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

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

Detailed Description
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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 ([Ca0.8,Mn0.2]Na3DPDP) are efficacious inhibitors of CIPN and other conditions caused by cellular oxidative stress, without interfering negatively with the tumoricidal activity of chemotherapy. This is a Phase 3, multicenter, double-blind, placebo-controlled study to establish the efficacious dose of PledOx in prevention of chronic 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) + mFOLFOX6 chemotherapy Arm C: Placebo + mFOLFOX6 chemotherapy Before March 2nd., 2020, the Investigational Medicinal Product, (IMP; i.e. PledOx or placebo) was administered by an intravenous infusion on the first day of each chemotherapy (mFOLFOX6) 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 may be continued. The addition of an appropriate biologic therapy (bevacizumab, panitumumab, cetuximab) will be left to the discretion of the Investigator. As of March 2nd., all patients have to stop IMP but may continue mFOLFOX 6

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 Patients With First-line mCRC

Conditions
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Colorectal Cancer, Chemotherapy-induced Peripheral Neuropathy

Intervention / Treatment
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* Drug: Calmangafodipir (2 µmol/kg)
* Drug: Calmangafodipir (5 µmol/kg)
* Drug: 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. 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.

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: 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PledOx (2 µmol/kg)<br>Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. | Drug: Calmangafodipir (2 µmol/kg)<br>* Solution in 20 mL single dose glass vials<br>* Other names: PledOx;|
| Experimental: PledOx (5 µmol/kg)<br>Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. | Drug: Calmangafodipir (5 µmol/kg)<br>* Solution in 20 mL single dose glass vials<br>* Other names: PledOx;|
| Placebo Comparator: Placebo<br>Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. | Drug: Placebo<br>* 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 (CIPN) | 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 of mFOLFOX6 chemotherapy, as assessed by the Cold Sensitivity Questionnaire (measuring sensitivity when touching or swallowing cold objects/fluid). 10 point scale from 0 meaning no sensitivity/discomfort at all to 10 meaning sensitivity/discomfort as bad as it can be. | 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 IMP. | 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 IMP. 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 the Pain Assessment (Numerical Rating Scale (NRS)), at 9 months after the first dose of IMP. The NRS is a 10 point scale with 0 as no pain at all and 10 as pain as bad as you can imagine and evaluates the intensity of pain in hands and feet during the past week. A higher value means worse outcome. | 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 IMP. | Baseline and 9 months | 
| Overall Response Rate (ORR) | Percentage of patients with an overall response (complete response or partial response) according to RECIST v1.1 for target lesions and assessed by CT (preferred) or MRI. Complete response=disappearance of all target lesions; partial response >=30% decrease in the sum of the longest diameter of target lesions. | 12, 15 and 18 months | 
| Progression-free Survival (PFS) | Patients with progression-free survival | Analyses at 12 and 24 months were planned; the analysis was performed once based on available data at cut-off 31 August 2020 as the study was terminated early by the Sponsor | 
| Overall Survival (OS) | Patients with overall survival | An analysis at 36 months was planned. The analysis was 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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Metastatic, Colorectal, Cancer, Metastatic Colorectal Cancer, Oxaliplatin induced CIPN, CIPN, Oxaliplatin