Ficlatuzumab and Cetuximab in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC)
Status:
Completed
Trial end date:
2018-02-01
Target enrollment:
Participant gender:
Summary
The epidermal growth factor receptor (EGFR) is both oncogene and prognostic biomarker in head
and neck squamous cell carcinoma (HNSCC). EGFR's functional importance in HNSCC resulted in
development of the first molecularly targeted strategy, the anti-EGFR monoclonal antibody
cetuximab. Given the lack of therapeutic options for patients with recurrent/metastatic HNSCC
after failure of cetuximab, there is strong scientific interest in understanding resistance
in order to identify new therapies for this population. A possible resistance mechanism to
anti-EGFR therapy in HNSCC is primary or compensatory activation of alternate growth factor
receptors including c-Met. The MET oncogene encodes c-Met, an RTK bound exclusively by the
ligand, hepatocyte growth factor (HGF). The HGF/c-Met signaling pathway converges with the
EGFR network at both the PI3K/Akt and MAPK nodes. Laboratory data suggest the ability for
reciprocal compensation between EGFR and c-Met. We hypothesize that HGF/c-Met pathway
inhibition may overcome resistance to cetuximab in patients with HNSCC, such as those with
clinical cetuximab resistance.
Ficlatuzumab (AV-299) is a humanized HGF-inhibitory immunoglobulin G1 (IgG1) monoclonal
antibody. The primary objective of this phase 1b study is to find the recommended phase II
dose (RP2D) of the combination of ficlatuzumab and cetuximab in patients with
recurrent/metastaticHNSCC. The dose-finding study design will follow a Narayana k-in-a-row
design with k set to 2 to target a 33% rate of dose-limiting toxicity (DLT). In the
dose-finding phase, a total of 8 patients will be treated if no DLTs are observed or 14
patients if at least one DLT occurs. An expansion cohort will then proceed at RP2D until 12
patients have been treated at that dose level with the combination of ficlatuzumab and
cetuximab. We will evaluate biomarkers of HGF/cMet pathway activation in baseline tissue,
plasma and immune cells for a preliminary relationship with clinical activity.