Clinical trial NCT01619423: A Trial of PledOx + FOLFOX6 Compared to Placebo + FOLFOX6 in Patients With Metastatic Colorectal Cancer
Official title: A Double Blinded Randomised Three Armed Phase II Trial of PledOx in Two Different Doses in Combination With FOLFOX6 Compared to Placebo + FOLFOX6 in Patients With Advanced Metastatic Colorectal (Stage IV) Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Advanced Metastatic (Stage IV) Colorectal Cancer
Keywords: Metastatic colorectal cancer
stage IV
FOLFOX6
Chemotherapy
PledOx
Mangafodipir
Febrile neutropenia
Oxidative stress
Antioxidant
neutropenia
neuropathy
Lead sponsor: Egetis Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Pharma Consulting Group AB
First posted: 2012-06-14
Enrollment: 186
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study is a three arm study, however, we changed the high dose in the secord part of the study, from 10 micromol/kg (part 2a) to 5 mictomol/kg (part 2b)
Primary purpose: TREATMENT

Brief summary: The present trial is designed to determine whether pre-treatment with PledOx lowers the frequency and severity of side effects from FOLFOX6 administration in patients with metastatic colorectal cancer.

The efficacy of PledOx will be assessed when added to FOLFOX6 chemotherapy as first line treatment of metastatic colorectal cancer.

This study was performed in multiple parts/phases. Part 1 was an open dose-escalation study with the doses 2, 5 and 10 micromol/kg of calmangafodipir. No study outcomes were planned for this part. In part 2a, participants randomly received either Placebo, 2 or 10 micromol/kg of calmangafodipir. In part 2b, participants randomly received either Placebo, 2 or 5 micromol/kg of calmangafodipir. The overall intent of the study was to compare the effect of antioxidant agent PledOx against placebo in one of three different doses/combinations (2 micromol/kg, 5/10 micromol/kg, 2/5/10 micromol/kg vs. placebo, in the first 8 cycles of FOLFOX6 treatment

Detailed description: Globally, nearly 800 000 colorectal cancers are believed to occur annually. Approximately about half of the patients with colorectal cancer develop metastatic disease. These patients are often offered chemotherapy with the FOLFOX6 regimen (FOL = FOLic acid; F = Fluorouracil (5-FU); OX = OXaliplatin) The use of FOLFOX6 is, however, hampered by a high incidence and severity of adverse reactions.

In the current trial patients will receive the antioxidant agent PledOx in one of two different doses, or placebo, in the first 8 cycles of FOLFOX6 treatment.

Eligibility criteria: Inclusion Criteria:

* Advanced metastatic colorectal (stage IV) cancer verified by biopsy
* Patients may have received up to three previous treatment lines of chemotherapy, which may include fluoropyrimidine, irinotecan and targeted therapies. The last dose of antitumor drug must be given at least 4 weeks prior to inclusion and all toxicity (except alopecia and fatigue) resolved. Patients may also be chemotherapy-naïve, have received prior adjuvant treatment but no previous treatment with oxaliplatin
* CT-scan or MRI of thorax, abdomen and pelvis; within ≤4 weeks before start of chemotherapy
* Evaluable disease and one measurable site of disease according to RECIST 1.1 criteria (at least 10mm for CT-scan or MRI)
* Neurological examination with no significant pathological findings
* ≥18 years
* WHO performance status 0≤2 and Life expectancy ≥ 3 months
* Adequate haematological function, Hb ≥ 100 g/L, ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L
* Adequate renal and hepatic functions: creatinine clearance \>50 cc/min, total bilirubin ≤ 1.5 times ULN, ASAT and ALAT ≤ 3 times ULN (ASAT and ALAT ≤ 5 times ULN in case of liver metastases)
* INR ≤1.5 times ULN, unless receiving therapeutic anticoagulation
* Negative pregnancy test for females of child-producing potential
* Written informed consent given

Exclusion Criteria:

* Tumours other than colorectal adenocarcinomas (within the previous 5 years) except for curatively treated non melanoma skin cancer or in situ carcinoma of the cervix
* Evidence of central nervous system metastases
* Unresolved bowel obstruction or sub-obstruction, uncontrolled Crohn's disease or ulcerative colitis
* History of cardiac disease with a New York Heart Association (NYHA) Class II or greater congestive heart failure, myocardial infarction or unstable angina in the past six (6) months prior to Day 1 of treatment and serious arrhythmias requiring medication for treatment
* Prolonged QTC interval \>450 msec
* Known history of stroke or cerebrovascular accident in the past six (6) months
* Severe diarrhoea
* Chronic infection or uncontrolled serious illness causing immunodeficiency
* Any uncontrolled serious illness or medical condition
* Received mangafodipir at any time
* Welders, mine workers or other workers in occupations (current or past) where high manganese exposure is likely
* Pre-existing neurodegenerative disease (Parkinson's, Alzheimer's, Huntington's etc.) or neuromuscular disorder (Multiple sclerosis, Amyotrophic lateral sclerosis, Polio, hereditary neuromuscular disease)
* Major psychiatric disorder (major depression, psychosis)
* Participation in another clinical study with an investigational medicinal product within 1 month prior to inclusion.
* Blood manganese concentration values \>18.3 μg/L at screening

