Not Yet RecruitingPhase 2ACTRN12614000133639

The STRICT pilot study - Simvastatin Therapy for Reducing Inflammation in Colorectal cancer Trial

In metastatic colorectal cancer patients with systemic inflammation, is daily simvastatin feasible and safe to add to standard chemotherapy?

Sponsor

University of Sydney

Enrollment

10 participants

Start Date

Apr 1, 2014

Study Type

Interventional

Conditions

Systemic Inflammation

Summary

The aim of this study is to assess the safety and feasibility of adding simvastatin to standard first-line chemotherapy regimens in untreated, metastatic colorectal cancer (CRC) patients with elevated inflammatory biomarkers. Who is it for? You may be eligible to join this study if you are aged 18 years or above and have been diagnosed with metastatic colorectal cancer with evidence of systemic inflammation. You must also be eligible for standard first-line chemotherapy regimens in accordance with local standards of care and pharmaceutical benefits scheme approvals. Study details All participants in this study will receive standard first line therapy, as chosen by their treating medical oncologist. In addition, participants will be asked to take a daily 40mg dose of simvastatin orally in the evening from the first day of chemotherapy until tumour progression or patient is withdrawn from treatment due to clinician or patient decision. Participants will be monitored for treatment toxicity and inflammation, and will also be asked to complete a questionnaire at 6 months to evaluate quality of life. The feasibility of the trial methods will also be evaluated in order to determine whether they could be used in a larger randomised clinical trial (RCT).

Eligibility

Sex: Both males and femalesMin Age: 18 Yearss

Inclusion Criteria26

Patients must fulfill ALL of the following criteria to be eligible for admission to the study:
Radiological or pathologically confirmed metastatic colorectal cancer
Measurable or evaluable disease
Eligible for XELOX, mFOLFOX6, or FOLFIRI plus bevacizumab in accordance with local standards of care and pharmaceutical benefits scheme approvals
Evidence of systemic inflammation - NLR > or = 5
WHO performance status of 0, 1 or 2
Adequately recovered from recent surgery. At least 4 weeks must have elapsed from major surgery.
Life expectancy of > 3 months
Hematology performed within 28 days of starting study treatment and with values within the ranges specified below
Absolute granulocytes/neutrophils > 1.5 x 109 /L
Platelets > 100 x 109/L
Hemoglobin > 80g/L
Biochemistry performed within 28 days of starting study treatment and with values within the ranges specified below
Total bilirubin < 1.5 x institutional upper limit of normal (< 2.0 x with documented liver metastases)
ALT < 2.5 x institutional upper limit of normal (< 5.0 x with documented liver metastases)
AST < 2.5 x institutional upper limit of normal (< 5.0 x with documented liver metastases)
Serum creatinine < 1.5 x institutional upper limit of normal or Creatinine Clearance > 50ml/min
Magnesium > 0.5mM (1.2 mg/dL)
Creatine phosphokinase < 2.5 x institutional upper limit of normal
Patient must consent to provision of access to a representative formalin fixed paraffin block of tumour tissue for future research studies to be conducted. Where no previously resected or biopsied tumour tissue exists the patient may still be eligible for the study.
Patient must consent to provision of blood samples.
Age over 18 years
Patient consent for trial participation must be obtained according to local Institutional Human Research Ethics Committee (HREC) requirements.
Patients must be accessible for treatment and follow-up.
The patient is not receiving therapy in a concurrent clinical study that involves systemic therapy or radiotherapy. The patient may enroll in biomarker studies and psychosocial studies.
Patient agrees not to seek statin therapy during and/or after the completion of the study.

Exclusion Criteria22

Patients who fulfill any of the following criteria are not eligible for admission to the study:
Prior chemotherapy for metastatic colorectal cancer or adjuvant chemotherapy completed in the last 6 months
Radiotherapy within 28 days prior to enrolment or not recovered from a radiotherapy course
A history of other malignancies with the exception of: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence for > 3 years.
Evidence of bleeding diathesis or significant coagulopathy (in absence of therapeutic anticoagulation). History of a significant bleeding event or felt by the investigator to be at risk of such events.
Significant vascular disease (e.g. aortic aneurysm requiring surgical intervention).
Peripheral arterial thrombosis or other arterial thrombotic events within 6 months
prior to commencement of study treatment.
Inadequately controlled hypertension (defined as values consistently 150/100 mmHg despite use of at least three standard antihypertensive medications).
Prior history of hypertensive crisis or hypertensive encephalopathy.
Clinically significant (i.e. active) cardiovascular disease (e.g. NYHA Class II or greater congestive heart failure).
Pregnant or lactating females (a serum pregnancy test to be assessed within 7 days prior to study treatment, or within 14 days with a confirmatory urine pregnancy test within 7 days prior to study treatment).
Women of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) not using appropriate method of contraception and not willing to use an effective method of contraception during the study and for 6 months after the last dose of study medication. Oral or injectable contraceptive agents cannot be the sole method of contraception.
Male patients must be surgically sterile or agree to use a barrier method of contraception.
Any condition (e.g. psychological, geographical etc) that does not permit compliance with the protocol.
Presence of active inflammatory bowel disease, infection or rheumatological condition.
Previous history or current evidence of rhabdomyolsis or myopathy.
Receipt of the investigational drug, simvastatin, or member of the statin class of drugs within the last 28 days
Receipt of regular dosing of NSAIDs for a period of 2 weeks or more (excluding 8mg dexamethasone used for preventing hypersensitivity reactions) or corticosteroids (dose > 10 mg/day methylprednisolone equivalent).
History of allergy to simvastatin or other statin drugs.
Currently taking contraindicated medications of simvastatin (CYP3A4 or OATP1B1 inhibitors). Simvastatin is a CYP3A4 and OATP1B1 substrate that has demonstrated clinically relevant drug interactions with other known CYP3A4 and OATP1B1 substrates, inhibitors and inducers. Warfarin is a weak substrate for CYP3A4 and use of warfarin as anticoagulant should be undertaken only with caution and close monitoring of INR and consideration should be given to switching the patient to low molecular weight heparin for the duration of the study.
Patients who are not able to swallow tablets.

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Interventions

Participants will receive standard first line chemotherapy, as chosen by their treating medical oncologist. In addition, participants will be asked to take a daily 40mg dose of simvastatin orally in the evening from the first day of chemotherapy until tumour progression or patient is withdrawn from treatment due to clinician or patient decision. Adherence to medication will be conducted using patient diaries, completion of a monthly Medication Adherence Record Scale-5 questionnaire, and pharmacy records.