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

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

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

Study Overview

• Status: Terminated
• Conditions: Colorectal Cancer; Chemotherapy-induced Peripheral Neuropathy
• Intervention / Treatment: Drug: Calmangafodipir (2 µmol/kg); Drug: Calmangafodipir (5 µmol/kg); Drug: Placebo

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 291
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Aalst, Belgium
    • Onze-Lieve-Vrouwziekenuis Aalst
  • Bonheiden, Belgium
    • Imelda GI Clinical Research Center
  • Brussels, Belgium
    • Cliniques Universitaires St-Luc
  • Gent, Belgium
    • UZ Gent
  • Liege, Belgium
    • CHU Liege
  • Mechelen, Belgium
    • AZ Sint Maarten
  • Roeselare, Belgium
    • AZ Delta
  • Yvoir, Belgium
    • CHU UCL Namur - site Godinne
• Czechia
  • Benešov, Czechia
    • Nemocnice Benesov
  • Hořovice, Czechia
    • Nemocnice Horovice
  • Nová Ves Pod Pleší, Czechia
    • Nemocnice Na Pleši
  • Prague, Czechia
    • Hospital Na Bulovce
  • Prague, Czechia
    • Onkologická Klinika 1. Lf Uk A Tn
  • Prague 2, Czechia
    • General University Hospital
• France
  • Brest, France
    • CHRU de Brest - Hôpital Morvan
  • Brest Cedex 2, France
    • Clinique Pasteur-Lanroze
  • LYON Cedex 03, France
    • Hôpital Edouard Herriot - HCL
  • La Roche-sur-Yon, France
    • Centre Hospitalier Départemental de Vendée - Unité de recherche clinique
  • Lille, France
    • Centre Oscar Lambret
  • Montbéliard Cedex, France
    • Hôpital Nord Franche-Comté Site du Mittan
  • NICE Cedex 3, France
    • Hopital l'Archet, CHU de Nice
  • Nantes, France
    • Institut de Cancérologie de l'Ouest
  • Reims, France
    • Hopital Robert Debre
  • Saint-Grégoire, France
    • Centre Hospitalier Prive Saint-Gregoire
  • Strasbourg, France
    • Hôpitaux Universitaires de Strasbourg
  • Strasbourg, France
    • Clinique Ste Anne
• Germany
  • Augsburg, Germany
    • Hämatolgisch-onkologische Praxis Augsburg
  • Dresden, Germany
    • Universitätsklinikum Carl Gustav Carus
  • Dresden, Germany
    • Onkozentrum Dresden
  • Frankfurt, Germany
    • Agaplesion Markus Krankenhaus
  • Gütersloh, Germany
    • Onkodok GmbH
  • München, Germany
    • Klinikum Neuperlach
• Hong Kong
  • Hong Kong, Hong Kong
    • Queen Mary Hospital
• Hungary
  • Budapest, Hungary
    • Országos Onkológiai Intézet
  • Budapest, Hungary
    • Semmelweis Egyetem
  • Miskolc, Hungary
    • Borsod-Abauj-Zemplen Megyei Kozponti Korhaz es Egyetemi Oktatokorhaz
  • Szekszárd, Hungary
    • Tolna Megyei Balassa János Kórház
  • Szolnok, Hungary
    • Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház-Rendelointézet
• Italy
  • Candiolo, Italy
    • IRCCS Candiolo
  • Cremona, Italy
    • Oncologia Istituti Ospitalieri
  • Meldola - FC, Italy
    • Irccs Irst
  • Modena, Italy
    • Azienda Ospedaliero - Universitaria di Modena Policlinico
  • Monza, Italy
    • Hospital San Gerardo
  • Napoli, Italy
    • Istituto Nazionale Tumori
  • Pavia, Italy
    • IRCCS Policlinico San Matteo
  • Ponderano, Italy
    • Ospedale Degli Infermi
  • Ravenna, Italy
    • Ospedale S. Maria delle Croci - Ravenna
  • Reggio Emilia, Italy
    • IRCCS azienda Ospedaliera S Maria Nuova
  • Rome, Italy
    • San Camillo Forlanini Hospital
  • San Giovanni Rotondo, Italy
    • Casa Sollievo della Sofferenza
• Japan
  • Aichi, Japan, 470-1192
    • Fujita Health University Hospital
  • Fukuoka-shi, Fukuoka, Japan, 812-8582
    • Kyushu University Hospital
  • Fukuoka-shi, Fukuoka, Japan, 814-0133
    • Fukuoka University Hospital
  • Hyōgo, Japan
    • Kansai Rosai Hospital
  • Kanagawa, Japan, 216-8511
    • St. Marianna University School of Medicine Hospital
  • Nagoya-shi, Aichi, Japan, 464-8681
    • Aichi Cancer Center Hospital
  • Osaka, Japan, 565-0871
    • Osaka University Hospital
  • Osaka-shi, Osaka, Japan, 540-0006
    • National Hospital Organization Osaka National Hospital
  • Sapporo-shi, Hokkaido, Japan, 065-0033
    • Sapporo Medical University Hospital
  • Shizuoka, Japan, 411-8777
    • Shizuoka Cancer Center
  • Tokyo, Japan, 135-8550
    • The Cancer Institute Hospital of JFCR
  • Osaka
    • Osaka-shi, Osaka, Osaka, Japan, 541-8567
      • Osaka International Cancer Institute
• Korea, Republic of
  • Anyang-si, Korea, Republic of
    • Hallym University Sacred Heart Hospital
  • Busan, Korea, Republic of
    • Dong-A University Hospital
  • Gwangju, Korea, Republic of
    • Chonnam National University Hwasun Hospital
  • Seongnam-si, Korea, Republic of
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Korea University Guro Hospital
• Spain
  • Barcelona, Spain
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain
    • Vall D'Hebron University Hospital
  • Barcelona, Spain
    • L´Hospitalet de Llobregat (Barcelona)
  • Jaén, Spain
    • Complejo Hospitalario de Jaén
  • Madrid, Spain
    • Centro Integral Oncologico Clara Campal
  • Madrid, Spain
    • Hospital Universitario La Paz
  • Madrid, Spain
    • H.G.U.Gregorio Marañón
  • Majadahonda, Spain
    • Hospital Universitario Puerta de Hierro
  • Sevilla, Spain
    • Hospital Universitario Virgen Macarena
  • València, Spain
    • Hospital Quirónsalud Valencia
  • Zaragoza, Spain
    • Hospital Miguel Servet
• Taiwan
  • Kaohsiung, Taiwan
    • KMUH: Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Tainan, Taiwan
    • CMMC: Chi Mei Medical Center
  • Tainan, Taiwan
    • NCKUH: National Cheng Kung University Hospital
• United Kingdom
  • London, United Kingdom, SW3 6JJ
    • Royal Marsden Hospital
  • North Shields, United Kingdom, NE29 8NH
    • North Tyneside General Hospital
  • Northwood, United Kingdom, HA6 2RN
    • Mount Vernon Cancer Centre
  • Sutton, United Kingdom, SM2 5PT
    • The Royal Marsden Hospital (Surrey)
  • York, United Kingdom, YO61 8HE
    • York Teaching Hospital
• United States
  • California
    • Fresno, California, United States, 93720
      • California Cancer Associates
  • Florida
    • Orange City, Florida, United States, 32763
      • Mid Florida Hematology and Oncology Center
  • Kansas
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • Willis-Knighton Cancer Center
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Mercy Clinic Oncology and Hematology
    • Springfield, Missouri, United States, 65804
      • Mercy Clinic - Cancer & Hematology
  • Nebraska
    • Grand Island, Nebraska, United States, 68803
      • CHI St Francis Cancer Treatment Center
  • New Jersey
    • Flemington, New Jersey, United States, 08822
      • Hunterdon Hematology Oncology
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Research
    • Lake Success, New York, United States, 11042
      • Monter Cancer Center
  • Texas
    • Temple, Texas, United States, 76508
      • Scott & White Vasicek Cancer Treatment Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: PledOx (2 µmol/kg); 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); Solution in 20 mL single dose glass vials; Other Names: PledOx
EXPERIMENTAL: PledOx (5 µmol/kg); 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); Solution in 20 mL single dose glass vials; Other Names: PledOx
PLACEBO_COMPARATOR: Placebo; Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy.	Drug: Placebo; Solution in 20 mL single dose glass vials

