Study Evaluating Neurotoxicity in Patients With Metastatic Gastro Intestinal Cancer Taking Phycocare® or Placebo During Oxaliplatin Based Chemotherapy

Study Overview
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Brief Summary
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Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by antineoplastic agents, with a prevalence from 19% to over 85%. Clinically, CIPN is a mostly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors as well as for their health care providers, especially because, at the moment, there is no single effective method of preventing CIPN; moreover, the possibilities of treating this syndrome are very limited. The phycocyanin (PC), a biliprotein pigment and an important constituent of the blue-green alga Spirulina platensis, has been reported to possess significant antioxidant and radical-scavenging properties, offering protection against oxidative stress. Study hypothesis is that phycocyanin may give protection against oxaliplatin-induced neuropathy in the treatment of gastro intestinal cancers including oesogastric, colo-rectal and pancreatic cancers. This trial will be a randomised placebo-controlled study.

Detailed Description
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The phycocyanin used in this protocol (Phycocare®) will be 5 times more concentrated than the Spirulysat (food supplement commercialized by Algosource). It will be administrated during Oxaliplatin based chemotherapy and 3 months after oxaliplatin stopped.

Official Title
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Randomized, Double-blind, Multicenter Placebo-controlled Study Evaluating Neurotoxicity in Patients With Metastatic Gastro Intestinal Cancer Taking Phycocare® or Placebo During Oxaliplatin Based Chemotherapy

Conditions
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Metastatic Gastric Cancer

