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
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- 入组人数
- 291
- 试验地点
- 98
- 主要终点
- Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN)
研究概览
简要总结
This study evaluates the investigational drug PledOx in the prevention of chronic chemotherapy induced peripheral neuropathy (CIPN) induced by the drug oxaliplatin.
详细描述
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.
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)
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.
- •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.
- •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
- •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.
排除标准
- •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.
研究组 & 干预措施
PledOx (2 µmol/kg)
Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy.
干预措施: Calmangafodipir (2 µmol/kg) (Drug)
PledOx (5 µmol/kg)
Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy.
干预措施: Calmangafodipir (5 µmol/kg) (Drug)
Placebo
Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy.
干预措施: Placebo (Drug)
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
- Mild, Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN)(9 months)
- Sensitivity to Touching Cold Items(Baseline and 8 weeks)
- Cumulative Dose of Oxaliplatin During Chemotherapy(9 months)
- Overall Survival (OS)(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)
- Worst Pain in Hands or Feet(Baseline and 9 months)
- Overall Response Rate (ORR)(12, 15 and 18 months)
- Progression-free Survival (PFS)(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)
- Vibration Sensitivity on the Lateral Malleolus(Baseline and 9 months)
- Functional Impairment (in the Non-dominant Hand)(Baseline and 9 months)