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
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- 入组人数
- 301
- 试验地点
- 65
- 主要终点
- Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN)
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Double-blind, placebo-controlled
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
排除标准
- •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.
研究组 & 干预措施
PledOx (5 µmol/kg)
Calmangafodipir 5 µmol/kg
干预措施: Calmangafodipir (5 µmol/kg) (Drug)
Placebo
0.9% sodium chloride in 20 mL vials
干预措施: Placebo (Other)
结局指标
主要结局
Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN)
时间窗: 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.
次要结局
- Sensitivity to Touching Cold Items(Baseline and 8 weeks)
- Mild, Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy(9 months)
- Cumulative Dose of Oxaliplatin During Chemotherapy(9 months)
- Vibration Sensitivity on the Lateral Malleolus(Baseline and 9 months)
- Worst Pain in Hands or Feet(Baseline and 9 months)
- Functional Impairment (in the Non-dominant Hand)(Baseline and 9 months)
- 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)