A Phase I, Dose Finding Study of the Combination of High-dose Statin Agent (Rosuvastatin) With Erlotinib in Patients With Advanced Solid Malignancies, With a Focus on Squamous Cell Carcinomas and NSCLC.
Cytotoxic chemotherapy remains the mainstay of anti-cancer medical treatment for the vast
majority of patients with locally advanced or metastatic squamous cell cancers. However,
curative success remains low and most patients eventually succumb to the disease or its
complications. Moreover, cytotoxic chemotherapy is frequently associated with severe
unwanted side effects. Therefore, in this patient population the unmet therapeutic need is
high and new treatment is required.
Statins are drugs which inhibit the cellular mevalonate pathway and are conventionally used
in the treatment of hypercholesterolemia in cardiovascular disorders. Increasing evidence
suggests that statins might be used for cancer prevention/treatment through their
interactions with essential cellular functions, such as cell proliferation and
differentiation. Recent in vitro data indicate that statins induce growth arrest and
apoptosis, inhibit secretion of proteolytic enzymes, reduce invasiveness and inhibit
angiogenesis. These effects contribute to the reduction of tumor growth and metastases in
preclinical in vivo models of a variety of tumors suggesting that statins may be useful in
anticancer therapy. Studies previously performed by our group demonstrated that targeting
the mevalonate pathway can induce tumor specific cytotoxicity in a number of tumor types
that included squamous cell carcinomas, myeloid leukemia and a variety of pediatric cancers.
Additionally, several clinical trials have also assessed the antitumor activity of statins.
Pre-clinically, we have demonstrated additive cytotoxic effects when combining lovastatin
with tyrosine kinase inhibitors of the Epidermal Growth Factor Receptor (EGFR) in HNSCC
cells (AG1478) and in 8 squamous cell carcinomas (gefitinib). Mechanistically, lovastatin
treatment inhibited EGF induced EGFR autophosphorylation by 24hrs and showed co-operative
targeting of the EGFR in combination with gefitinib. Taken together, these results
demonstrate that targeting the mevalonate pathway can inhibit EGFR function and suggest the
potential utility of combining these classes of drugs (i.e. an EGFR tyrosine kinase
inhibitor and a statin).
The use of lovastatin is not optimal due to greatly enhanced toxicity with drugs such as
gefitinib and erlotinib that are simultaneously metabolized by the same enzyme (cytP450A4).
In contrast, rosuvastatin a relatively novel potent mevalonate pathway inhibitor is not
metabolized significantly by cytP450A4. Due to the enhanced clinical activity of erlotinib
in comparison to other EGFR tyrosine kinase inhibitors, the combination of erlotinib and
rosuvastatin appears ideal.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the RPTD of rosuvastatin given orally daily x 3 weeks then 1 week off (28-day cycle) in combination with erlotinib given orally daily in patients with advanced solid tumors, especially squamous cell carcinomas and NSCLC.
Within 6 months
Glenwood Goss, MD, FRCPC
Ottawa Hospital Research Institute
Canada: Health Canada
2007908-01H (OTT 08-07)