh K Nering Rachel R Kubasek William W Adiwijaya Bambang B Czibere Akos A Naumann R Wendel RW Coleman Robert L RL Vergote Ignace I MacBeath Gavin G Pujade-Lauraine Eric E

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20161023 36

Purpose Seribantumab is a fully human immunoglobulin G2 monoclonal antibody that binds to human epidermal growth factor receptor (HER) 3 (ErbB3), blocking heregulin (HRG) -mediated ErbB3 signaling and inducing ErbB3 receptor downregulation. This open-label randomized phase II study evaluated progression-free survival (PFS) with seribantumab in combination with once-per-week paclitaxel compared with paclitaxel alone in patients with platinum-resistant or -refractory ovarian cancer. A key secondar ...[more]

PMID: 27998236

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Project description:BACKGROUND:Olaratumab is a platelet-derived growth factor receptor-? (PDGFR?)-targeting monoclonal antibody blocking PDGFR? signaling. PDGFR? expression is associated with a more aggressive phenotype and poor ovarian cancer outcomes. This randomized, open label phase II study evaluated olaratumab plus liposomal doxorubicin compared with liposomal doxorubicin alone in advanced ovarian cancer patients. METHODS:Patients with platinum-refractory or platinum-resistant advanced ovarian cancer were randomized 1:1 to receive liposomal doxorubicin (40?mg/m2, intravenous infusion) administered every 4?weeks with or without olaratumab (20?mg/kg, IV infusion) every 2?weeks. Patients were stratified based on prior response to platinum therapy (refractory vs resistant). The primary efficacy endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, duration of response, and safety. RESULTS:A total of 123 patients were treated (62 olaratumab+liposomal doxorubicin; 61 liposomal doxorubicin). Median PFS was 4.2?months for olaratumab+liposomal doxorubicin and 4.0?months for liposomal doxorubicin (stratified hazard ratio [HR]?=?1.043; 95% confidence interval [CI] 0.698-1.558; p?=?0.837). Median OS was 16.6?months and 16.2?months in the olaratumab+liposomal doxorubicin and liposomal doxorubicin arms, respectively (HR?=?1.098; 95% CI 0.71-1.71). In the platinum-refractory subgroup, median PFS was 5.5?months (95% CI 1.6-9.2) and 3.7?months (95% CI 1.9-9.2) in the olaratumab+liposomal doxorubicin (n?=?15) and liposomal doxorubicin arms (n?=?16), respectively (HR?=?0.85; 95% CI 0.38-1.91). Overall, 59.7% (olaratumab+liposomal doxorubicin) and 65.6% (liposomal doxorubicin) of patients reported grade???3 adverse events regardless of causality. The most common treatment-emergent adverse events (all grades) regardless of causality were fatigue related (61%), nausea (57%), and constipation (52%) with olaratumab+liposomal doxorubicin and nausea (64%), fatigue related (62%), and mucositis (46%) with liposomal doxorubicin. CONCLUSIONS:The addition of olaratumab to liposomal doxorubicin did not result in significant prolongation of PFS or OS in platinum-resistant or platinum-refractory ovarian cancer. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT00913835 ; registered June 2, 2009.

Project description: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/m(2) 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/m(2) 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.

Project description:Purpose To determine the maximum tolerated dose (MTD) of F14512, a topoisomerase II inhibitor designed to target cancer cells through the polyamine transport system, (three-hour daily infusion given for 3 consecutive days every 3 weeks) in platinum-refractory or resistant ovarian cancer. Other objectives were safety, pharmacokinetics (PK), PK/pharmacodynamics relationship, and efficacy. Methods This was an open-label, dose-escalation, multicenter phase I study. Results Eleven patients were enrolled and were treated at dose levels (DLs) of 10 and 5 mg/m2/day. All patients received the 3 injections per cycle as per study protocol (median, 1 cycle (Ferlay et al. Int J Cancer 136:E359-386, 2015; Siegel et al. CA Cancer J Clin 65:5-29, 2015; Oronsky et al. Med Oncol 34:103, 2017; Barret et al. Cancer Res 68:9845-9853, 2008; Ballot et al. Apoptosis 17:364-376, 2012; Brel et al. Biochem Pharmacol 82:1843-1852, 2011; Gentry et al. Biochemistry 50:3240-3249, 2011; Kruczynski et al. Investig New Drugs 29:9-21, 2011; Chelouah et al. PLoS One 6:e23597, 2011)) with no dose reductions. At DL 10 mg/m2/day, 6 dose-limiting toxicities (DLTs) were reported (3/4 evaluable patients: 2 grade 3 febrile neutropenia, 1 grade 4 neutropenia lasting at least 7 days, 1 grade 3 nausea, 1 decreased appetite, and 1 grade 3 asthenia). At dose 5 mg/m2/day, 2 DLTs were reported (2/6 treated patients: 2 grade 3 febrile neutropenia). Both DLs were defined as MTD. Stable disease was reported as best overall response in 2 (40%) patients having both received 9 cycles, one at each DL. 90.9% of patients experienced grade 4 neutropenia, but for only one (9.1%) it was reported as a serious adverse event. Conclusion Although there was some encouraging efficacy signal, grade 4 neutropenia led to complications and it was decided to stop the study. A DL below 5 mg/m2/day was not tested as this would not allow reaching the minimum serum concentration needed for the pharmacological activity of the drug.

Dataset Information

Randomized Phase II Trial of Seribantumab in Combination With Paclitaxel in Patients With Advanced Platinum-Resistant or -Refractory Ovarian Cancer.

Publications

Randomized Phase II Trial of Seribantumab in Combination With Paclitaxel in Patients With Advanced Platinum-Resistant or -Refractory Ovarian Cancer.

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