Effect of GM1 in Prevention of Oxaliplatin Induced Neurotoxicity in Stage II/III Colorectal Cancer

The Effect of Monosialotetrahexosylganglioside (GM1) in Prevention of Oxaliplatin Induced Neurotoxicity in Colorectal Cancer Patients Who Received Oxaliplatin-based Adjuvant Chemotherapy: A Multi-center, Randomized, Placebo-controlled Trial

The primary objective of this study is to assess the efficacy of monosialotetrahexosylganglioside (GM1) for preventing oxaliplatin induced neurotoxicity in colorectal cancer patients who received oxaliplatin-based adjuvant chemotherapy.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Chemotherapy-induced Neutropenia
• Intervention / Treatment: Drug: GM1; Drug: mFOLFOX6 or XELOX; Drug: placebo

Detailed Description

Oxaliplatin is a key agent in the treatment of colorectal cancer. However, peripheral neuropathy markedly limits the use of oxaliplatin. Many drugs have been tried to decrease the development of oxaliplatin induced peripheral neurotoxicity, however, the results remain disappointing. This multi-center, randomized, placebo-controlled trial was performed to assess the efficacy of monosialotetrahexosylganglioside (GM1) for preventing oxaliplatin induced neurotoxicity in colorectal cancer patients who received oxaliplatin-based adjuvant chemotherapy.

• Study Type: Interventional
• Enrollment (Actual): 196
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Sun Yat-sen University Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age: 18-75 years old, male or female
• Histologically confirmed diagnosis of colorectal adenocarcinoma with a phase II or III disease, within 2 months from radical resection, and intends to receive 6 months of adjuvant chemotherapy with mFOLOFX6 or XELOX, without adjuvant radiation indications
• No prior any level of peripheral nerve system disease
• Patients have not received any other possible neurotoxic-reaction-causing drugs (such as oxaliplatin, cisplatin and paclitaxel drugs etc)
• With the capability to accurately record the occurrence and severity of neurotoxicity by questionnaire
• With normal functions of major organs
• No contraindication to chemotherapy
• Life expectancy ≥ 3 months
• Patients have provided a signed Informed Consent Form

Exclusion Criteria:

