| General information |
| Database: | DB00718 |
| Objective: | To determine doselimiting toxicities (DLTs), recommendedphase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5fluorouracil and leucovorin (LV5FU2). |
| Authors: | Van Cutsem E, et al |
| Title: | Phase I doseescalation study of intravenous aflibercept administered in combination with irinotecan, 5fluorouracil and leucovorin in patients with advanced solid tumours. |
| Journal: | Eur J Cancer. |
| Year: | 2013 |
| PMID: | 22921183 |
| Trial Design |
| Clinical Trial Id: | NA |
| Agent: | aflibercept
|
| Target: | Vascular endothelial growth factor receptor 2
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | com |
| Therapeutic Combination Type: | 2 |
| Therapeutic Combination Content: | aflibercept administered + irinotecan, 5fluorouracil and leucovorin |
| Study Type: | an openlabel, sequential cohort, doseescalation study |
| Key Patients Feature: | Key eligibility criteria included men or nonpregnantwomen aged P18 years with histologically or cytologically confirmed solid malignancy with metastatic orunresectable disease for which no standard therapyexisted but for which irinotecan and 5fluorouracil andleucovorin (LV5FU2) was considered appropriate; Eastern Cooperative Oncology Group (ECOG) performancestatus 62; adequate haematological, hepatic and renalfunction; obtention of informed consent. |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | patients with advanced solid tumours received aflibercept 2, 4, 5, or 6 mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2 weeks. |
| Primary End Point: | DLTs and the recommended phase II trial dose (RPTD) |
| Secondary End Point: | pharmacokinetics, the safety profile, any aflibercept immunogenicity and preliminary antitumour activity during the study period |
| Patients Number: | 38 |
| Trial Results |
| DLT_MTD: | Two grade 3/4 afliberceptassociated DLTs occurred with 4 mg/kg: proteinuria lasting >2 weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6 mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. |
| Objective Response Rate: | Nine patients had partial responses, five with 4 mg/kg. Twentytwo patients had stable disease (five with 4 mg/kg), lasting >3 months in 17 patients. |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4 mg/kg. Twentytwo patients had stable disease (five with 4 mg/kg), lasting >3 months in 17 patients. No antiaflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4 mg/kg. |
| Conclusions: | Based on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4 mgkg was selected as the RPTD with irinotecan and LV5FU2 every 2 weeks. |