Phase 1/2 Study of Lenalidomide and Cetuximab in Patients With Advanced Solid Tumors
Background: For metastatic cancer such as head and neck, lung and colorectal cancer,
standard therapy comprises chemotherapy regimen partially in combination with monoclonal
antibodies blocking the vascular endothelial growth factor (VEGF) or the epidermal growth
factor receptor (EGFR). When disease progression occurs during or after these treatment
options have been applied, no established therapy is available and the clinical development
of new strategies is warranted. Lenalidomide (Revlimid®) is a thalidomide derivative and
belongs to the so-called ImiDs, a class of immunostimulatory molecules. IMiDs have profound
effects on the immune system. Obviously, IMiDs are able to function as co-stimulatory
molecule for mature T cells. In addition, IMiDs are able to mitigate the negative effects of
CTLA-4 signalling. On the molecular level, IMiDs induce phosphorylation of CD28, underlining
the concept that they act as costimulatory signals during T cell activation. Furthermore,
the induction of specific CTL responses by dendritic cells (DC) is enhanced and the activity
of suppressive regulatory T cells (Treg) inhibited.
In addition to their effects on cells of the adaptive immune system, IMiDs also target the
innate immune response. Natural killer cells (NK) as well as natural killer T-cells (NKT)
are activated by Immunomodulatory Drugs (IMiDs), and the effects of IMiDs on NK and NKT
cells might further contribute to the immune-activating properties of ImiDs.
Therefore the rationale of the combination of lenalidomide with a therapeutic IgG1 antibody
such as cetuximab (Erbitux®) is based on the fact that several reports suggest a role of
antibody-dependent cellular cytotoxicity (ADCC) as a mode of action of cetuximab.
However, the exact definition of these anti-cancer mechanisms of lenalidomide alone and in
combination with cetuximab in vivo require further investigation in early clinical trials.
The goal of this phase I/II trial is to define the toxicity of the combination of
lenalidomide and cetuximab and to study potential effects on the tumor and the immune
Subjects meeting all inclusion criteria will be enrolled in cohorts of three patients to
receive a single, oral dose of lenalidomide administered on Days 1-28 and intravenous (IV)
infusions of cetuximab (400 mg/m2 first infusion only, then 250 mg/m2 subsequently)
administered on Days 1, 8, 15, and 22 of each 28-day cycle.
Prior to combination therapy, there will be a 21 day lead in treatment period with
lenalidomide monotherapy (Days -21 to -1). Combination treatment will start at Day 1. Tumor
biopsies will be taken before monotherapy lenalidomide treatment (between d-25 and -22) and
between Day -3 and -1 (before starting cetuximab). A third tumor biopsy will be taken
between Cycle 1 Day 21 and 28 after starting combination therapy. Cycles will be repeated
every 28 days. All subjects will continue on study drug until disease progression,
unacceptable toxicity or treatment discontinuation for any other reason. The MTD of
lenalidomide will be defined as the highest dose level at which no more than 1 out of 6
subjects experience a dose-limiting toxicity (DLT) during the first cycle of administration
in combination with cetuximab. Safety measurements and analysis will be performed at each
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose
Determination of the maximum tolerated dose (MTD) of lenalidomide administered in combination with cetuximab. For each cohort of subjects (3 patients), the decision of whether or not to dose-escalate will be made after subjects have received the first treatment cycle of study drug. Once 2 subjects have experienced DLT, enrollment at that dose will end and that dose will be declared to have exceeded the MTD.
on the end of every treatment cycle (28 day-cycles).
Heinz Zwierzina, Prof. Dr.
Medical University of Innsbruck, Deparmtment of Internal Medicince I