Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy in Adjuvant Colorectal Cancer

Study Overview
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Brief Summary
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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).

Detailed Description
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This is a Phase 3, multicenter, double-blind, placebo-controlled study with PledOx for prevention of chronic CIPN induced by oxaliplatin in patients with Stage III or high-risk Stage II colorectal cancer (CRC). Patients with 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 Before March 2nd., 2020, the investigational medicinal product (IMP; i.e. PledOx or placebo) was administered by an intravenous (i.v.) infusion on the first day of each chemotherapy cycle. IMP was not to be administered if mFOLFOX6 was not given to the patient. If a patient later discontinues oxaliplatin, treatment with 5-FU/folinate and IMP may be continued. As of March 2nd., all patients have to stop IMP but may continue mFOLFOX6.

Official Title
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A Phase 3, Double-blind, Multicenter, Placebo-controlled Study of PledOx Used on Top of Modified FOLFOX6 (5-FU/FA and Oxaliplatin) to Prevent Chemotherapy Induced Peripheral Neuropathy (CIPN) in the Adjuvant Treatment of Patients With Stage III or High-risk Stage II Colorectal Cancer

Conditions
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Colorectal Cancer, Chemotherapy-induced Peripheral Neuropathy

Intervention / Treatment
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* Drug: Calmangafodipir (5 µmol/kg)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent form before any study related assessments and willing to follow all study procedures. Male or female aged ≥18 years. 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). The patient has undergone curative (R0) surgical resection performed within 12 weeks prior to randomization 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). No prior anti-cancer therapy for CRC except radiotherapy or concomitant chemo-radiotherapy using a fluoropyrimidine alone for locoregional rectal cancer. 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. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate hematological parameters: hemoglobin ≥100 g/L, absolute neutrophil count ≥1.5 x 109 /L, platelets ≥100 x 109 /L. Adequate renal function: creatinine clearance >50 cc/min using the Cockcroft and Gault formula or measured. 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. Baseline blood manganese (Mn) level <2.0 x ULN. For patients with a history of diabetes mellitus, HbA1c ≤7%. Negative pregnancy test for women of child-bearing potential (WOCBP). 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: Any evidence of metastatic disease. 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. 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. 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. Any history of seizures. A surgical incision that is not healed. 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. 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 Mn exposure is likely.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PledOx (5 µmol/kg)<br>Calmangafodipir 5 µmol/kg | Drug: Calmangafodipir (5 µmol/kg)<br>* 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.<br>* Other names: PledOx;|
| Placebo Comparator: Placebo<br>0.9% sodium chloride in 20 mL vials | Other: Placebo<br>* Placebo will be administered via the same route as PledOx (i.v. infusion). Placebo is a solution in 20 mL single dose glass vials.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN) | Percentage of patients (with moderate or severe chronic CIPN) scoring 3 or 4 in at least 1 of the first 4 items of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity-13-item subscale (FACT/GOG-NTX-13; i.e., FACT/GOG-NTX-4) 9 months after the first dose of IMP (i.e. PledOx or placebo administered on Day 1, Cycle 1 of mFOLFOX6 chemotherapy). The FACT/GOG-13 questionnaire includes 13 items that measure the severity and impact of symptoms of neurotoxicity over the past 7 days. Patients rate each item as 0 (not at all), 1 ( a little bit), 2 (somewhat), 3 (quite a bit) or 4 (very much). These 13 items are summed to create a total score, ranging from 0 to 52, with a higher score representing a worse outcome. The FACT/GOG-NTX-4 is a 4 item subscale targeting numbness, tingling or discomfort in hands and/or feet. | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mild, Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy | Percentage of patients (with mild, moderate or severe chronic CIPN) scoring 2, 3 or 4 in at least 1 of the first 4 items of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity-13-item subscale (FACT/GOG-NTX-13; i.e., FACT/GOG-NTX-4) 9 months after the first dose of IMP (i.e. PledOx or placebo administered on Day 1, Cycle 1 of mFOLFOX6 chemotherapy). The FACT/GOG-13 questionnaire includes 13 items that measure the severity and impact of symptoms of neurotoxicity over the past 7 days. Patients rate each item as 0 (not at all), 1 ( a little bit), 2 (somewhat), 3 (quite a bit) or 4 (very much). These 13 items are summed to create a total score, ranging from 0 to 52, with a higher score representing a worse outcome. The FACT/GOG-NTX-4 is a 4 item subscale targeting numbness, tingling or discomfort in hands and/or feet. | 9 months | 
| Sensitivity to Touching Cold Items | Mean change from baseline in sensitivity to touching cold items on Day 2, Cycle 4 (cycle is 14 days) of mFOLFOX6 chemotherapy, as assessed by the Cold Sensitivity questionnaire. Cold sensitivity was rated 0 (not at all) to 10 (as bad as you can imagine). | Baseline and 8 weeks | 
| Cumulative Dose of Oxaliplatin During Chemotherapy | Mean cumulative dose of oxaliplatin administered per patient during mFOLFOX6 chemotherapy, 9 months after the first dose of Investigational Medicinal Product | 9 months | 
| Vibration Sensitivity on the Lateral Malleolus | Mean change from baseline in vibration sense, on the lateral malleolus (left and right), using a graduated tuning fork, at 9 months after the first dose of Investigational Medicinal Product. When the tuning fork was struck against the ball of the thumb, the base of the tuning fork was placed over the appropriate bony surface (i.e. lateral malleolus left and right) and the patient was asked to indicate the moment when the vibration was no longer detected. The intensity at which the patient no longer detected the vibration is reported on a scale of 0 (minimum score, representing the maximum vibration amplitude) to 8 (maximum score, representing the minimum vibration amplitude) | Baseline and 9 months | 
| Worst Pain in Hands or Feet | Mean change from baseline in worst pain in hands or feet in the past week, using a numerical rating scale (Numeric Rating Scale; Scale range of 0-10;0 = no pain, 10= pain as bad as you can imagine), at 9 months after the first dose of Investigational Medicinal Product | Baseline and 9 months | 
| Functional Impairment (in the Non-dominant Hand) | Mean change from baseline in the time to complete the grooved Pegboard with the non-dominant hand, at 9 months after the first dose of Investigational Medicinal Product | Baseline and 9 months | 
| Patients With Disease Free Survival | Patients with disease free survival. | Analysis was planned at 24 months but performed based on available data at cut-off 31 August 2020 as the study was terminated early by the Sponsor | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neuropathy, colorectal cancer, cancer, peripheral neuropathy