Preventive Treatment of Oxaliplatin Induced Peripheral Neuropathy in Metastatic Colorectal Cancer (POLAR-M)
Condition: Colorectal Cancer; Chemotherapy-induced Peripheral Neuropathy
MeSH terms: Colorectal Neoplasms; Peripheral Nervous System Diseases
Intervention: Calmangafodipir (2 µmol/kg); Calmangafodipir (5 µmol/kg); Placebo
Intervention description: Solution in 20 mL single dose glass vials; Solution in 20 mL single dose glass vials; Solution in 20 mL single dose glass vials
Intervention MeSH terms: Pyridoxal Phosphate; Edetic Acid
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a Phase 3, multicenter, double-blind, placebo-controlled study to establish the efficacious dose of PledOx in prevention of chronic chemotherapy induced peripheral neuropathy (CIPN) induced by oxaliplatin.
Patients with metastatic colorectal cancer (mCRC), who are indicated for first-line modified FOLFOX6 (mFOLFOX6) chemotherapy for at least 3 months, without any pre-planned treatment breaks, will be randomized in a 1:1:1 ratio, stratified by region (Asia, non-Asia) and PK sub-study (yes, no) to one of three treatment arms:
Arm A: PledOx (2 µmol/kg) + mFOLFOX6 chemotherapy
Arm B: PledOx (5 µmol/kg) + m
Arm C: Placebo + mFOLFOX6 chemotherapy
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 291.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Metastatic; Colorectal; Cancer; Metastatic Colorectal Cancer; Oxaliplatin induced CIPN; CIPN; Oxaliplatin

Summary:

      This study evaluates the investigational drug PledOx in the prevention of chronic
      chemotherapy induced peripheral neuropathy (CIPN) induced by the drug oxaliplatin.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Signed informed consent form before any study related assessments and willing to
             follow all study procedures.

          -  Male or female aged >=18 years.

          -  Non-resectable 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 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.

          -  Any history of seizures.

          -  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.