Preventive Treatment of Oxaliplatin Induced Peripheral Neuropathy in Metastatic Colorectal Cancer (POLAR-M)

Oxaliplatin, in combination with 5-fluorouracil plus folinate (or capecitabine), has
increased survival in stage III colorectal cancer and prolonged life in stage IV patients,
but its use is compromised because of severe toxicity. Chemotherapy-induced peripheral
neuropathy (CIPN) is the most problematic dose-limiting toxicity of oxaliplatin. No
treatments have been clinically proven to prevent CIPN. There is a body of evidence that CIPN
is caused by cellular oxidative stress. Clinical and preclinical data suggest that the
manganese chelate and superoxide dismutase mimetic mangafodipir (MnDPDP) and calmangafodipir
(Ca4Mn(DPDP)5) are efficacious inhibitors of CIPN and other conditions caused by cellular
oxidative stress, without interfering negatively with the tumoricidal activity of
chemotherapy.

Inclusion Criteria:

- Signed informed consent form before any study related assessments and willing to
follow all study procedures.

- Male or female aged >=18 years.

- Metastatic (stage IV) CRC, pathologically confirmed adenocarcinoma of the colon or
rectum.

- No prior chemotherapy (within the previous 12 months) and/or biologic/targeted therapy
for mCRC.

- Measurable disease according to RECIST 1.1.

- Patient indicated for at least 3 months of oxaliplatin-based chemotherapy (without any
pre-planned treatment breaks) and without any clinically observed neurological
disorders.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

- Adequate hematological parameters: hemoglobin >=100 g/L, absolute neutrophil count
(ANC) >=1.5 x 10^9 /L, platelets >=100 x 10^9 /L.

- Adequate renal function: creatinine clearance >50 cc/min using the Cockroft and Gault
formula or measured.

- Adequate hepatic function: total bilirubin <=1.5 times the upper limit of normal (ULN)
(except in the case of known Gilbert's syndrome); aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) <=3 times ULN (AST and ALT <=5 times ULN in case of
liver metastases).

- Baseline blood manganese (Mn) level <2.0 times ULN.

- For patients with a history of diabetes mellitus, HbA1c <=7%.

- Negative pregnancy test for females of child-bearing potential.

- For men and females of childbearing potential, use of adequate contraception (oral
contraceptives, intrauterine device or barrier method of contraception in conjunction
with spermicidal jelly or surgically sterile) while on study drug and for at least 6
months after completion of study therapy.

Exclusion Criteria:

- Any unresolved toxicity by Common Terminology Criteria for Adverse Events Version
(CTCAE v4.03) > Grade 1 from previous anti-cancer therapy (including radiotherapy),
except alopecia.

- Any grade of neuropathy from any cause.

- Any prior oxaliplatin-based chemotherapy <1 year before the randomization.

- Any evidence of severe or uncontrolled systemic diseases (e.g., unstable or
uncompensated respiratory, cardiac, unresolved bowel obstruction, hepatic or renal
disease).

- Chronic infection or uncontrolled serious illness causing immunodeficiency.

- A surgical incision that is not healed.

- Significant hemorrhage (>30 mL/bleeding episode in previous 3 months), hemoptysis (>5
mL fresh blood in previous 4 weeks) or thrombotic event (including transient ischemic
attack) in the previous 12 months if the patient is expected to receive
anti-VEGF/VEGFR therapy.

- Known hypersensitivity to any of the components of mFOLFOX6 and, if applicable,
biological therapies to be used in conjunction with the chemotherapy regimen or any of
the excipients of these products.

- History of other malignancies (except for adequately treated basal or squamous cell
carcinoma or carcinoma in situ) within 5 years, unless the patient has been disease
free for that other malignancy for at least 2 years.

- Known dihydropyrimidine dehydrogenase deficiency.

- Pre-existing neurodegenerative disease (e.g., Parkinson's, Alzheimer's, Huntington's)
or neuromuscular disorder (e.g., multiple sclerosis, amyotrophic lateral sclerosis,
polio, hereditary neuromuscular disease).

- Major psychiatric disorder (major depression, psychosis), alcohol and/or drug abuse.

- Patients with a history of second or third degree atrioventricular block or a family
heredity.

- A history of a genetic or familial neuropathy.

- Treatment with any investigational drug within 30 days prior to randomization.

- Pregnancy, lactation or reluctance to using contraception.

- Any other condition that, in the opinion of the Investigator, places the patient at
undue risk.

- Previous exposure to mangafodipir or calmangafodipir.

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