TY - JOUR
T1 - Phase 1-2 study of docetaxel plus aflibercept in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer
AU - Coleman, Robert L.
AU - Duska, Linda R.
AU - Ramirez, Pedro T.
AU - Heymach, John V.
AU - Kamat, Aparna A.
AU - Modesitt, Susan C.
AU - Schmeler, Kathleen M.
AU - Iyer, Revathy B.
AU - Garcia, Michael E.
AU - Miller, Debbie L.
AU - Jackson, Edward F.
AU - Ng, Chaan S.
AU - Kundra, Vikas
AU - Jaffe, Robert
AU - Sood, Anil K.
N1 - Funding Information:
This study was supported in part by grants from the US National Institutes of Health ( CA083639, CA098258 ) and Department of Defense ( W81XWH-10-1-0158 ), the Gynecologic Cancer Foundation, the Marcus Foundation, the Commonwealth Foundation, the Betty Anne Asche Murray Distinguished Professorship (AKS), and the Ann Rife Cox Chair in Gynecology (RLC). Sanofi Aventis supported some of the costs of the phase 2 monitoring, oversight, and data collecting.
Funding Information:
This clinical trial was mainly funded by the US National Institutes of Health, which supplied the investigational drug, held the multicentre investigational new drug application, and was the primary contact for trial amendments and toxicity reporting. Funding from the US Department of Defense, the Marcus Foundation, the Gynecologic Cancer Foundation, and the Commonwealth Foundation supported the translational elements, pharmacokinetic testing, and dynamic imaging. Sanofi-Aventis supported some of the costs for the phase 2 multisite monitoring, oversight, and data collection. Regeneron was responsible for analysis and interpretation of pharmacokinetic data in phase 1. The corresponding author had access to all the data and the final decision to submit for publication.
PY - 2011/11
Y1 - 2011/11
N2 - Background: Biologically targeted therapies have been postulated as a viable strategy to improve outcomes for women with ovarian cancer. We assessed the safety, tolerance, pharmacokinetics, relevant circulating and image-derived biomarkers, and clinical activity of combination aflibercept and docetaxel in this population. Methods: For the phase 1 (pharmacokinetic) study, eligible patients had measurable, recurrent or persistent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with a maximum of two prior chemotherapy regimens. Aflibercept was administered intravenously over three dose levels (2, 4, or 6 mg/kg; one dose every 21 days) to identify the maximum tolerated dose for the phase 2 study. Pharmacokinetics were assessed and dynamic imaging was done during a lead-in phase with single-agent aflibercept (cycle 0) and during combination therapy with intravenous docetaxel (75 mg/m 2). Eligibility for the phase 2 study was the same as for phase 1. Patients were enrolled in a two-stage design and given aflibercept 6 mg/kg intravenously and docetaxel 75 mg/m 2 intravenously, every 3 weeks. The primary endpoint was objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors version 1.0. The trial has completed enrolment and all patients are now off study. The trial is registered at ClinicalTrials.gov, number NCT00436501. Findings: From the phase 1 study, the recommended phase 2 doses of aflibercept and docetaxel were found to be 6 mg/kg and 75 mg/m 2, respectively. Log-linear pharmacokinetics (for unbound aflibercept) were observed for the three dose levels. No dose-limiting toxicities were noted. 46 evaluable patients were enrolled in the phase 2 trial; 33 were platinum resistant (15 refractory) and 13 were platinum sensitive. The confirmed ORR was 54% (25 of 46; 11 patients had a complete response and 14 had a partial response). Grade 3-4 toxicities observed in more than two patients (5%) were: neutropenia in 37 patients (80%); leucopenia in 25 patients (54%); fatigue in 23 patients (50%); dyspnoea in ten patients (22%); and stomatitis in three patients (7%). Adverse events specifically associated with aflibercept were grade 1-2 hypertension in five patients (11%), and grade 2 proteinuria in one patient (2%). Interpretation: Combination aflibercept plus docetaxel can be safely administered at the dose and schedule reported here, and is associated with substantial antitumour activity. These findings suggest that further clinical development of this combination in ovarian cancer is warranted. Funding: US National Cancer Institute, US Department of Defense, Sanofi-Aventis, Gynecologic Cancer Foundation, Marcus Foundation, and the Commonwealth Foundation.
AB - Background: Biologically targeted therapies have been postulated as a viable strategy to improve outcomes for women with ovarian cancer. We assessed the safety, tolerance, pharmacokinetics, relevant circulating and image-derived biomarkers, and clinical activity of combination aflibercept and docetaxel in this population. Methods: For the phase 1 (pharmacokinetic) study, eligible patients had measurable, recurrent or persistent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with a maximum of two prior chemotherapy regimens. Aflibercept was administered intravenously over three dose levels (2, 4, or 6 mg/kg; one dose every 21 days) to identify the maximum tolerated dose for the phase 2 study. Pharmacokinetics were assessed and dynamic imaging was done during a lead-in phase with single-agent aflibercept (cycle 0) and during combination therapy with intravenous docetaxel (75 mg/m 2). Eligibility for the phase 2 study was the same as for phase 1. Patients were enrolled in a two-stage design and given aflibercept 6 mg/kg intravenously and docetaxel 75 mg/m 2 intravenously, every 3 weeks. The primary endpoint was objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors version 1.0. The trial has completed enrolment and all patients are now off study. The trial is registered at ClinicalTrials.gov, number NCT00436501. Findings: From the phase 1 study, the recommended phase 2 doses of aflibercept and docetaxel were found to be 6 mg/kg and 75 mg/m 2, respectively. Log-linear pharmacokinetics (for unbound aflibercept) were observed for the three dose levels. No dose-limiting toxicities were noted. 46 evaluable patients were enrolled in the phase 2 trial; 33 were platinum resistant (15 refractory) and 13 were platinum sensitive. The confirmed ORR was 54% (25 of 46; 11 patients had a complete response and 14 had a partial response). Grade 3-4 toxicities observed in more than two patients (5%) were: neutropenia in 37 patients (80%); leucopenia in 25 patients (54%); fatigue in 23 patients (50%); dyspnoea in ten patients (22%); and stomatitis in three patients (7%). Adverse events specifically associated with aflibercept were grade 1-2 hypertension in five patients (11%), and grade 2 proteinuria in one patient (2%). Interpretation: Combination aflibercept plus docetaxel can be safely administered at the dose and schedule reported here, and is associated with substantial antitumour activity. These findings suggest that further clinical development of this combination in ovarian cancer is warranted. Funding: US National Cancer Institute, US Department of Defense, Sanofi-Aventis, Gynecologic Cancer Foundation, Marcus Foundation, and the Commonwealth Foundation.
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U2 - 10.1016/S1470-2045(11)70244-3
DO - 10.1016/S1470-2045(11)70244-3
M3 - Article
C2 - 21992853
AN - SCOPUS:81255185158
SN - 1470-2045
VL - 12
SP - 1109
EP - 1117
JO - The lancet oncology
JF - The lancet oncology
IS - 12
ER -