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Rosuvastatin in the Treatment of Rectal Cancer

This study is currently recruiting participants.
Verified August 2016 by AHS Cancer Control Alberta
Sponsor:
ClinicalTrials.gov Identifier:
NCT02569645
First Posted: October 7, 2015
Last Update Posted: September 20, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Ozmosis Research Inc.
Information provided by (Responsible Party):
AHS Cancer Control Alberta
  Purpose
This study will evaluate whether the addition of Rosuvastatin to standard chemoradiation therapy for the treatment of locally advanced rectal cancer may improve the pathological response rate and survival compared to standard chemoradiation therapy alone.

Condition Intervention Phase
Rectal Cancer Drug: Rosuvastatin Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Trial of Rosuvastatin (Crestor®) Combined With Standard Chemoradiation Therapy in the Treatment of High-Risk Locally Advanced Rectal Cancer

Resource links provided by NLM:


Further study details as provided by AHS Cancer Control Alberta:

Primary Outcome Measures:
  • To determine the pathological complete response rate in patients with high-risk locally advanced rectal cancer treated with standard neo-adjuvant chemotherapy and radiation in combination with rosuvastatin. [ Time Frame: Up to 3 years ]
    The rate of post-surgical specimens that demonstrate absence of any residual invasive disease or Grade 4 (complete) histological regression using the Dworak classification.


Secondary Outcome Measures:
  • To determine the Ro resection rate [ Time Frame: Up to 3 years ]
    The rate that the surgical margins are negative of any invasive disease.

  • To determine the pathological near-complete or complete tumour response rate [ Time Frame: Up to 3 years ]
    Grade 3 (near-complete) or 4 (complete) histological regression using the Dworak classification.

  • To determine the sphincter preservation rate [ Time Frame: Up to 3 years ]
    The proportion of patients that undergo a sphincter preservation surgery versus abdominoperineal resection.

  • To determine the down staging rate [ Time Frame: Up to 3 years ]
    Proportion of patients that have a down staging of the primary tumour and/or lymph nodes; i.e. comparison between cT/N and ypT/N

  • To determine 3-year disease free survival [ Time Frame: Up to 3 years ]
    The proportion of patients alive with no clinical, radiological, or pathological evidence of rectal cancer recurrence at 3 years, starting at the time treatment was initiated. This definition includes, recurrence or relapse of rectal cancers, second primary cancer or death as events

  • To determine 3-year overall survival [ Time Frame: Up to 3 years ]
    The proportion of patients alive at 3 years, starting at the time treatment was initiated.

  • To determine the neoadjuvant rectal cancer (NAR) score [ Time Frame: Up to 3 years ]
    A surrogate endpoint of overall survival following neoadjuvant rectal cancer therapy.

  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.0. [ Time Frame: Up to 3 years ]
  • To identify the genetic biomarkers that may be both prognostic and predictive of response and toxicity to treatment. [ Time Frame: up to 3 years ]
    BRAF and KRAS genetic testing. Direct exon sequencing.

  • To identify serological biomarkers that may be both prognostic and predictive of response and toxicity to treatment. [ Time Frame: up to 3 years ]
    Changes in the levels of HMG CoA reductase pathway metabolites (Mevalonate, Ubiquinone) will also be performed using pre- and post-treatment serological markers.

  • To identify pathological biomarkers that may be both prognostic and predictive of response and toxicity to treatment. [ Time Frame: up to 3 years ]
    IHC using pre- and post FFPE tumour tissue samples. (Ki67, phopsorylated AKT, HMG CoA reductase, GGPS1 and ApopTag, p21, p27 and rhoA)

  • Tmax will be collected as pharmacokinetic data [ Time Frame: up to 3 years ]
  • Cmax will be collected as pharmacokinetic data [ Time Frame: up to 3 years ]
  • T1/2 will be collected as pharmacokinetic data [ Time Frame: up to 3 years ]
  • Dose normalized Cmax will be collected as pharmacokinetic data [ Time Frame: up to 3 years ]
  • Area under the curve (AUC) will be collected as pharmacokinetic data [ Time Frame: up to 3 years ]
  • Dose normalized AUC will be collected as pharmacokinetic data [ Time Frame: up to 3 years ]

