Purpose

This study evaluates the investigational drug PledOx in the prevention of chronic chemotherapy induced peripheral neuropathy (CIPN) induced by the drug oxaliplatin.

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • Signed informed consent form before any study related assessments and willing to follow all study procedures.
  • Male or female aged >=18 years.
  • Non-resectable metastatic (stage IV) CRC, pathologically confirmed adenocarcinoma of the colon or rectum.
  • No prior chemotherapy (within the previous 12 months) and/or biologic/targeted therapy for mCRC.
  • Measurable disease according to RECIST 1.1.
  • Patient indicated for at least 3 months of oxaliplatin-based chemotherapy (without any pre-planned treatment breaks) and without any clinically observed neurological disorders.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Adequate hematological parameters: hemoglobin >=100 g/L, absolute neutrophil count (ANC) >=1.5 x 10^9 /L, platelets >=100 x 10^9 /L.
  • Adequate renal function: creatinine clearance >50 cc/min using the Cockroft and Gault formula or measured.
  • Adequate hepatic function: total bilirubin <=1.5 times the upper limit of normal (ULN) (except in the case of known Gilbert's syndrome); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=3 times ULN (AST and ALT <=5 times ULN in case of liver metastases).
  • Baseline blood manganese (Mn) level <2.0 times ULN.
  • For patients with a history of diabetes mellitus, HbA1c <=7%.
  • Negative pregnancy test for females of child-bearing potential.
  • For men and females of childbearing potential, use of adequate contraception (oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) while on study drug and for at least 6 months after completion of study therapy.

Exclusion Criteria

  • Any unresolved toxicity by Common Terminology Criteria for Adverse Events Version (CTCAE v4.03) > Grade 1 from previous anti-cancer therapy (including radiotherapy), except alopecia.
  • Any grade of neuropathy from any cause.
  • Any prior oxaliplatin-based chemotherapy <1 year before the randomization.
  • Any evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, cardiac, unresolved bowel obstruction, hepatic or renal disease).
  • Chronic infection or uncontrolled serious illness causing immunodeficiency.
  • A surgical incision that is not healed.
  • Significant hemorrhage (>30 mL/bleeding episode in previous 3 months), hemoptysis (>5 mL fresh blood in previous 4 weeks) or thrombotic event (including transient ischemic attack) in the previous 12 months if the patient is expected to receive anti-VEGF/VEGFR therapy.
  • Known hypersensitivity to any of the components of mFOLFOX6 and, if applicable, biological therapies to be used in conjunction with the chemotherapy regimen or any of the excipients of these products.
  • History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within 5 years, unless the patient has been disease free for that other malignancy for at least 2 years.
  • Known dihydropyrimidine dehydrogenase deficiency.
  • Pre-existing neurodegenerative disease (e.g., Parkinson's, Alzheimer's, Huntington's) or neuromuscular disorder (e.g., multiple sclerosis, amyotrophic lateral sclerosis, polio, hereditary neuromuscular disease).
  • Major psychiatric disorder (major depression, psychosis), alcohol and/or drug abuse.
  • Patients with a history of second or third degree atrioventricular block or a family heredity.
  • A history of a genetic or familial neuropathy.
  • Treatment with any investigational drug within 30 days prior to randomization.
  • Pregnancy, lactation or reluctance to using contraception.
  • Any other condition that, in the opinion of the Investigator, places the patient at undue risk.
  • Previous exposure to mangafodipir or calmangafodipir.
  • Welders, mine workers or other workers in occupations (current or past) where high manganese exposure is likely.

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
This is a Phase 3, multicenter, double-blind, placebo-controlled study to establish the efficacious dose of PledOx in prevention of chronic chemotherapy induced peripheral neuropathy (CIPN) induced by oxaliplatin. Patients with metastatic colorectal cancer (mCRC), who are indicated for first-line modified FOLFOX6 (mFOLFOX6) chemotherapy for at least 3 months, without any pre-planned treatment breaks, will be randomized in a 1:1:1 ratio, stratified by prior oxaliplatin exposure (yes/no), to one of three treatment arms: Arm A: PledOx (2 µmol/kg) + mFOLFOX6 chemotherapy Arm B: PledOx (5 µmol/kg) + mFOLFOX6 chemotherapy Arm C: Placebo + mFOLFOX6 chemotherapy The Investigational Medicinal Product, IMP (i.e. PledOx or placebo) will be administered by an intravenous infusion on the first day of each chemotherapy (mFOLFOX6) cycle.
Primary Purpose
Prevention
Masking
Triple (Participant, Care Provider, Investigator)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
PledOx (2 µmol/kg)
Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy.
  • Drug: Calmangafodipir (2 µmol/kg)
    Bright yellow, clear solution in 20 mL colourless, single dose, glass vial
    Other names:
    • PledOx
Experimental
PledOx (5 µmol/kg)
Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy.
  • Drug: Calmangafodipir (5 µmol/kg)
    Bright yellow, clear solution in 20 mL colourless, single dose, glass vial
    Other names:
    • PledOx
Placebo Comparator
Placebo
Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy.
  • Drug: Placebo
    Bright yellow, clear solution in 20 mL amber, single dose, glass vial

Recruiting Locations

Montefiore Medical Research
Bronx, New York 10461
Contact:
Sanjay Goel, MD
516-470-6911

More Details

NCT ID
NCT03654729
Status
Recruiting
Sponsor
PledPharma AB

Study Contact

Stefan Carlsson, MD
+46709641009
stefan.carlsson@pledpharma.se

Detailed Description

Oxaliplatin, in combination with 5-fluorouracil plus folinate (or capecitabine), has increased survival in stage III colorectal cancer and prolonged life in stage IV patients, but its use is compromised because of severe toxicity. Chemotherapy-induced peripheral neuropathy (CIPN) is the most problematic dose-limiting toxicity of oxaliplatin. No treatments have been clinically proven to prevent CIPN. There is a body of evidence that CIPN is caused by cellular oxidative stress. Clinical and preclinical data suggest that the manganese chelate and superoxide dismutase mimetic mangafodipir (MnDPDP) and calmangafodipir (Ca4Mn(DPDP)5) are efficacious inhibitors of CIPN and other conditions caused by cellular oxidative stress, without interfering negatively with the tumoricidal activity of chemotherapy.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.