Phase I Study of a Statin + Erlotinib for Advanced Solid Malignancies With Focus on Squamous Cell Carcinomas and NSCLC
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|ClinicalTrials.gov Identifier: NCT00966472|
Recruitment Status : Completed
First Posted : August 27, 2009
Last Update Posted : April 21, 2020
|Condition or disease||Intervention/treatment||Phase|
|Squamous Cell Carcinoma Non-Small Cell Lung Cancer||Drug: Erlotinib + Rosuvastatin||Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||24 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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.|
|Study Start Date :||March 2009|
|Actual Primary Completion Date :||September 2014|
|Actual Study Completion Date :||September 2014|
Experimental: Erlotinib + Rosuvastatin
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.
Drug: Erlotinib + Rosuvastatin
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.
- 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. [ Time Frame: Within 6 months ]To determine the RPTD of rosuvastatin
- To determine the safety, tolerability, toxicity profile, dose limiting toxicities and PK profile of rosuvastatin and erlotinib when given as combination therapy. [ Time Frame: Within 6 months ]To determine the safety, tolerability, toxicity profile, dose limiting toxicities
- To perform preliminary assessment of the anti-tumor activity of rosuvastatin in combination with erlotinib in patients with measurable disease. [ Time Frame: Within one year ]To perform preliminary assessment of the anti-tumor activity
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00966472
|The Ottawa Hospital Cancer Centre|
|Ottawa, Ontario, Canada, K1H 8L6|
|Principal Investigator:||Glenwood Goss, MD, FRCPC||Ottawa Hospital Research Institute|