Estimated Enrollment: 48
Study Start Date: November 2015
Estimated Study Completion Date: May 2021
Estimated Primary Completion Date: November 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single Arm - Rosuvastatin
This is a single arm, of Rosuvastatin (Crestor®) 40 mg orally daily starting 2 weeks prior to the initiation of radiation at week 1 and stopped 4 weeks after the completion of radiation at the start of week 12 or 13, depending on whether 25 or 30 fractions of radiotherapy are given.
Drug: Rosuvastatin
40 mg rosuvastatin orally once per day with or without food, swallowed whole (not chewed, crushed or divided) starting 2 weeks prior to the initiation of radiation therapy and stopped at 4 weeks after the completion of radiation. Total duration of Rosuvastatin is 11 weeks if 25 fractions of radiotherapy are given, or 12 weeks if 30 fractions of radiotherapy are given.
Other Name: Crestor

Detailed Description:

The standard treatment of locally advanced rectal cancer involves neoadjuvant chemoradiation therapy (CRT) followed by surgery and further adjuvant chemotherapy. The pathologic complete responses associated with neoadjuvant CRT are 10-20%. The prognosis of patients undergoing neoadjuvant CRT is associated to the extent of post-treatment tumour regression, the final primary tumour stage and presence of involved lymph nodes in the surgical specimen. This data suggests that treatments that enhance the pathological response may result in improvements in survival.

Overwhelming preclinical and clinical evidence suggests that statins demonstrate anticancer properties and sensitize cancer tissues and protects normal tissues to the effects of radiation. Hence, the investigators hypothesize that the addition of rosuvastatin to standard CRT for the treatment of locally advanced rectal cancer may improve the pathological response rate. This protocol describes an open-label single-arm phase 2 study designed to test this hypothesis. Moreover, this study will also identify genetic, serological, and pathological biomarkers that may be both prognostic and predictive of response and toxicity to treatment.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Clinical stage 2-3 rectal adenocarcinoma, cT3/4N0/M0 or Tx N1-2/M0, within 5 cm of anal verge or less than 12cm from anal verge and threatened circumferential resection margin (≤3mm). Patients must have histological confirmation of rectal adenocarcinoma prior to registration.
  2. Patients must be 18 years or older.
  3. Able to swallow oral medication.
  4. Previous surgery, not for primary treatment of current rectal cancer, is permitted provided that wound healing has occurred and at least 14 days have elapsed prior to registration if surgery was major.
  5. ECOG 2 or less.
  6. Laboratory Requirements (must be done within 7 days prior to registration):

    a. Hematology: i. Hemoglobin ≥90 g/L ii. Granulocytes (AGC) ≥ 1.5 x 109/L iii. Platelets ≥ 100 x 109/L b. Chemistry: i. Bilirubin ≤1.5 x UNL ii. ALT or AST ≤ 1.5 x UNL iii. Proteinuria ≤ grade 1 iv. Thyroid function within normal limits (TSH or free T4 within normal limits after correction) v. CPKs ≤ ULN, vi. Urinary myoglobin within normal limits Note: If serum creatinine is abnormal, a creatinine clearance should be calculated and be ≥ 60 ml/min.

  7. Women must be post-menopausal, surgically sterile or use two reliable forms of contraception if of child-bearing potential. Women of childbearing potential must have a urine pregnancy test taken and proven negative within 7 days prior to registration. Men must be surgically sterile or use an effective barrier method of contraception if sexually active with a woman of child-bearing potential. Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose.
  8. Patient consent must be obtained according to local Institutional and/or University Human Experimentation Committee requirements. It will be the responsibility of the local participating investigators to obtain the necessary local clearance. The patient must sign the consent form prior to registration. The consent form for this study must contain a statement, which gives permission for the sponsor and monitoring agencies to review patient records.
  9. Patients must be accessible for treatment and follow-up. Patients registered on this trial must be treated and followed at the participating centre. This implies there must be reasonable geographical limits (for example: 1 1⁄2 hours driving distance) placed on patients being considered for this trial. Investigators must assure themselves the patients registered on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.