Intervention / Treatment
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* Other: Phycocare
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female with the age > or = to 18 years old. Negative pregnancy test for women with child-bearing potential if applicable (without hysterectomy for example) Information given to the patient who must have signed informed consent Patient with Histologically or cytologically proven gastro intestinal cancer including oesogastric, colo-rectal, pancreatic cancers, locally advanced pancreatic cancers and planned to be treated with oxaliplatin Patient with metastatic disease not previously treated Patient willing not to take any plant-based therapy during the study (including phytotherapy and gemmotherapy) Previous radiotherapy is authorized if discontinued ≥15 days prior to randomization Sites of disease evaluated within 42 days prior C1 day 1 of chemotherapy with thoracic-abdominal-pelvic CT scan (or abdominal-pelvic MRI and chest X-ray) Patient with ECOG Performance status 0 or 1 Patients with a Life expectancy ≥12 weeks Laboratory results: Hematologic function: polynuclear neutrophils ≥ 1.5.109/L platelets ≥100.109/L haemoglobin ≥9 g/dL Hepatic function: transaminases ≤2.5 times upper limit of normal (ULN) (≤5 ULN in case of hepatic metastases), alkaline phosphatases ≤2.5 x ULN (≤5 ULN in case of hepatic metastases), total bilirubin ≤1.5 x ULN Renal function: creatinemia clearance >50 ml/min (Cockcroft and Gault) - Patient with Public Health insurance coverage Exclusion Criteria: Patients with phenylketonuria Patients with known meningeal or brain metastases Patient previously treated for their metastatic cancer Patient previously treated with oxaliplatin Patient with specific contraindication or known hypersensitivity to spirulina Patient with specific contraindication or known hypersensitivity to oxaliplatin. Known allergy or hypersensitivity to antibodies or any preservatives if patient is treated with a monoclonal antibody combined to chemotherapy (bevacizumab or cetuximab or panitumumab or nivolumab or Trastuzumab For patients treated with trastuzumab : patient without HER2 overexpression (defined by positive IHC3 or positive IHC2 and confirmed by a positive FISH result) Patient with clinically significant coronaries affection or myocardial infarction within 6 months prior to randomization. Patient with peripheral neuropathy >1 (CTCAE scale version 5.0). Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. Patient with acute intestinal obstruction or sub-obstruction, history of inflammatory intestinal disease or extended resection of the small intestine or presence of a colic prosthesis. Patient with unhealed wound, active oesogastric or duodenal ulcer, or bone fracture Patient with an history of abdominal fistulas, trachea-esophageal fistulas or any other grade 4, gastro-intestinal perforations or non-gastrointestinal fistulas or intra-abdominal abscesses during the 6 months before randomization. For patient treated with bevacizumab: patient with uncontrolled arterial hypertension (systolic pressure >150 mmHg and/or diastolic pressure >100 mmHg) with and without antihypertensive medication. Patients with high hypertension are eligible if antihypertensive medication lowers their arterial pressure to the level specified by the criterion. Patient with an history of hypertensive crisis or hypertensive encephalopathy Patient with other concomitant malignancy or history of cancer (except in situ carcinoma of the cervix, or non-melanoma skin cancer, treated with curative intent treatment) except if considered in complete remission for at least 2 years before randomization Existence of any other pathology, metabolic problem, anomaly during the clinical examination or biological anomaly which may reasonable suspect an underlying pathology which would contra- indicate the use of the study medication or any other risk of complication related to the treatment. Any treatment including an experimental drug, or participation in another clinical trial within 28 days before randomization. Pregnant women, or women who could possibly be pregnant (or who expect to fall pregnant within 6 months of the end of treatment), or who are breast feeding are not eligible. Men and women of child-bearing potential who do not accept to use a highly effective contraceptive (as per currently acceptable institutional standards) or abstinence during the study and for the month after the last administration of the study treatments. Persons deprived of liberty or under guardianship. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Arm A: Phycocare Arm B: Placebo
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phycocare<br>PHYCOCARE during 12 cycles of 14 days from day -3 before oxaliplatin based chemotherapy until cycle 3 months after the last dose of oxaliplatin (18 cycles, about 9 months) From D-3 to D14 before cycle 1 chemotherapy: patient will take Phycocare From D1 to D14 of cycle 2 chemotherapy and further chemotherapy cycles : patient will take Phycocare On days of chemotherapy the patient does not take Phycocare | Other: Phycocare<br>* Phycocare every day during 9 months (except days of chemotherapy: no Phycocare)<br>|
| Placebo Comparator: Placebo<br>Placebo during 12 cycles of 13 days from day -3 before cycle 1 of oxaliplatin based chemotherapy until 3 months after the last dose of oxaliplatin (9 months). From D-3 to D13 before cycle 1 chemotherapy: patient will take Placebo From D1 to D13 of cycle 2 chemotherapy and further chemotherapy cycles : patient will take Placebo. On days of chemotherapy the patient does not take Placebo | Other: Placebo<br>* Placebo every day during 9 months (except days of chemotherapy = no Placebo)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Demonstrate a 50% decrease of the grade> or = 2 neurotoxicity at 4 months after oxaliplatin-based chemotherapy start in the PHYCOCARE arm | neurotoxicity according to NCI (National Cancer Institute) criteria in both arms | 4 months after oxaliplatin-based chemotherapy start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison between the two arms of percentage of patients who stopped oxaliplatin for neurological toxicity | Delay of definitive interruption or decrease of oxaliplatin treatment | last day of chemotherapy | 
| Comparison between the two arms of percentage of patients with oxaliplatin dose decrease | Dose intensity of oxaliplatin | last day of chemotherapy | 
| Comparison between the two arms of Neurological toxicities according to the Common Terminology Criteria for adverse Event (CTCAE) v5.0 | Neurological AE at following hospital visit : baseline, M4 and M9/end of study visit | end of study visit (an average of 9 months after cycle 1 day1) | 
| Comparison between the two arms of Overall Toxicity (including hematological toxicity, gastro-intestinal toxicity, etc…) | Adverse events grade 1 to 4 | end of study visit (an average of 9 months after cycle 1 day1) | 
| Comparison between the two arms of Patient 's Quality of Life according with EORTC-QLQ-C30 | QLQ C30 - score questions 1 to 28: score frame [30-114] . 30= good quality of life questions 29 and 30 : score frame [2-14] . 2 = bad quality of lifre | end of study visit (an average of 9 months after cycle 1 day1) | 
| Comparison between the two arms of Neurological toxicities | ElectroNeuroMyography (ENMG) and neurology questionnaire ONLS (overall neuropathy limitations scale) ONLS score: sub-score upper limbs : [0-5] . 5= worst neuropathic injury sub score lower limbs [0-7]: 7= worst neuropathic injury total score = upper limbs score + lower limbs score [0-12] ; 0= no injury; 12= maximal incapacity | end of study visit (an average of 9 months after cycle 1 day1) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oxaliplatin based chemotherapy, neurotoxicity