A Trial of PledOx + FOLFOX6 Compared to Placebo + FOLFOX6 in Patients With Metastatic Colorectal Cancer

NCT01619423 | Completed Phase 1 Results DMC

• 2 other identifiers: PP095, (PLIANT)2012-001367-76
• Study Type: interventional
• Target: 186
• Locations: 7 countries
• Sites: 28

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

Conditions

Advanced Metastatic (Stage IV) Colorectal Cancer

Keywords

Metastatic colorectal cancer; stage IV; FOLFOX6; Chemotherapy; PledOx; Mangafodipir; Febrile neutropenia; Oxidative stress; Antioxidant; neutropenia; neuropathy

Outcome Measures

Primary Outcomes (1)

• Number of Patients With Neuropathy Grade 2 or Higher (According to the Oxaliplatin Specific Sanofi Scale (OSSS) Criteria Related Paraesthesia/Dysaesthesia)

  Percentage of patients, over cycle 1 to 8, with neuropathy grade 2 or higher (according to the Oxaliplatin Specific Sanofi Scale (OSSS) criteria related paraesthesiae/dysaesthesiae)

  Every second week during cycle 1-8, for up to 16 weeks

Study Arms (4)

FOLFOX6 + PledOx 2 µmol/kg

ACTIVE COMPARATOR

PledOx active ingredient= Calmangafodipir; FOLFOX6=Combination of FOLinic Acid, 5-Fluorouracil (5-FU), and Oxaliplatin.

Drug: PledOx (2 µmol/kg)

FOLFOX6 + PledOx 5 µmol/kg

ACTIVE COMPARATOR

PledOx active ingredient= Calmangafodipir; FOLFOX6=Combination of FOLinic Acid, 5-Fluorouracil (5-FU), and Oxaliplatin.

Drug: PledOx (5 µmol/kg)

FOLFOX6 + PledOx 10 µmol/kg

ACTIVE COMPARATOR

PledOx active ingredient= Calmangafodipir; FOLFOX6=Combination of FOLinic Acid, 5-Fluorouracil (5-FU), and Oxaliplatin.

Drug: PledOx (10 µmol/kg)

FOLFOX6 + 0,9% NaCl

PLACEBO COMPARATOR

Placebo= 0.9% NaCl; FOLFOX6=Combination of FOLinic Acid, 5-Fluorouracil (5-FU), and Oxaliplatin.

Drug: Placebo (0,9% NaCl)

Interventions

PledOx (2 µmol/kg) DRUG

PledOx is administered intravenously for up to 5 minutes, about 10 min prior to start of FOLFOX6 chemotherapy which will be administered day 1 and 2 every second week for up to 8 cycles.

Also known as: Calmangafodipir

FOLFOX6 + PledOx 2 µmol/kg

PledOx (5 µmol/kg) DRUG

PledOx is administered intravenously for up to 5 minutes, about 10 min prior to start of FOLFOX6 chemotherapy which will be administered day 1 and 2 every second week for up to 8 cycles

Also known as: Calmangafodipir

FOLFOX6 + PledOx 5 µmol/kg

PledOx (10 µmol/kg) DRUG

PledOx is administered intravenously for up to 5 minutes, about 10 min prior to start of FOLFOX6 chemotherapy which will be administered day 1 and 2 every second week for up to 8 cycles

Also known as: Calmangafodipir

FOLFOX6 + PledOx 10 µmol/kg

Placebo (0,9% NaCl) DRUG

Placebo (0,9% NaCl) is administered intravenously for up to 5 minutes, about 10 min prior to start of FOLFOX6 chemotherapy which will be administered day 1 and 2 every second week for up to 8 cycles.

Also known as: Sodium chloride

FOLFOX6 + 0,9% NaCl

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Advanced metastatic colorectal (stage IV) cancer verified by biopsy
• 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

You may not qualify if:

• 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)
• Blood manganese concentration values \>18.3 μg/L at screening

Sponsors & Collaborators

• Egetis Therapeutics: lead
• Pharma Consulting Group AB: collaborator

Study Sites (33)

Moores UCSD Cancer Center

La Jolla, California, 92093-0698, United States

Location

Center for Cancer and Blood Disorders

Bethesda, Maryland, 20817, United States

Location

Associates in Oncology & Hematology

Chattanooga, Tennessee, 37421, United States

Location

Wellmont Medical Associates Oncology and Hematology

Kingsport, Tennessee, 37660, United States

Location

The University of Texas, Health Science Center at San Antonio

San Antonio, Texas, 78229, United States

Location

Benaroya Research Institute @ Virginia Mason

Seattle, Washington, 98101, United States

Location

Complex Oncology Center-Plovdiv EOOD, Department of Medical Oncology and oncology diseases in gastroenterology

