Clinical trial NCT03654729: Preventive Treatment of Oxaliplatin Induced Peripheral Neuropathy in Metastatic Colorectal Cancer (POLAR-M)
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 Patients With First-line mCRC
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Colorectal Cancer
Chemotherapy-induced Peripheral Neuropathy
Keywords: Metastatic
Colorectal
Cancer
Metastatic Colorectal Cancer
Oxaliplatin induced CIPN
CIPN
Oxaliplatin
Lead sponsor: Egetis Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Solasia Pharma K.K.
First posted: 2018-08-31
Enrollment: 291
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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
Primary purpose: PREVENTION

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

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

Eligibility criteria: 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.

Primary outcomes:
measure: Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN)
timeFrame: 9 months
Secondary outcomes:
measure: Mild, Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN)
timeFrame: 9 months
measure: Sensitivity to Touching Cold Items
timeFrame: Baseline and 8 weeks
measure: Cumulative Dose of Oxaliplatin During Chemotherapy
timeFrame: 9 months
measure: Vibration Sensitivity on the Lateral Malleolus
timeFrame: Baseline and 9 months
measure: Worst Pain in Hands or Feet
timeFrame: Baseline and 9 months
measure: Functional Impairment (in the Non-dominant Hand)
timeFrame: Baseline and 9 months
measure: Overall Response Rate (ORR)
timeFrame: 12, 15 and 18 months
measure: Progression-free Survival (PFS)
timeFrame: 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
measure: Overall Survival (OS)
timeFrame: 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
Other outcomes:
Locations:
city: Fresno
country: United States
facility: California Cancer Associates
state: California
city: Orange City
country: United States
facility: Mid Florida Hematology and Oncology Center
state: Florida
city: Wichita
country: United States
facility: Cancer Center of Kansas
state: Kansas
city: Shreveport
country: United States
facility: Willis-Knighton Cancer Center
state: Louisiana
city: Saint Louis
country: United States
facility: Mercy Clinic Oncology and Hematology
state: Missouri
city: Springfield
country: United States
facility: Mercy Clinic - Cancer & Hematology
state: Missouri
city: Grand Island
country: United States
facility: CHI St Francis Cancer Treatment Center
state: Nebraska
city: Flemington
country: United States
facility: Hunterdon Hematology Oncology
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Research
state: New York
city: Lake Success
country: United States
facility: Monter Cancer Center
state: New York
city: Temple
country: United States
facility: Scott & White Vasicek Cancer Treatment Center
state: Texas
city: Aalst
country: Belgium
facility: Onze-Lieve-Vrouwziekenuis Aalst
city: Bonheiden
country: Belgium
facility: Imelda GI Clinical Research Center
city: Brussels
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Gent
country: Belgium
facility: UZ Gent
city: Liege
country: Belgium
facility: CHU Liège
city: Mechelen
country: Belgium
facility: AZ Sint Maarten
city: Roeselare
country: Belgium
facility: AZ Delta
city: Yvoir
country: Belgium
facility: CHU UCL Namur - Site Godinne
city: Benešov
country: Czechia
facility: Nemocnice Benesov
city: Hořovice
country: Czechia
facility: Nemocnice Horovice
city: Nová Ves Pod Pleší
country: Czechia
facility: Nemocnice Na Pleši
city: Prague 2
country: Czechia
facility: General University Hospital
city: Prague
country: Czechia
facility: Hospital Na Bulovce
city: Prague
country: Czechia
facility: Onkologická Klinika 1. Lf Uk A Tn
city: Brest Cedex 2
country: France
facility: Clinique Pasteur-Lanroze
city: Brest
country: France
facility: CHRU de Brest - Hôpital Morvan
city: La Roche-sur-Yon
country: France
facility: Centre Hospitalier Départemental de Vendée - Unité de recherche clinique
city: Lille
country: France
facility: Centre Oscar Lambret
city: LYON Cedex 03
country: France
facility: Hôpital Edouard Herriot - HCL
city: Montbéliard Cedex
country: France
facility: Hôpital Nord Franche-Comté Site du Mittan
city: Nantes
country: France
facility: Institut de Cancérologie de l'Ouest
city: NICE Cedex 3
country: France
facility: Hopital l'Archet, CHU de Nice
city: Reims
country: France
facility: Hôpital Robert Debré
city: Saint-Grégoire
country: France
facility: Centre Hospitalier Privé Saint-Grégoire
city: Strasbourg
country: France
facility: Clinique Ste Anne
city: Strasbourg
country: France
facility: Hopitaux Universitaires de Strasbourg
city: Augsburg
country: Germany
facility: Hämatolgisch-onkologische Praxis Augsburg
city: Dresden
country: Germany
facility: Onkozentrum Dresden
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus
city: Frankfurt
country: Germany
facility: Agaplesion Markus Krankenhaus
city: Gütersloh
country: Germany
facility: Onkodok GmbH
city: München
country: Germany
facility: Klinikum Neuperlach
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Budapest
country: Hungary
facility: Országos Onkológiai Intézet
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Miskolc
country: Hungary
facility: Borsod-Abaúj-Zemplén Megyei Központi Kórház és Egyetemi Oktatókórház
city: Szekszárd
country: Hungary
facility: Tolna Megyei Balassa Janos Korhaz
city: Szolnok
country: Hungary
facility: Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház-Rendelőintézet
city: Candiolo
country: Italy
facility: IRCCS Candiolo
city: Cremona
country: Italy
facility: Oncologia Istituti Ospitalieri
city: Meldola - FC
country: Italy
facility: Irccs Irst
city: Modena
country: Italy
facility: Azienda Ospedaliero - Universitaria di Modena Policlinico
city: Monza
country: Italy
facility: Hospital San Gerardo
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori
city: Pavia
country: Italy
facility: IRCCS Policlinico San Matteo
city: Ponderano
country: Italy
facility: Ospedale degli infermi
city: Ravenna
country: Italy
facility: Ospedale S. Maria delle Croci - Ravenna
city: Reggio Emilia
country: Italy
facility: IRCCS azienda Ospedaliera S Maria Nuova
city: Rome
country: Italy
facility: San Camillo Forlanini Hospital
city: San Giovanni Rotondo
country: Italy
facility: Casa Sollievo della Sofferenza
city: Osaka-shi, Osaka
country: Japan
facility: Osaka International Cancer Institute
state: Osaka
city: Aichi
country: Japan
facility: Fujita Health University Hospital
city: Fukuoka-shi, Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Fukuoka-shi, Fukuoka
country: Japan
facility: Fukuoka University Hospital
city: Hyōgo
country: Japan
facility: Kansai Rosai Hospital
city: Kanagawa
country: Japan
facility: St. Marianna University School of Medicine Hospital
city: Nagoya-shi, Aichi
country: Japan
facility: Aichi Cancer Center Hospital
city: Osaka-shi, Osaka
country: Japan
facility: National Hospital Organization Osaka National Hospital
city: Osaka
country: Japan
facility: Osaka University Hospital
city: Sapporo-shi, Hokkaido
country: Japan
facility: Sapporo Medical University Hospital
city: Shizuoka
country: Japan
facility: Shizuoka Cancer Center
city: Tokyo
country: Japan
facility: The Cancer Institute Hospital Of JFCR
city: Anyang-si
country: Korea, Republic of
facility: Hallym University Sacred Heart Hospital
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Gwangju
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Barcelona
country: Spain
facility: Hospital de La Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: L´Hospitalet de Llobregat (Barcelona)
city: Barcelona
country: Spain
facility: Vall d'hebron university hospital
city: Jaén
country: Spain
facility: Complejo Hospitalario de Jaén
city: Madrid
country: Spain
facility: Centro Integral Oncologico Clara Campal
city: Madrid
country: Spain
facility: H.G.U.Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: València
country: Spain
facility: Hospital Quironsalud Valencia
city: Zaragoza
country: Spain
facility: Hospital Miguel Servet
city: Kaohsiung
country: Taiwan
facility: KMUH: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Tainan
country: Taiwan
facility: CMMC: Chi Mei Medical Center
city: Tainan
country: Taiwan
facility: NCKUH: National Cheng Kung University Hospital
city: London
country: United Kingdom
facility: Royal Marsden Hospital
city: North Shields
country: United Kingdom
facility: North Tyneside General Hospital
city: Northwood
country: United Kingdom
facility: Mount Vernon Cancer Centre
city: Sutton
country: United Kingdom
facility: The Royal Marsden Hospital (Surrey)
city: York
country: United Kingdom
facility: York Teaching Hospital
Study officials:
affiliation: Chief Medical Officer
name: Stefan Carlsson, MD
role: STUDY_DIRECTOR
References:
citation: 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.