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Randomized, Double Blind, Placebo Controlled, Cross-over Phase II Study on the Effects of Lactobacillus Rhamnosus GG Supplementation in Patients on 1st Line XELOXA Treatment for Metastatic Colorectal Cancer

Phase 2
18 Years
Open (Enrolling)
Colorectal Cancer

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Trial Information

Randomized, Double Blind, Placebo Controlled, Cross-over Phase II Study on the Effects of Lactobacillus Rhamnosus GG Supplementation in Patients on 1st Line XELOXA Treatment for Metastatic Colorectal Cancer

This is a prospective, multicenter, randomized, cross-over, double-blind, placebo-controlled
study. Patients diagnosed with advanced colorectal cancer with overt distant metastases and
who will receive chemotherapy consisting of capecitabine, oxaliplatin and bevacizumab, given
as 3-weekly cycles, will be randomly assigned to receive either lactobacilli (GefilusR) or
placebo during the first 3 cycles of chemotherapy (for 9 weeks). Following this, the groups
will be crossed over and those study participants who were allocated to lactobacilli will
receive placebo for 9 weeks, and vice versa. Lactobacilli and placebo are administered twice
daily. The total daily dose of lactobacilli is 20 billion CFU. The primary outcome measure
is frequency of moderate/severe diarrhoea (grade 2-4). Adverse effects (including the
frequency of diarrhoea, flatulence, bloating, constipation, and nausea) will be
longitudinally monitored based on a patient diary and study visits. The study will also
address safety and tolerability of chemotherapy, response to chemotherapy, progression-free
survival, resectability of liver metastases, and serum growth factor levels. A total of 84
patients are planned to be entered.

Inclusion Criteria:

- Patients with histologically confirmed diagnosis of CRC, chemotherapy naïve for
metastatic disease (prior adjuvant chemotherapy for CRC allowed), who are scheduled
to start capecitabine treatment as first line chemotherapy for metastatic disease

- Age 18 or older

- Measurable or non-measurable metastatic disease

- Performance status ECOG performance status 0-2

- Life expectancy greater than 3 months

- Thrombocytes 100,000/µL or greater, neutrophils 1.500/µl or greater, Aspartate amino
transferase/Alanine amino transferase <= 2.5 x Upper limit of normal (ULN) (< 5 x
ULN if liver metastases present), Alkaline phosphatase <=2.5 x ULN (< 5 x ULN if
liver metastases present), Serum bilirubin <= 1.5 x ULN, Serum Creatinine <= 1.5 x
ULN, Urine dipstick of proteinuria <2+ (or U-Prot <100mg/dl). Patients discovered to
have 2+ or greater proteinuria on dipstick urinalysis at baseline, must undergo a
24-hour urine collection and must have <= 1 g of protein/24 hr

- Women of childbearing potential must have a negative serum pregnancy test done prior
to the administration of bevacizumab. Patient and their partner should prevent
pregnancy (oral contraceptives, intrauterine contraceptive device, barrier method of
contraception in conjunction with spermicidal jelly or surgically sterile) up to at
least 6 months after last treatment completion or the last drug dose, whatever
happens first

- Signed written informed consent according to ICH/GCP and the local regulations
(approved by the Independent Ethics Committee [IEC]) will be obtained prior to any
study specific screening procedures

- Patient must be able to comply with the protocol

Exclusion Criteria:

- Prior treatment with first-line chemotherapy for metastatic CRC

- Adjuvant treatment with bevacizumab within 12 months

- Acute or chronic diarrhea or colostomy

- Major surgical procedure, open biopsy or significant traumatic injury within 28 days
prior to Day 0 (Patients must have recovered from any major surgery)

- Near future planned radiotherapy for underlying disease (prior completed radiotherapy
treatment allowed)

- Clinical or radiological evidence of CNS metastases

- Past or current history within the last 5 years of malignancies except for the
indication under this study and curatively treated Basal and squamous cell carcinoma
of the skin or In-situ carcinoma of the cervix

- Serious non-healing wound or ulcer

- Evidence of bleeding diathesis or coagulopathy

- Uncontrolled hypertension

- Clinically significant (i.e. active) cardiovascular disease for example
cerebrovascular accidents (≤ 6 months), myocardial infarction (≤ 6 months), unstable
angina, New York Heart Association (NYHA) grade II or greater congestive heart
failure, serious cardiac arrhythmia requiring medication

- Treatment with any investigational drug (including IMMP, EGFR inhibitors) or
participation in another investigational study within 30 days prior to enrolment

- Evidence of other disease, metabolic dysfunction, physical examination finding, or
clinical laboratory finding giving reasonable suspicion of a disease or condition
that contraindicates the treatment or patient at high risk from treatment

- Ongoing treatment with aspirin (> 325 mg/day), continuous high dose NSAIDS or other
medications known to predispose to gastrointestinal ulceration

- Pregnancy (positive serum pregnancy test) and lactation

- Any other serious or uncontrolled illness which, in the opinion of the investigator,
makes it undesirable for the patient to enter the trial

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Outcome Measure:

Effect on the treatment-related grade 2 to 4 diarrhoea

Outcome Time Frame:

18 weeks

Safety Issue:


Principal Investigator

Heikki Joensuu, M.D.

Investigator Role:

Study Director

Investigator Affiliation:

Department of Oncology, Helsinki University Central Hospital


Finland: Finnish Medicines Agency

Study ID:




Start Date:

September 2005

Completion Date:

October 2013

Related Keywords:

  • Colorectal Cancer
  • colorectal cancer
  • probiotics
  • chemotherapy
  • prevention
  • adverse effects
  • diarrhoea
  • Colorectal Neoplasms