• Patients who received radical resection, but are expected not be able to complete 6 months of adjuvant chemotherapy
• Patients who receive palliative chemotherapy
• Patients who need adjuvant or palliative radiotherapy during chemotherapy
• Be allergic to GM1
• Hereditary abnormal metabolism of glucose and lipid
• Doctors believe that patients are not suitable for receiving GM1 treatment
• With confirmed history of neurological or psychiatric disorders, including epilepsy and dementia
• With concomitant diseases that will seriously harm the patients' safety or impact the completion of the study
• Patients (male or female) have fertility possibility but not willing or not to take effective contraceptive measures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Adjuvant Chemotherapy plus GM1; Patients will receive mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) or XELOX (capecitabine and oxaliplatin) for adjuvant chemotherapy. While GM1 will be delivered to patients through the day before the initiation of chemotherapy (Day0) to the completion of chemotherapy (Day4), and the dosages of GM1 for patients who receive mFOLFOX6 or XELOX are 80mg or 120mg per day.	Drug: GM1; GM1 will be delivered to patients through the day before the initiation of chemotherapy (Day0) to the completion of chemotherapy (Day4), and the dosages of GM1 for patients who receive mFOLFOX6 or XELOX are 80mg or 120mg per day.; Other Names: monosialotetrahexosylganglioside; Drug: mFOLFOX6 or XELOX; mFOLFOX6: Patients will receive mFOLFOX6 every 14 days, Oxaliplatin 85mg/m2 IV over 3 hours on Day1; Calcium Folinate IV over 2h on Day 1(Leucovorin 200mg/m2 or CF 400 mg/m2); 5-Fluorouracil 400mg/m2 IV on Day1; followed by 5-Fluorouracil 2.4g/m2 for 46 hours continuous infusion on Day1. XELOX: Patients will receive XELOX every 21 days, Oxaliplatin 130mg/m2 IV over 3 hours on Day1;followed by Capecitabine 1000mg/m2 oral twice daily for 14 days. The optimum chemotherapy regimen is at the discretion of the investigators based on the condition of each patient.; Other Names: Capecitabine; Leucovorin; Calcium Folinate; 5-Fluorouracil; Oxalipaltin
Placebo Comparator: Adjuvant Chemotherapy plus placebo; Patients will receive mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) or XELOX (capecitabine and oxaliplatin) for adjuvant chemotherapy. While placebo will be delivered to patients through the day before the initiation of chemotherapy (Day0) to the completion of chemotherapy (Day4).	Drug: mFOLFOX6 or XELOX; mFOLFOX6: Patients will receive mFOLFOX6 every 14 days, Oxaliplatin 85mg/m2 IV over 3 hours on Day1; Calcium Folinate IV over 2h on Day 1(Leucovorin 200mg/m2 or CF 400 mg/m2); 5-Fluorouracil 400mg/m2 IV on Day1; followed by 5-Fluorouracil 2.4g/m2 for 46 hours continuous infusion on Day1. XELOX: Patients will receive XELOX every 21 days, Oxaliplatin 130mg/m2 IV over 3 hours on Day1;followed by Capecitabine 1000mg/m2 oral twice daily for 14 days. The optimum chemotherapy regimen is at the discretion of the investigators based on the condition of each patient.; Other Names: Capecitabine; Leucovorin; Calcium Folinate; 5-Fluorouracil; Oxalipaltin; Drug: placebo; Placebo will be delivered to patients through the day before the initiation of chemotherapy (Day0) to the completion of chemotherapy (Day4), and the dosages of placebo for patients who receive mFOLFOX6 or XELOX are 80mg or 120mg per day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
rates of grade 2 or more chronic cumulative neurotoxicity of both arms	measured by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0, with standardized questions regarding neurotoxic symptoms and examples of answers	9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
rates of chronic cumulative neurotoxicity of both arms	measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20	9 months
time to grade 2 or more neurotoxicity of both arms		9 months
rates of dose reduction or withdrawal due to oxaliplatin induced neurotoxicity of both arms		9 months
rates of acute neurotoxicity of both arms	measured by a numerical analog scale ranging from 0 to 10 that addressed sensitivity touching cold items, discomfort swallowing cold items, throat discomfort, and muscle cramps	6 months
rates and grades of adverse reactions of both arms		6 months
rates of 3 year disease free survival of both arms		3 years

Other Outcome Measures

Outcome Measure	Time Frame
change degrees of the levels of nerve growth factor and other neurotrophic factors of both arms	6 months
genetic polymorphisms of oxaliplatin induced severe and cumulative neurotoxicity	6 months

Collaborators and Investigators

• Sponsor: Yuhong Li
• Investigators: Principal Investigator: Yuhong Li, MD, Sun Yat-sen University

Publications and helpful links

General Publications

• Wang DS, Wang ZQ, Chen G, Peng JW, Wang W, Deng YH, Wang FH, Zhang JW, Liang HL, Feng F, Xie CB, Ren C, Jin Y, Shi SM, Fan WH, Lu ZH, Ding PR, Wang F, Xu RH, Li YH. Phase III randomized, placebo-controlled, double-blind study of monosialotetrahexosylganglioside for the prevention of oxaliplatin-induced peripheral neurotoxicity in stage II/III colorectal cancer. Cancer Med. 2020 Jan;9(1):151-159. doi: 10.1002/cam4.2693. Epub 2019 Nov 13.

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): September 5, 2017
• Study Completion (Actual): September 5, 2017

Study Registration Dates

• First Submitted: September 21, 2014
• First Submitted That Met QC Criteria: September 25, 2014
• First Posted (Estimate): September 29, 2014

Study Record Updates

• Last Update Posted (Actual): October 7, 2019
• Last Update Submitted That Met QC Criteria: October 3, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Hematologic Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Poisoning; Colorectal Neoplasms; Neutropenia; Neurotoxicity Syndromes; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Fluorouracil; Capecitabine; Leucovorin
• Other Study ID Numbers: GOXL-18