Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy in Adjuvant Colorectal Cancer
- Conditions
- Colorectal CancerChemotherapy-induced Peripheral Neuropathy
- Interventions
- Other: Placebo
- Registration Number
- NCT04034355
- Lead Sponsor
- Egetis Therapeutics
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 301
- 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.
- 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.
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo 0.9% sodium chloride in 20 mL vials PledOx (5 µmol/kg) Calmangafodipir (5 µmol/kg) Calmangafodipir 5 µmol/kg
- Primary Outcome Measures
Name Time Method Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN) 9 months 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.
- Secondary Outcome Measures
Name Time Method Sensitivity to Touching Cold Items Baseline and 8 weeks 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).
Mild, Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy 9 months 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.
Cumulative Dose of Oxaliplatin During Chemotherapy 9 months Mean cumulative dose of oxaliplatin administered per patient during mFOLFOX6 chemotherapy, 9 months after the first dose of Investigational Medicinal Product
Vibration Sensitivity on the Lateral Malleolus Baseline and 9 months 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)
Worst Pain in Hands or Feet Baseline and 9 months 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
Functional Impairment (in the Non-dominant Hand) Baseline and 9 months 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
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 Patients with disease free survival.
Trial Locations
- Locations (65)
AZ Delta
🇧🇪Roeselare, Belgium
North Tyneside General Hospital
🇬🇧North Shields, United Kingdom
Aichi Cancer Center Hospital
🇯🇵Nagoya, Japan
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Nemocnice Horovice
🇨🇿Horovice, Czechia
CHU UCL Namur - Site Godinne
🇧🇪Yvoir, Belgium
Onze-Lieve-Vrouwziekenuis Aalst
🇧🇪Aalst, Belgium
Imelda GI Clinical Research Center
🇧🇪Bonheiden, Belgium
UZ Gent
🇧🇪Gent, Belgium
Cliniques Universitaires St-Luc
🇧🇪Brussels, Belgium
CHU Liège
🇧🇪Liège, Belgium
AZ Sint Maarten
🇧🇪Mechelen, Belgium
Nemocnice Na Pleši
🇨🇿Nová Ves pod Plesi, Czechia
Nemocnice Benesov
🇨🇿Benesov, Czechia
General University Hospital
🇨🇿Prague 2, Czechia
Onkologická Klinika 1. Lf Uk A Tn
🇨🇿Prague, Czechia
Clinique Pasteur-Lanroze
🇫🇷Brest Cedex 2, France
CHRU de Brest - Hôpital Morvan
🇫🇷Brest, France
Centre Hospitalier Départemental de Vendée - Unité de recherche clinique
🇫🇷La Roche-sur-Yon, France
Centre Oscar Lambret
🇫🇷Lille, France
Hôpital Edouard Herriot - HCL
🇫🇷LYON Cedex 03, France
Hôpital Nord Franche-Comté Site du Mittan
🇫🇷Montbéliard, France
CHU Nice L'Archet 2
🇫🇷Nice, France
Clinique Ste Anne
🇫🇷Strasbourg, France
Hopitaux Universitaires de Strasbourg
🇫🇷Strasbourg, France
Hämatolgisch-onkologische Praxis Augsburg
🇩🇪Augsburg, Germany
Universitätsklinikum Carl Gustav Carus
🇩🇪Dresden, Germany
Onkozentrum Dresden
🇩🇪Dresden, Germany
Onkodok GmbH / Onkologische Schwerpunktpraxis
🇩🇪Gütersloh, Germany
Klinikum Neuperlach
🇩🇪Munchen, Germany
Oncologia Istituti Ospitalieri
🇮🇹Cremona, Italy
Hospital San Gerardo
🇮🇹Monza, Italy
Irccs Irst
🇮🇹Meldola - FC, Italy
Istituto Nazionale Tumori
🇮🇹Napoli, Italy
IRCCS Policlinico San Matteo
🇮🇹Pavia, Italy
Ospedale degli infermi
🇮🇹Ponderano, Italy
Fukuoka University Hospital
🇯🇵Fukuoka, Japan
IRCCS azienda Ospedaliera S Maria Nuova
🇮🇹Reggio Emilia, Italy
Casa Sollievo della Sofferenza
🇮🇹San Giovanni Rotondo, Italy
Kyushu University Hospital
🇯🇵Fukuoka, Japan
St. Marianna University School of Medicine Hospital
🇯🇵Kawasaki, Japan
Osaka International Cancer Institute
🇯🇵Osaka, Japan
National Hospital Organization Osaka National Hospital
🇯🇵Osaka, Japan
Osaka University Hospital
🇯🇵Osaka, Japan
Shizuoka Cancer Center
🇯🇵Shizuoka, Japan
The Cancer Institute Hospital of JFCR
🇯🇵Tokyo, Japan
Sapporo Medical University Hospital
🇯🇵Sapporo, Japan
Hallym University Sacred Heart Hospital
🇰🇷Anyang-si, Korea, Republic of
Dong-A University Hospital
🇰🇷Busan, Korea, Republic of
Granvia de L´Hospitalet 199-203
🇪🇸Barcelona, Spain
Chonnam National University Hwasun Hospital
🇰🇷Gwangju, Korea, Republic of
Korea University Guro Hospital
🇰🇷Seoul, Korea, Republic of
Mount Vernon Cancer Centr
🇬🇧Northwood, United Kingdom
Centro Integral Oncologico
🇪🇸Madrid, Spain
Hospital de La Santa Creu I Sant Pau
🇪🇸Barcelona, Spain
Hospital Univ Virgen Macarena
🇪🇸Sevilla, Spain
Hospital Universitario Puerta de Hierro
🇪🇸Majadahonda, Spain
H.G.U.Gregorio Marañón
🇪🇸Madrid, Spain
Hospital Quironsalud Valencia
🇪🇸Valencia, Spain
KMUH: Kaohsiung Medical University Chung-Ho Memorial Hospital
🇨🇳Kaohsiung, Taiwan
Mid Essex Hospital Services NHS Trust - Broomfield Hospital
🇬🇧Chelmsford, United Kingdom
The Royal Marsden Hospital (Surrey)
🇬🇧Sutton, United Kingdom
Vall d'hebron university hospital
🇪🇸Barcelona, Spain
Fujita Health University Hospital
🇯🇵Toyoake, Japan
Seoul National University Bundang Hospital
🇰🇷Seongnam-si, Korea, Republic of