Phase I Study of a Statin + Erlotinib for Advanced Solid Malignancies With Focus on Squamous Cell Carcinomas and NSCLC
Condition: Squamous Cell Carcinoma; Non-Small Cell Lung Cancer
MeSH terms: Carcinoma; Carcinoma, Squamous Cell
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to determine the recommended phase II dose (RP2D) of
      rosuvastatin that can be given in combination with standard erlotinib treatment in patients
      with advanced incurable squamous cell cancer and NSCLC.
    

Detailed description: 
      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.
    

Intervention name(s): Erlotinib + Rosuvastatin
Intervention type(s): Drug
Intervention description(s): Patients will receive Erlotinib 150mg po daily. They will also receive Rosuvastatin at escalating dose levels starting at 1mg/kg po daily for 3 weeks, followed by a 1-week rest period. Patients may continue to receive rosuvastatin and erlotinib in the absence of disease progression or unacceptable toxicity.
Other intervention name(s): Tarceva; Crestor
Intervention MeSH terms: Erlotinib Hydrochloride; Rosuvastatin Calcium
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Rosuvastatin; Erlotinib; Squamous Cell Carcinoma; Nom-Small Cell Lung Cancer