Exclusion Criteria:

  1. Patients of Asian ethnicity (having Filipino, Chinese, Japanese, Korean, Vietnamese, or South Asian origin) will be excluded due to increased risk of toxicity.
  2. Previous and concurrent, experimental, chemotherapy, or radiotherapy treatment for primary rectal carcinoma.
  3. Statin exposure in the last 5 years.
  4. Known evidence of distant metastatic disease on staging investigation, including a CT of the chest, abdomen, and pelvis performed within 6 weeks prior to registration.
  5. Known history of previous malignancy, except adequately treated non-melanoma skin cancer or other solid tumour treated curatively with no evidence of disease for >5 years.
  6. Patients with malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease significantly affecting gastrointestinal (GI) function.
  7. Patients with a known history of documented upper GI bleeding or upper GI ulcerative disease.
  8. Patients with hyperlipidemia with clinical indication for statin therapy or other prescribed medication (determination of acceptable fasting lipid values should be in accordance with current dyslipidemia management guidelines).
  9. Patients with inadequately treated hypothyroidism, as determined by the investigator.
  10. Patients with a known history of myopathy or rhabdomyolysis.
  11. Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic cardiac dysfunction.
  12. Deemed by the physician to be at low risk for recurrence.
  13. No other non-malignant systemic disease that would preclude rosuvastatin administration or prolonged follow-up.
  14. Concurrent chronic use of NSAIDs.
  15. Concurrent chronic drug therapy with cyclosporine, colchicine, coumarin anticoagulants, amiodarone, gemfibrozil, other lipid-lowering therapies (e.g., fibrates or niacin), lopinavir/ritonavir, azole antifungals, and macrolide antibiotics.
  16. Known personal or family history of hereditary neuromuscular disorders.
  17. Known previous history of muscular toxicity with another HMG-CoA reductase inhibitor.
  18. Known history of alcohol abuse.
  19. Any known condition that could affect absorption of study oral drugs (capecitabine and rosuvastatin).
  20. Known contraindication to statin.
  21. Pregnant or nursing.
  22. Patients with symptomatic inflammatory bowel disease.
  23. Patients with uncontrolled hypothyroidism.
  24. Patients with chronic liver or disease.
  25. Patients with unexplained elevated serum transaminases exceeding 3x ULN.
  26. Patients known to be suffering from infection with HIV, Tuberculosis, Hepatitis C or Hepatitis B.
  Contacts and Locations
Information from the National Library of Medicine

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): NCT02569645


Contacts
Contact: Jose Monzon, PhD MD FRCPC (403) 521-3196 jose.monzon@albertahealthservices.ca
Contact: Devey Page, RN (403) 521-3769 devey.page@albertahealthservices.ca

Locations
Canada, Alberta
Tom Baker Cancer Centre Recruiting
Calgary, Alberta, Canada, T2N 4N2
Sponsors and Collaborators
AHS Cancer Control Alberta
Ozmosis Research Inc.
Investigators
Principal Investigator: Jose Monzon, PhD MD FRCPC Tom Baker Cancer Centre
  More Information

Responsible Party: AHS Cancer Control Alberta
ClinicalTrials.gov Identifier: NCT02569645     History of Changes
Other Study ID Numbers: OZM-064
First Submitted: September 24, 2015
First Posted: October 7, 2015
Last Update Posted: September 20, 2016
Last Verified: August 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by AHS Cancer Control Alberta:
Rectal cancer
Rosuvastatin

Additional relevant MeSH terms:
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Rosuvastatin Calcium
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors