Clinical trial NCT04034355: Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy in Adjuvant Colorectal Cancer
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Colorectal Cancer
Chemotherapy-induced Peripheral Neuropathy
Keywords: colorectal cancer
cancer
peripheral neuropathy
neuropathy
Lead sponsor: Egetis Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Solasia Pharma K.K.
First posted: 2019-07-26
Enrollment: 301
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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
Primary purpose: PREVENTION

Brief 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).

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.

Eligibility criteria: 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.

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
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: Patients With Disease Free Survival
timeFrame: 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
Other outcomes:
Locations:
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: Liège
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: Benesov
country: Czechia
facility: Nemocnice Benesov
city: Horovice
country: Czechia
facility: Nemocnice Horovice
city: Nová Ves pod Plesi
country: Czechia
facility: Nemocnice Na Pleši
city: Prague 2
country: Czechia
facility: General University Hospital
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
country: France
facility: Hôpital Nord Franche-Comté Site du Mittan
city: Nice
country: France
facility: CHU Nice L'Archet 2
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: Gütersloh
country: Germany
facility: Onkodok GmbH / Onkologische Schwerpunktpraxis
city: Munchen
country: Germany
facility: Klinikum Neuperlach
city: Cremona
country: Italy
facility: Oncologia Istituti Ospitalieri
city: Meldola - FC
country: Italy
facility: Irccs Irst
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: Reggio Emilia
country: Italy
facility: IRCCS azienda Ospedaliera S Maria Nuova
city: San Giovanni Rotondo
country: Italy
facility: Casa Sollievo della Sofferenza
city: Fukuoka
country: Japan
facility: Fukuoka University Hospital
city: Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Kawasaki
country: Japan
facility: St. Marianna University School of Medicine Hospital
city: Nagoya
country: Japan
facility: Aichi Cancer Center Hospital
city: Osaka
country: Japan
facility: National Hospital Organization Osaka National Hospital
city: Osaka
country: Japan
facility: Osaka International Cancer Institute
city: Osaka
country: Japan
facility: Osaka University Hospital
city: Sapporo
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: Toyoake
country: Japan
facility: Fujita Health University Hospital
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: Granvia de L´Hospitalet 199-203
city: Barcelona
country: Spain
facility: Hospital de La Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: Vall d'hebron university hospital
city: Madrid
country: Spain
facility: Centro Integral Oncologico
city: Madrid
country: Spain
facility: H.G.U.Gregorio Marañón
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro
city: Sevilla
country: Spain
facility: Hospital Univ Virgen Macarena
city: Valencia
country: Spain
facility: Hospital Quironsalud Valencia
city: Kaohsiung
country: Taiwan
facility: KMUH: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Chelmsford
country: United Kingdom
facility: Mid Essex Hospital Services NHS Trust - Broomfield Hospital
city: North Shields
country: United Kingdom
facility: North Tyneside General Hospital
city: Northwood
country: United Kingdom
facility: Mount Vernon Cancer Centr
city: Sutton
country: United Kingdom
facility: The Royal Marsden Hospital (Surrey)
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.