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

This study has been completed.
Sponsor:
Collaborator:
Pharma Consulting Group AB
Information provided by (Responsible Party):
PledPharma AB
ClinicalTrials.gov Identifier:
NCT01619423
First received: May 25, 2012
Last updated: January 11, 2017
Last verified: January 2017
  Purpose

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 two different doses of PledOx will be assessed when added to FOLFOX6 chemotherapy as first line treatment of metastatic colorectal cancer.


Condition Intervention Phase
Advanced Metastatic (Stage IV) Colorectal Cancer
Drug: PledOx (2 µmol/kg)
Drug: PledOx (5 µmol/kg)
Drug: Placebo (0,9% NaCl)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by PledPharma AB:

Primary Outcome Measures:
  • Presence of neuropathy grade 2 or higher (according to the Sanofi-NCI criteria for oxaliplatin related paraesthesiae/dysaesthesiae) [ Time Frame: Every second week, in 16 weeks and thereafter every 12th week for up to 12 months ]

Secondary Outcome Measures:
  • Febrile neutropenia [ Time Frame: Every second week, in 16 weeks ]
  • CT or MRI of thorax, abdomen and pelvis [ Time Frame: From baseline until progression or up to 16 months, whichever comes first ]
    Response Rate (RR) and Progression Free Survival (PFS)as assessed by RECIST 1.1

  • Presence of positive cold allodynia test assessed by subjects [ Time Frame: Every second week, in 16 weeks ]
    This assessment is novel and will be measured on 0-10 numerical rating scales where 0 = no pain and 10 = worst possible pain.

  • Oxaliplatin-associated sensory neuropathy [ Time Frame: Every second week, in 16 weeks and thereafter every 12th week for up to 12 months. ]
    Assessed by a patient reported outcome scale (Leonard et al.).

  • Change in Absolute Neutrophil count from both baseline and in between readings [ Time Frame: Every second week, in 16 weeks ]
    As defined by neutropenia

  • Oral mucositis [ Time Frame: Every second week, in 16 weeks and thereafter every 12th week for up to 12 months ]
  • Change in white blood cell count both from baseline and in between readings [ Time Frame: Every second week, in 16 weeks and thereafter every 12th week up to 12 months ]
  • Change in platelet count from both baseline and in between readings [ Time Frame: Every second week, in 16 weeks adn thereafter every 12th week for up to 12 months ]
  • Change in haemoglobin from both baseline and in between readings [ Time Frame: Every second week, in 16 weeks and thereafter every 12th week for up to 12 months ]
  • Change in FOLFOX6 dose frequency and intensity [ Time Frame: Every second week for up to 16 weeks ]
    As compared to standard treatment guidelines

  • Survival [ Time Frame: from baseline up to 24 months ]
  • Change in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) from baseline [ Time Frame: Every second week, in 16 weeks and thereafter every 12th week for up to 12 months ]
  • Plasma concentration half-life of of PledOx (metabolites ZnDPDP, ZnPLED, ZnDPMP) [ Time Frame: From time 0 to last observed concentration ]
    Dose Escalation phase

  • The maximum plasma concentration (Cmax) and the corresponding time (Tmax) of PledOx (metabolites ZnDPDP, ZnPLED, ZnDPMP) [ Time Frame: From time 0 to last observed concentration ]
    Dose Escalation phase

  • Area under the plasma concentration versus time curve (AUC) of PledOx (metabolites ZnDPDP, ZnPLED, ZnDPMP) [ Time Frame: From time 0 to last observed concentration ]
    Dose Escalation phase

  • Plasma concentration half-life of of PledOx (metabolites ZnDPDP, ZnPLED, ZnDPMP) [ Time Frame: From time 0 to last observed concentration ]
    Randomization phase

  • The maximum plasma concentration (Cmax) and the corresponding time (Tmax) of PledOx (metabolites ZnDPDP, ZnPLED, ZnDPMP) [ Time Frame: From time 0 to last observed concentration ]
    Randomization phase

  • Area under the plasma concentration versus time curve (AUC) of PledOx (metabolites ZnDPDP, ZnPLED, ZnDPMP) [ Time Frame: From time 0 to last observed concentration ]
    Randomization phase

  • Electrocardiogram (ECG) [ Time Frame: at appropriate timepoints during the 30 minutes following PledOx administration at the every cycle ]
    Dose Escalation phase

  • Electrocardiogram (ECG) [ Time Frame: at appropriate timepoints during the 30 minutes following PledOx administration at the first cycle only ]
    Randomization phase

  • Manganese level in whole blood [ Time Frame: Change from baseline at 16 weeks or end-of-treatment, whatever comes first ]

Enrollment: 186
Study Start Date: September 2012
Study Completion Date: December 2016
Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: FOLFOX6 + PledOx 2 µmol/kg
PledOx active ingredient= Calmangafodipir; FOLFOX6=Combination of FOLinic Acid, 5-Fluorouracil (5-FU), and Oxaliplatin.
Drug: PledOx (2 µmol/kg)
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.
Other Name: Calmangafodipir
Active Comparator: FOLFOX6 + PledOx 5 µmol/kg
PledOx active ingredient= Calmangafodipir; FOLFOX6=Combination of FOLinic Acid, 5-Fluorouracil (5-FU), and Oxaliplatin.
Drug: PledOx (5 µmol/kg)
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
Other Name: Calmangafodipir
Placebo Comparator: FOLFOX6 + 0,9% NaCl
Placebo= 0.9% NaCl; FOLFOX6=Combination of FOLinic Acid, 5-Fluorouracil (5-FU), and Oxaliplatin.
Drug: Placebo (0,9% NaCl)
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.
Other Name: Sodium chloride

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

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01619423

  Show 33 Study Locations
Sponsors and Collaborators
PledPharma AB
Pharma Consulting Group AB
Investigators
Study Director: Marie Bengtson PledPharma AB
  More Information

Responsible Party: PledPharma AB
ClinicalTrials.gov Identifier: NCT01619423     History of Changes
Other Study ID Numbers: PP095, (PLIANT)
2012-001367-76 ( EudraCT Number )
Study First Received: May 25, 2012
Last Updated: January 11, 2017

Keywords provided by PledPharma AB:
Metastatic colorectal cancer
stage IV
FOLFOX6
Chemotherapy
PledOx
Mangafodipir
Febrile neutropenia
Oxidative stress
Antioxidant
neutropenia
neuropathy

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Fluorouracil
Oxaliplatin
Leucovorin
Pyridoxal Phosphate
Edetic Acid
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antidotes
Protective Agents
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Anticoagulants

ClinicalTrials.gov processed this record on April 28, 2017