Phase I Study of a Statin + Erlotinib for Advanced Solid Malignancies With Focus on Squamous Cell Carcinomas and NSCLC

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Ozmosis Research Inc.
Information provided by (Responsible Party):
Ottawa Hospital Research Institute
ClinicalTrials.gov Identifier:
NCT00966472
First received: August 26, 2009
Last updated: February 17, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Squamous Cell Carcinoma
Non-Small Cell Lung Cancer
Drug: Erlotinib + Rosuvastatin
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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.

Resource links provided by NLM:


Further study details as provided by Ottawa Hospital Research Institute:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: No ]

Estimated Enrollment: 45
Study Start Date: March 2009
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Other Names:
  • Tarceva
  • Crestor

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically documented advanced and/or metastatic incurable tumor (especially squamous cell carcinoma or NSCLC).
  • Clinically or radiologically documented (measurable or evaluable)disease.
  • 18 years or older and less than 70 years of age.
  • ECOG performance status: 0, 1 or 2
  • No previous therapy with EGFR inhibitor (monoclonal antibody or TKI).
  • Must have recovered from any treatment related toxicities prior to registration.
  • Curative radiotherapy must be completed at least 3 months prior to registration
  • Palliative radiotherapy is permitted providing a minimum of 14 days have elapsed between the end of radiotherapy and registration onto the study and patients have recovered from any acute toxic effects from radiation prior to registration.
  • Previous surgery is permitted provided wound healing has occurred and at least 14 days have elapsed prior to registration if surgery was major.
  • Adequate hematopoietic, hepatic and renal function defined as follows: hemoglobin >= 90g/L, platelets > 100 x 10^9/L, bilirubin <1.5 x ULN, ALT or AST <1.5 x ULN, proteinuria < grade 1, normal thyroid function (normal TSH or free T4 level after correction), serum creatinine institution normal limits or calculated creatinine clearance > 60 mls/min (except for patients with cervical cancer who require a creatinine clearance of 72 mls/min.)
  • Women must be post menopausal, surgically sterile or use two reliable forms of contraception. Women of childbearing potential must have a serum or urine pregnancy test taken and proven negative within 7 days prior to registration. Men must be surgically sterile or use a barrier method of contraception
  • Accessible for repeat dosing and follow-up

Exclusion Criteria:

  • Asian ethnicity (Filipino, Chinese, Japanese, Korean, Vietnamese, or South Asian origin)
  • History of other malignancies, except adequately treated non-melanoma skin cancer or other solid tumors curatively treated with no evidence of disease for > 5 years.
  • Untreated brain or meningeal metastases. Patients with treated and radiologic or clinical evidence of stable brain metastases are eligible providing that they are asymptomatic and do not require corticosteroids (must have discontinued steroids at least 4 weeks prior to registration).
  • Untreated and/or uncontrolled cardiovascular conditions and/or symptomatic cardiac dysfunction.
  • Active or uncontrolled infections or with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol.
  • Concurrent treatment with other experimental drugs or anti-cancer therapy.
  • Patients who require oral anticoagulants (coumadin, warfarin) are eligible provided there is strict vigilance with respect to monitoring INR. The investigator should consider switching these patients to LMW heparin or an oral anti-platelet agent such as aspirin
  • Patients who are taking concomitant medications, which are highly protein bound, nephrotoxic, or which are known strong inhibitors or inducers of the hepatic p450 (especially CYP3A4) system, which have not been discontinued prior to study registration. Caution should be exercised, and patients monitored closely, for patients taking concomitant drugs with the potential to inhibit or induce the hepatic p450 (especially CYP3A4) system.
  • Any use of hypocholesterolemia agent such as niacin, fibrates or any statin should be discontinued at least 7 days prior to study registration.
  • Personal or family history of hereditary muscular disorders
  • Previous history of muscular toxicity with another HMG-CoA reductase inhibitor
  • Alcohol abuse
  • Any condition that could affect absorption of study oral drugs (erlotinib and rosuvastatin)
  • Inflammatory bowel disease
  • Uncontrolled hypothyroidism
  • Chronic liver disease (ex: biliary sclerosis)
  • Suffering from infection with HIV, Tuberculosis, Hepatitis C or Hepatitis
  • Inability to give written, informed consent prior to study participation.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00966472

Locations
Canada, Ontario
The Ottawa Hospital Cancer Centre
Ottawa, Ontario, Canada, K1H 8L6
Sponsors and Collaborators
Ottawa Hospital Research Institute
Ozmosis Research Inc.
Investigators
Principal Investigator: Glenwood Goss, MD, FRCPC Ottawa Hospital Research Institute
  More Information

No publications provided

Responsible Party: Ottawa Hospital Research Institute
ClinicalTrials.gov Identifier: NCT00966472     History of Changes
Other Study ID Numbers: 2007908-01H (OTT 08-07)
Study First Received: August 26, 2009
Last Updated: February 17, 2014
Health Authority: Canada: Health Canada

Keywords provided by Ottawa Hospital Research Institute:
Rosuvastatin
Erlotinib
Squamous Cell Carcinoma
Nom-Small Cell Lung Cancer

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Non-Small-Cell Lung
Carcinoma, Squamous Cell
Lung Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Neoplasms, Squamous Cell
Rosuvastatin
Erlotinib
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Enzyme Inhibitors
Lipid Regulating Agents
Therapeutic Uses
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on August 28, 2014