A phase I study of the combination of oxaliplatin/docetaxel and vandetanib for the treatment of advanced gastroesophageal cancer.

Abstract

e14644 Background: Metastatic gastroesophageal carcinoma is a devastating illness and there is a strong need for improved therapies incorporating novel targeted agents, such as anti-angiogenic agents into active chemotherapy programs. We set out to assess the safety and tolerability of the dual VEGFR/EGFR inhibitor, vandetanib (V) in combination with two active chemotherapeutic agents in this illness, oxaliplatin (O) and docetaxel (D). Methods: Phase I study (NCT00732745) with a standard 3+3 dose escalation design with the primary aim to determine the MTD of V added to OD chemotherapy in advanced GE cancer. GE cancer pts with either adeno or squamous cell histology were eligible with adequate organ function and ECOG PS of 0-1. Patients could not have received prior chemotherapy for advanced disease. Results: Initial treatment for the first cohort consisted of O at 100mg/m2 day 1, D at 35 mg/m2 days 1, 8 and V 100 mg PO QD of 21-day treatment cycles. Due to DLT reached in 2/3 patients in cohort 1 (one grade 3 and one grade 4 diarrhea/dehydration), 6 patients were treated then at dose level -1 (O 80 mg/m2 day 1, D 30 mg/m2 days 1,8, V 100 mg PO QD days 1-21). At dose level -1 no further DLTs were noted and the combination overall was well-tolerated with expected hematological toxicities and one grade 3 episode of anorexia noted and this dose was assessed as MTD and RP2D. All enrolled patients had adenocarcinoma histology. At dose level 1, 1/3 documented PR and 2SD and at dose level -1 2/6 SD and 1 documented CR was noted (the patient with CR completed 8 cycles of therapy and continues in CR on maintenance V). 3/6 had PD as best response at dose level -1. The median number of cycles received was 4 (range 2-8+). Conclusions: The MTD of the combination of oxaliplatin/docetaxel and vandetanib is O 80 mg/m2 day1, D 30 mg/m2 days 1,8 and V 100 mg PO QD and the DLT is gastrointestinal toxicity, such as diarrhea and concomitant dehydration. At this dose the regimen has manageable toxicity and shows promising activity in the management of advanced gastroesophageal carcinoma. This study was supported by an ISS research grant from Aventis and investigational drug by AstraZeneca.