Primary outcomes:
measure: Number of Patients With Neuropathy Grade 2 or Higher (According to the Oxaliplatin Specific Sanofi Scale (OSSS) Criteria Related Paraesthesia/Dysaesthesia)
timeFrame: Every second week during cycle 1-8, for up to 16 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Moores UCSD Cancer Center
state: California
city: Bethesda
country: United States
facility: Center for Cancer and Blood Disorders
state: Maryland
city: Chattanooga
country: United States
facility: Associates in Oncology & Hematology
state: Tennessee
city: Kingsport
country: United States
facility: Wellmont Medical Associates Oncology and Hematology
state: Tennessee
city: San Antonio
country: United States
facility: The University of Texas, Health Science Center at San Antonio
state: Texas
city: Seattle
country: United States
facility: Benaroya Research Institute @ Virginia Mason
state: Washington
city: Plovdiv
country: Bulgaria
facility: Complex Oncology Center-Plovdiv EOOD, Department of Medical Oncology and oncology diseases in gastroenterology
city: Shumen
country: Bulgaria
facility: Complex Oncology Center-Shumen EOOD, Department of Medical Oncology
city: Sofia
country: Bulgaria
facility: MHAT "Serdika" EOOD, Department of Medical Oncology
city: Sofia
country: Bulgaria
facility: UMHAT "Tzaritza Joanna-ISUL" EAD, Clinic of Medical Oncology
city: Sofia
country: Bulgaria
facility: SHATO EAD, Sofia, Clinic of Chemotherapy
city: Aalborg
country: Denmark
facility: Aalborg University Hospital, Dept of Oncology, Clinical Research Unit
city: Odense
country: Denmark
facility: Odense Universitetshospital, Klinisk Forsknings Enhed, Onkologisk Afdelig R
city: Batumi
country: Georgia
facility: LTD Clinic Medina
city: Tbilisi
country: Georgia
facility: Resaerch Institte of Clinical Medicine
city: Tbilisi
country: Georgia
facility: JSC "Neo Medi"
city: Tbilisi
country: Georgia
facility: LTD " High Technology Medical Center University Clinic"
city: Tbilisi
country: Georgia
facility: S. Khechinashvili University Hospital
city: Bochum
country: Germany
facility: St. Josef-Hospital -Universitätsklinik Ruhr-Universität Bochum, Leitende Ärztin der Abt. für Hämatologie und Onkologie, Medizinische Klinik I
city: Dresden
country: Germany
facility: BAG Freiberg-Richter, Jacobasch, Illmer, Wolf; Gemeinschaftspraxis Hämatologie -Onkologie
city: Wuppertal
country: Germany
facility: HELIOS Klinikum Wuppertal, Klinik für Hämatologie und Onkologie
city: Aveiro
country: Portugal
facility: Centro Hospitalar do Baixo Vouga, E.P.E. (Hospital Infante D. Pedro), Oncologia Médica
city: Braga
country: Portugal
facility: Hospital de Braga, Oncologia Médica
city: Porto
country: Portugal
facility: Instituto Português de Oncologia do Porto, Francisco Gentil, E.P.E., Oncologia Médica
city: Belgrade
country: Serbia
facility: Institute for Oncology and Radiology of Serbia, Clinic for Medical Oncology
city: Belgrade
country: Serbia
facility: Military Medical Academy, Gastroenterology department
city: Belgrade
country: Serbia
facility: Clinical Hospital Center Zemun, Insitute for Oncology
city: Kragujevac
country: Serbia
facility: Clinical Center Kragujevac, Center for Oncology
city: Gävle
country: Sweden
facility: Gävle sjukhus, Oncology unit
city: Göteborg
country: Sweden
facility: Sahlgrenska/Östra sjukhuset
city: Linköping
country: Sweden
facility: Universitetssjukhuset i Linköping
city: Stockholm
country: Sweden
facility: Karolinska Sjukhuset
city: Uppsala
country: Sweden
facility: Akademiska Sjukhuset
Study officials:
affiliation: Egetis Therapeutics
name: Marie Bengtson
role: STUDY_DIRECTOR
References:
citation: Glimelius B, Manojlovic N, Pfeiffer P, Mosidze B, Kurteva G, Karlberg M, Mahalingam D, Buhl Jensen P, Kowalski J, Bengtson M, Nittve M, Nasstrom J. Persistent prevention of oxaliplatin-induced peripheral neuropathy using calmangafodipir (PledOx(R)): a placebo-controlled randomised phase II study (PLIANT). Acta Oncol. 2018 Mar;57(3):393-402. doi: 10.1080/0284186X.2017.1398836. Epub 2017 Nov 15.