Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy in Adjuvant Colorectal Cancer (POLAR-A)

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

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).

Study Overview

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

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 301
• 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
  • Liège, Belgium
    • CHU Liege
  • Mechelen, Belgium
    • AZ Sint Maarten
  • Roeselare, Belgium
    • AZ Delta
  • Yvoir, Belgium
    • CHU UCL Namur - Site Godinne
• Czechia
  • Benesov, Czechia
    • Nemocnice Benesov
  • Horovice, Czechia
    • Nemocnice Horovice
  • Nová Ves pod Plesi, Czechia
    • Nemocnice Na Pleši
  • Prague, Czechia
    • Onkologická Klinika 1. Lf Uk A Tn
  • Prague 2, Czechia
    • General University Hospital
• France
  • Brest, France
    • CHRU de Brest - Hopital 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, France
    • Hôpital Nord Franche-Comté Site du Mittan
  • Nice, France
    • CHU Nice L'Archet 2
  • Strasbourg, France
    • Hopitaux 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
  • Gütersloh, Germany
    • Onkodok GmbH / Onkologische Schwerpunktpraxis
  • Munchen, Germany
    • Klinikum Neuperlach
• Italy
  • Cremona, Italy
    • Oncologia Istituti Ospitalieri
  • Meldola - FC, Italy
    • Irccs Irst
  • Monza, Italy
    • Hospital San Gerardo
  • Napoli, Italy
    • Istituto Nazionale Tumori
  • Pavia, Italy
    • IRCCS Policlinico San Matteo
  • Ponderano, Italy
    • Ospedale degli Infermi
  • Reggio Emilia, Italy
    • IRCCS azienda Ospedaliera S Maria Nuova
  • San Giovanni Rotondo, Italy
    • Casa Sollievo della Sofferenza
• Japan
  • Fukuoka, Japan
    • Fukuoka University Hospital
  • Fukuoka, Japan
    • Kyushu University Hospital
  • Kawasaki, Japan
    • St. Marianna University School of Medicine Hospital
  • Nagoya, Japan
    • Aichi Cancer Center Hospital
  • Osaka, Japan
    • Osaka International Cancer Institute
  • Osaka, Japan
    • Osaka University Hospital
  • Osaka, Japan
    • National Hospital Organization Osaka National Hospital
  • Sapporo, Japan
    • Sapporo Medical University Hospital
  • Shizuoka, Japan
    • Shizuoka Cancer Center
  • Tokyo, Japan
    • The Cancer Institute Hospital of JFCR
  • Toyoake, Japan
    • Fujita Health University Hospital
• 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
    • Granvia de L´Hospitalet 199-203
  • Madrid, Spain
    • H.G.U.Gregorio Marañón
  • Madrid, Spain
    • Centro Integral Oncologico
  • Majadahonda, Spain
    • Hospital Universitario Puerta de Hierro
  • Sevilla, Spain
    • Hospital Univ Virgen Macarena
  • Valencia, Spain
    • Hospital Quirónsalud Valencia
• Taiwan
  • Kaohsiung, Taiwan
    • KMUH: Kaohsiung Medical University Chung-Ho Memorial Hospital
• United Kingdom
  • Chelmsford, United Kingdom
    • Mid Essex Hospital Services NHS Trust - Broomfield Hospital
  • North Shields, United Kingdom
    • North Tyneside General Hospital
  • Northwood, United Kingdom
    • Mount Vernon Cancer Centr
  • Sutton, United Kingdom
    • The Royal Marsden Hospital (Surrey)

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:

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PledOx (5 µmol/kg); Calmangafodipir 5 µmol/kg	Drug: Calmangafodipir (5 µmol/kg); 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.; Other Names: PledOx
Placebo Comparator: Placebo; 0.9% sodium chloride in 20 mL vials	Other: Placebo; Placebo will be administered via the same route as PledOx (i.v. infusion). Placebo is a 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	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

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): January 7, 2019
• Primary Completion (Actual): August 31, 2020
• Study Completion (Actual): August 31, 2020

Study Registration Dates

• First Submitted: May 14, 2019
• First Submitted That Met QC Criteria: July 23, 2019
• First Posted (Actual): July 26, 2019

Study Record Updates

• Last Update Posted (Actual): January 26, 2022
• Last Update Submitted That Met QC Criteria: November 19, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: colorectal cancer; cancer; peripheral neuropathy; neuropathy
• 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
• Other Study ID Numbers: PP06489; 2017-004707-43 (EudraCT Number)

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: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No