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Egetis Therapeutics
• Collaborators: Solasia Pharma K.K.

Publications and helpful links

General Publications

• Pfeiffer P, Lustberg M, Nasstrom J, Carlsson S, Persson A, Nagahama F, Cavaletti G, Glimelius B, Muro K. Calmangafodipir for Prevention of Oxaliplatin-Induced Peripheral Neuropathy: Two Placebo-Controlled, Randomized Phase 3 Studies (POLAR-A/POLAR-M). JNCI Cancer Spectr. 2022 Nov 1;6(6):pkac075. doi: 10.1093/jncics/pkac075.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 7, 2018
• Primary Completion (ACTUAL): August 31, 2020
• Study Completion (ACTUAL): August 31, 2020

Study Registration Dates

• First Submitted: August 29, 2018
• First Submitted That Met QC Criteria: August 29, 2018
• First Posted (ACTUAL): August 31, 2018

Study Record Updates

• Last Update Posted (ACTUAL): December 17, 2021
• Last Update Submitted That Met QC Criteria: November 19, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Cancer; Metastatic; Oxaliplatin; Metastatic Colorectal Cancer; Colorectal; CIPN; Oxaliplatin induced CIPN
• Additional Relevant MeSH Terms: Digestive System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Neuromuscular Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Peripheral Nervous System Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Micronutrients; Vitamins; Anticoagulants; Vitamin B Complex; Chelating Agents; Sequestering Agents; Calcium Chelating Agents; Edetic Acid; Pyridoxal Phosphate
• Other Study ID Numbers: PP06490

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No