Trial Information

A Phase II Study Evaluating the Toxicity and Efficacy of Single Agent Lenalidomide (Revlimid®) in Chemotherapy-Naïve Androgen-Independent Prostate Cancer Patients

The standard of care in patients with androgen independent prostate cancer (AIPC) is
debated. Systemic chemotherapy has shown a survival advantage with a Taxotere-based
regimen, but this therapeutic approach is associated with significant toxicity and
morbidity. Furthermore, some patients with AIPC are asymptomatic with minimal disease
burden making systemic chemotherapy a less attractive option. Identifying active agents
that are effective in this patient population is of vital importance, as this may delay the
need to chemotherapy, palliate symptoms, delay progression, and potentially prolong
survival. Acceptable approaches in this setting include vaccine therapies, targeted agents,
immunotherapy, or non-taxotere based chemotherapeutic programs. Targeted therapy is of
particular interest as this usually avoids side effects of chemotherapy by attacking tumor
cells and sparing normal tissue. Ongoing research continues to identify pathways by which
the prostate cancer cells become refractory to androgen blockade. During the development of
prostate cancer, cell survival depends primarily on the androgen receptor, which is bound to
heat shock proteins in the cytoplasm. The active metabolite of testosterone, namely
dihydrotestosterone (DHT) binds to the receptor relocating it to the nucleus where it
dimerizes, activating transcription genes that are involved in the growth and survival of
the cancer cell. Plausible etiologies for the development of hormone resistance and
continued cell growth despite adequate castration include changes in antigen receptor
expression, changes in the receptor structure, and changes in androgen receptor function
with more than one mechanism contributing to this resistance. Several investigators have
shown that the androgen receptor gene is the only gene that is consistently up regulated
during tumor progression. This increase in androgen receptor mRNA and protein was both
necessary and sufficient to convert prostate cancer growth from hormone-sensitive to
hormone-refractory, and was dependent on a functional ligand-binding domain. Consequently,
one can divide mechanisms of androgen resistance into those that involve the androgen
receptor and those that do not.Pathways involving the androgen receptor allow for prostate
cancer progression through amplification or mutations of the receptor, deregulation of
growth factors or cytokines, and alteration of activators. Amplification of the androgen
receptor gene leads to enhanced activation of that receptor even at lower levels of
androgens. In addition, mutations in the receptor gene allow for activation of the receptor
by different ligands. Peptide growth factors, such as insulin-like growth factor,
keratinocyte growth factor, epidermal growth factor, and interleukin-6 (IL 6) can activate
the antigen receptor independent of androgens.Deregulation of the apoptotic genes is another
important pathway in AIPC development. PTEN tumor suppressor gene (Phosphatase and Tensin
Homologue) is mutated in AIPC allowing for the loss of the inhibitory effect that it usually
exhibits on the phosphatidylinositol 3-kinase pathway, causing overproduction of akt
allowing for cell survival to continue. Another deregulated proapoptotic oncogene, namely
bcl-2 allows for cell survival and eventually progression of disease. It has been postulated
for years that tumors need an alternative source of nutrients once they outgrow their own
supply. Folkman suggested that an angiogenic switch takes place, which accelerates tumor
proliferation. Inhibiting tumor proangiogenic factors without affecting normal vasculature
has become an attractive theory to inhibit tumor growth. Since prostate cancer, like other
malignancies, require blood vessel formation to develop metastases, finding methods that
would disrupt this process became of paramount importance. Two separate studies have shown
that elevated levels of the vascular endothelial growth factor (VEGF) correspond with
advanced stage, progression, and poor survival in prostate cancer. Since VEGF is a major
regulator of angiogenesis; a process that is increased in AIPC and since VEGF also
correlates with increased microvessel density as well as prognosis, a logical step was to
evaluate the activity of VEGF inhibitors and other anti-angiogenesis agents in AIPC.
Lenalidomide (Revlimid®) is an analogue of thalidomide that has demonstrated enhanced
immunomodulatory properties and a more favorable toxicity profile. The fact that AIPC
depends on angiogenesis and lack of appropriate immune reaction to malignant cells and the
fact that Revlimid® exhibits its activity by inhibiting angiogenesis with appropriate
immunomodulation, makes this agent an attractive option to study in this disease
setting.Several investigations suggested activity with thalidomide in AIPC but most studies
were in patients who have failed systemic chemotherapy. In addition, Revlimid® has been
shown in phase I trials to be safe, less toxic and more tolerable than Thalidomide, with
potential activity. This study aims at evaluating the toxicity and efficacy of Revlimid® in
AIPC patients who are chemotherapy-naive.