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

Phase 2

• Conditions: Colorectal cancer; Systemic Inflammation; Cancer - Bowel - Back passage (rectum) or large bowel (colon); Inflammatory and Immune System - Other inflammatory or immune system disorders

• Registration Number: ACTRN12614000133639
• Lead Sponsor: niversity of Sydney

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2014-02-05
• Last Update Posted: 13 January 2020

Recruitment & Eligibility

• Status: ot yet recruiting
• Sex: All
• Target Recruitment: 10

Inclusion Criteria

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 Criteria

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.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Toxicity: Incidence of serious Grade 3 or 4 toxicity graded according to NCI CTCAE version 4.03[until tumour progression (anticipated to be <12 months)]

Secondary Outcome Measures

Name	Time	Method
Feasibility<br>- recruitment rates will be assessed using screening/enrollment logs collected at each recruitment site <br>- study drug adherence will be assessed using patient diaries, monthly Medicines Adherence Report Scale and pharmacy records. [6 months];Quality of Life will be assessed by EuroQoL 5D and EORTC QolC30 questionnaires[12 weeks ];Changes in inflammatory biomarkers<br>- IL-6 and IL-8 will be assessed by plasma ELISA assays<br>- WBC and differential will be assessed by full blood count<br>- Myeloid derived suppressor cell phenotype will be assessed by whole blood flow cytometry assays<br>- inflammatory plasma protein will be assessed by mass spectroscopy and western blot assays.[12 weeks]