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Colorectal CancerPhase 3POLAR-ANCT04034355

Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy in Adjuvant Colorectal Cancer

A Phase 3 study testing Calmangafodipir (5 µmol/kg) in people with Colorectal Cancer and Chemotherapy-induced Peripheral Neuropathy, run by Egetis Therapeutics AB (publ) at 65 sites in 10 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Calmangafodipir (5 µmol/kg)
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
301 participants
Where
65 sitesin 10 countries
Study dates
7 Jan 2019to 31 Aug 2020
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

65 sites in 10 countries.

65 sites in 10 countries

Japan11 sites

  • Fukuoka University Hospital

    Fukuoka

  • Kyushu University Hospital

    Fukuoka

  • St. Marianna University School of Medicine Hospital

    Kawasaki

  • Aichi Cancer Center Hospital

    Nagoya

  • National Hospital Organization Osaka National Hospital

    Osaka

  • Osaka International Cancer Institute

    Osaka

  • Osaka University Hospital

    Osaka

  • Sapporo Medical University Hospital

    Sapporo

  • Shizuoka Cancer Center

    Shizuoka

  • The Cancer Institute Hospital of JFCR

    Tokyo

  • Fujita Health University Hospital

    Toyoake

Other trials in Japan

France9 sites

  • CHRU de Brest - Hôpital Morvan

    Brest

  • Clinique Pasteur-Lanroze

    Brest

  • Centre Hospitalier Départemental de Vendée - Unité de recherche clinique

    La Roche-sur-Yon

  • Centre Oscar Lambret

    Lille

  • Hôpital Edouard Herriot - HCL

    Lyon

  • Hôpital Nord Franche-Comté Site du Mittan

    Montbéliard

  • CHU Nice L'Archet 2

    Nice

  • Clinique Ste Anne

    Strasbourg

  • Hopitaux Universitaires de Strasbourg

    Strasbourg

Other trials in France

Belgium8 sites

  • Onze-Lieve-Vrouwziekenuis Aalst

    Aalst

  • Imelda GI Clinical Research Center

    Bonheiden

  • Cliniques Universitaires St-Luc

    Brussels

  • UZ Gent

    Ghent

  • CHU Liège

    Liège

  • AZ Sint Maarten

    Mechelen

  • AZ Delta

    Roeselare

  • CHU UCL Namur - Site Godinne

    Yvoir

Other trials in Belgium

Italy8 sites

  • Oncologia Istituti Ospitalieri

    Cremona

  • Irccs Irst

    Meldola - FC

  • Hospital San Gerardo

    Monza

  • Istituto Nazionale Tumori

    Naples

  • IRCCS Policlinico San Matteo

    Pavia

  • Ospedale degli infermi

    Ponderano

  • IRCCS azienda Ospedaliera S Maria Nuova

    Reggio Emilia

  • Casa Sollievo della Sofferenza

    San Giovanni Rotondo

Other trials in Italy

Spain8 sites

  • Granvia de L´Hospitalet 199-203

    Barcelona

  • Hospital de La Santa Creu I Sant Pau

    Barcelona

  • Vall d'hebron university hospital

    Barcelona

  • Centro Integral Oncologico

    Madrid

  • H.G.U.Gregorio Marañón

    Madrid

  • Hospital Universitario Puerta de Hierro

    Majadahonda

  • Hospital Univ Virgen Macarena

    Seville

  • Hospital Quironsalud Valencia

    Valencia

Other trials in Spain

South Korea6 sites

  • Hallym University Sacred Heart Hospital

    Anyang-si

  • Dong-A University Hospital

    Busan

  • Chonnam National University Hwasun Hospital

    Gwangju

  • Seoul National University Bundang Hospital

    Seongnam-si

  • Korea University Guro Hospital

    Seoul

  • Seoul National University Hospital

    Seoul

Other trials in South Korea

Czechia5 sites

  • Nemocnice Benesov

    Benešov

  • Nemocnice Horovice

    Hořovice

  • Nemocnice Na Pleši

    Nová Ves Pod Plesi

  • General University Hospital

    Prague

  • Onkologická Klinika 1. Lf Uk A Tn

    Prague

Other trials in Czechia

Germany5 sites

  • Hämatolgisch-onkologische Praxis Augsburg

    Augsburg

  • Onkozentrum Dresden

    Dresden

  • Universitätsklinikum Carl Gustav Carus

    Dresden

  • Onkodok GmbH / Onkologische Schwerpunktpraxis

    Gütersloh

  • Klinikum Neuperlach

    München

Other trials in Germany

United Kingdom4 sites

  • Mid Essex Hospital Services NHS Trust - Broomfield Hospital

    Chelmsford

  • North Tyneside General Hospital

    North Shields

  • Mount Vernon Cancer Centr

    Northwood

  • The Royal Marsden Hospital (Surrey)

    Sutton

Other trials in United Kingdom

Taiwan1 site

  • KMUH: Kaohsiung Medical University Chung-Ho Memorial Hospital

    Kaohsiung City

Other trials in Taiwan

About this study

Official title: 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).

Read the 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.

Being tested
Calmangafodipir (5 µmol/kg), Placebo
Keywords
colorectal cancer, cancer, peripheral neuropathy, neuropathy
Medical subject headings
Colorectal Neoplasms, Neoplasms, Peripheral Nervous System Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Calmangafodipir (5 µmol/kg)Drug

    Also called PledOx

    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.

  • PlaceboOther

    Placebo will be administered via the same route as PledOx (i.v. infusion). Placebo is a solution in 20 mL single dose glass vials.

Study groups in NCT04034355
Study groupRoleWhat they receive
PledOx (5 µmol/kg)ExperimentalCalmangafodipir 5 µmol/kg
Receives: Drug: Calmangafodipir (5 µmol/kg)
PlaceboPlacebo comparator0.9% sodium chloride in 20 mL vials
Receives: Other: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 9 months

Secondary outcomes (7)

  1. 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.

    Measured: 9 months

  2. 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).

    Measured: Baseline and 8 weeks

  3. 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

    Measured: 9 months

  4. 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)

    Measured: Baseline and 9 months

  5. 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

    Measured: Baseline and 9 months

  6. 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

    Measured: Baseline and 9 months

  7. Patients With Disease Free Survival

    Patients with disease free survival.

    Measured: 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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Jul 2019
  2. Study start7 Jan 2019
  3. Primary completion31 Aug 2020
  4. Study completion31 Aug 2020

Why it stopped: On 01 March 2020, the Sponsor decided to place recruitment and dosing of patients on hold following interactions with the French regulatory authority, ANSM and the US clinical hold of another study (POLAR-M).

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
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 blind
Who is masked
Participant, Care provider, Investigator
Enrolment
301 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04034355
Sponsor's protocol ID
PP06489
Other IDs
2017-004707-43, 2017
Acronym
POLAR-A
Status last verified
Nov 2021
First submitted
14 May 2019
Last updated
26 Jan 2022
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

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.

    PubMed 36308441

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Calmangafodipir (5 µmol/kg) in people with Colorectal Cancer and Chemotherapy-induced Peripheral Neuropathy, run by Egetis Therapeutics AB (publ) at 65 sites in 10 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 26 Jan 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 65 sites in Japan, France, Belgium, Italy, Spain and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 26 Jan 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN) (time frame: 9 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04034355, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jan 2022.

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