Plovdiv, 4004, Bulgaria

Location

Complex Oncology Center-Shumen EOOD, Department of Medical Oncology

Shumen, 9700, Bulgaria

Location

MHAT "Serdika" EOOD, Department of Medical Oncology

Sofia, 1303, Bulgaria

Location

UMHAT "Tzaritza Joanna-ISUL" EAD, Clinic of Medical Oncology

Sofia, 1527, Bulgaria

Location

SHATO EAD, Sofia, Clinic of Chemotherapy

Sofia, 1756, Bulgaria

Location

Aalborg University Hospital, Dept of Oncology, Clinical Research Unit

Aalborg, 9000, Denmark

Location

Odense Universitetshospital, Klinisk Forsknings Enhed, Onkologisk Afdelig R

Odense, 5000, Denmark

Location

LTD Clinic Medina

Batumi, 6000, Georgia

Location

Resaerch Institte of Clinical Medicine

Tbilisi, 0112, Georgia

Location

JSC "Neo Medi"

Tbilisi, 0131, Georgia

Location

LTD " High Technology Medical Center University Clinic"

Tbilisi, 0144, Georgia

Location

S. Khechinashvili University Hospital

Tbilisi, 179, Georgia

Location

St. Josef-Hospital -Universitätsklinik Ruhr-Universität Bochum, Leitende Ärztin der Abt. für Hämatologie und Onkologie, Medizinische Klinik I

Bochum, 44791, Germany

Location

BAG Freiberg-Richter, Jacobasch, Illmer, Wolf; Gemeinschaftspraxis Hämatologie -Onkologie

Dresden, 01307, Germany

Location

HELIOS Klinikum Wuppertal, Klinik für Hämatologie und Onkologie

Wuppertal, 42283, Germany

Location

Centro Hospitalar do Baixo Vouga, E.P.E. (Hospital Infante D. Pedro), Oncologia Médica

Aveiro, 3814-501, Portugal

Location

Hospital de Braga, Oncologia Médica

Braga, 4710-243, Portugal

Location

Instituto Português de Oncologia do Porto, Francisco Gentil, E.P.E., Oncologia Médica

Porto, 4200-072, Portugal

Location

Institute for Oncology and Radiology of Serbia, Clinic for Medical Oncology

Belgrade, 11000, Serbia

Location

Military Medical Academy, Gastroenterology department

Belgrade, 11000, Serbia

Location

Clinical Hospital Center Zemun, Insitute for Oncology

Belgrade, 11080, Serbia

Location

Clinical Center Kragujevac, Center for Oncology

Kragujevac, 34000, Serbia

Location

Gävle sjukhus, Oncology unit

Gävle, 80187, Sweden

Location

Sahlgrenska/Östra sjukhuset

Gothenburg, 41685, Sweden

Location

Universitetssjukhuset i Linköping

Linköping, SE-581 85, Sweden

Location

Karolinska Sjukhuset

Stockholm, Sweden

Location

Akademiska Sjukhuset

Uppsala, Sweden

Location

Related Publications (1)

• 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.

  PMID: 29140155 RESULT

MeSH Terms

Conditions

Colorectal Neoplasms; Febrile Neutropenia; Neutropenia

Interventions

N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid; Sodium Chloride

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Agranulocytosis; Leukopenia; Cytopenia; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukocyte Disorders

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Limitations and Caveats

The pre-specified statistical analysis plan (SAP) states; if the primary outcome meassure failed, then all additional outcome measures are considered exploratory. A selected number of the exploratory outcomes are presented in the linked publication

Results Point of Contact

• Title: Stefan Carlsson, MD, PhD, Chief Medical Officer
• Organization: PledPharma AB

stefan.carlsson@pledpharma.se

+46 8 679 72 10

Study Officials

• Marie Bengtson

  Egetis Therapeutics

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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)

Study Record Dates

• First Submitted: May 25, 2012
• First Posted: June 14, 2012
• Study Start: September 1, 2012
• Primary Completion: March 1, 2016
• Study Completion: December 1, 2016
• Last Updated: July 6, 2018
• Results First Posted: July 6, 2018

Record last verified: 2018-07

Locations

SE (4); US (6); DE (3); PT (3); DK (2); BU (5); GE (5)