Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy in Adjuvant Colorectal Cancer
Condition: Colorectal Cancer; Chemotherapy-induced Peripheral Neuropathy
MeSH terms: Colorectal Neoplasms; Peripheral Nervous System Diseases
Intervention: Calmangafodipir (5 µmol/kg); Placebo
Intervention description: PledOx will be given to patients as an i.v. infusion, on top of mFOLFOX6 chemotherapy. PledOx is a solution in 20 mL single dose glass vials.; Placebo will be administered via the same route as PledOx (i.v. infusion). Placebo is a solution in 20 mL single dose glass vials.
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients with colorectal cancer (CRC), who are indicated for adjuvant modified FOLFOX6 (mFOLFOX6) chemotherapy for up to 6 months, will be randomized in a 1:1 ratio to 1 of 2 treatment arms:
Arm A: PledOx (5 µmol/kg) + mFOLFOX6 chemotherapy
Arm B: Placebo + mFOLFOX6 chemotherapy
Masking: Triple (Participant, Care Provider, Investigator)
Masking description: Double-blind, placebo-controlled
Enrollment: 301.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: colorectal cancer; cancer; peripheral neuropathy; neuropathy

Summary:

      This study is to evaluate PledOx for prevention of chronic chemotherapy induced peripheral
      neuropathy induced by oxaliplatin in patients with Stage III or high-risk Stage II colorectal
      cancer (CRC).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Signed informed consent form before any study related assessments and willing to
             follow all study procedures.

          2. Male or female aged ≥18 years.

          3. Pathologically confirmed adenocarcinoma of the colon or rectum including: Stage III
             carcinoma (any T N1,2 M0) or Stage II carcinoma (T3,4 N0 M0).

          4. The patient has undergone curative (R0) surgical resection performed within 12 weeks
             prior to randomization

          5. The patient has a postsurgical carcinoembryonic antigen (CEA) level ≤1.5 x upper limit
             of normal (ULN, in current smokers, CEA level ≤2.0 x ULN is allowed).

          6. No prior anti-cancer therapy for CRC except radiotherapy or concomitant
             chemo-radiotherapy using a fluoropyrimidine alone for locoregional rectal cancer.

          7. Patient indicated for up to 6 months of oxaliplatin-based chemotherapy and without
             pathological findings of a neurologic exam performed prior to oxaliplatin treatment
             according to local practice.

          8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          9. Adequate hematological parameters: hemoglobin ≥100 g/L, absolute neutrophil count ≥1.5
             x 109 /L, platelets ≥100 x 109 /L.

         10. Adequate renal function: creatinine clearance >50 cc/min using the Cockcroft and Gault
             formula or measured.

         11. Adequate hepatic function: total bilirubin ≤1.5 x ULN (except in the case of known
             Gilbert's syndrome); aspartate aminotransferase (AST) and alanine aminotransferase
             (ALT) ≤3 x ULN.

         12. Baseline blood manganese (Mn) level <2.0 x ULN.

         13. For patients with a history of diabetes mellitus, HbA1c ≤7%.

         14. Negative pregnancy test for women of child-bearing potential (WOCBP).

         15. For men and WOCBP, use of adequate contraception (oral contraceptives, intrauterine
             device or surgically sterile) while on study drug and for at least 6 months after
             completion of study therapy.

        Exclusion Criteria:

          1. Any evidence of metastatic disease.

          2. Any unresolved toxicity by National Cancer Institute-Common Terminology Criteria for
             Adverse Events Version (NCI-CTCAE) v.4.03 >Grade 1 from previous anti-cancer therapy
             (including radiotherapy), except alopecia.

          3. Any grade of neuropathy from any cause.

          4. Any evidence of severe or uncontrolled systemic diseases (e.g., unstable or
             uncompensated respiratory, cardiac, unresolved bowel obstruction, hepatic or renal
             disease).

          5. Chronic infection or uncontrolled serious illness causing immunodeficiency. Patients
             with known history of chronic hepatitis B can be enrolled if they are asymptomatic and
             an acute and active HBV infection can be excluded.

          6. Any history of seizures.

          7. A surgical incision that is not healed.

          8. Known hypersensitivity to any of the components of mFOLFOX6 and, if applicable,
             therapies to be used in conjunction with the chemotherapy regimen or any of the
             excipients of these products.

          9. 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.

         10. Known dihydropyrimidine dehydrogenase deficiency.

         11. 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).

         12. Major psychiatric disorder (major depression, psychosis), alcohol and/or drug abuse.

         13. Patients with a history of second or third degree atrioventricular block or a family
             heredity.

         14. A history of a genetic or familial neuropathy.

         15. Treatment with any investigational drug within 30 days prior to randomization.

         16. Pregnancy, lactation or reluctance to using contraception.

         17. Any other condition that, in the opinion of the Investigator, places the patient at
             undue risk.

         18. Previous exposure to mangafodipir or calmangafodipir.

         19. Welders, mine workers or other workers in occupations (current or past) where high Mn
             exposure is likely.