A Trial of PledOx + FOLFOX6 Compared to Placebo + FOLFOX6 in Patients With Metastatic Colorectal Cancer

Globally, nearly 800 000 colorectal cancers are believed to occur annually. Approximately
about half of the patients with colorectal cancer develop metastatic disease. These patients
are often offered chemotherapy with the FOLFOX6 regimen (FOL = FOLic acid; F = Fluorouracil
(5-FU); OX = OXaliplatin) The use of FOLFOX6 is, however, hampered by a high incidence and
severity of adverse reactions.

In the current trial patients will receive the antioxidant agent PledOx in one of two
different doses, or placebo, in the first 8 cycles of FOLFOX6 treatment.

Inclusion Criteria:

- Advanced metastatic colorectal (stage IV) cancer verified by biopsy

- Patients may have received up to three previous treatment lines of chemotherapy, which
may include fluoropyrimidine, irinotecan and targeted therapies. The last dose of
antitumor drug must be given at least 4 weeks prior to inclusion and all toxicity
(except alopecia and fatigue) resolved. Patients may also be chemotherapy-naïve, have
received prior adjuvant treatment but no previous treatment with oxaliplatin

- CT-scan or MRI of thorax, abdomen and pelvis; within ≤4 weeks before start of
chemotherapy

- Evaluable disease and one measurable site of disease according to RECIST 1.1 criteria
(at least 10mm for CT-scan or MRI)

- Neurological examination with no significant pathological findings

- ≥18 years

- WHO performance status 0≤2 and Life expectancy ≥ 3 months

- Adequate haematological function, Hb ≥ 100 g/L, ANC ≥ 1.5 x 109/L, platelets ≥ 100 x
109/L

- Adequate renal and hepatic functions: creatinine clearance >50 cc/min, total bilirubin
≤ 1.5 times ULN, ASAT and ALAT ≤ 3 times ULN (ASAT and ALAT ≤ 5 times ULN in case of
liver metastases)

- INR ≤1.5 times ULN, unless receiving therapeutic anticoagulation

- Negative pregnancy test for females of child-producing potential

- Written informed consent given

Exclusion Criteria:

- Tumours other than colorectal adenocarcinomas (within the previous 5 years) except for
curatively treated non melanoma skin cancer or in situ carcinoma of the cervix

- Evidence of central nervous system metastases

- Unresolved bowel obstruction or sub-obstruction, uncontrolled Crohn's disease or
ulcerative colitis

- History of cardiac disease with a New York Heart Association (NYHA) Class II or
greater congestive heart failure, myocardial infarction or unstable angina in the past
six (6) months prior to Day 1 of treatment and serious arrhythmias requiring
medication for treatment

- Prolonged QTC interval >450 msec

- Known history of stroke or cerebrovascular accident in the past six (6) months

- Severe diarrhoea

- Chronic infection or uncontrolled serious illness causing immunodeficiency

- Any uncontrolled serious illness or medical condition

- Received mangafodipir at any time

- Welders, mine workers or other workers in occupations (current or past) where high
manganese exposure is likely

- Pre-existing neurodegenerative disease (Parkinson's, Alzheimer's, Huntington's etc.)
or neuromuscular disorder (Multiple sclerosis, Amyotrophic lateral sclerosis, Polio,
hereditary neuromuscular disease)

- Major psychiatric disorder (major depression, psychosis)

- Participation in another clinical study with an investigational medicinal product
within 1 month prior to inclusion.

- Blood manganese concentration values >18.3 μg/L at screening