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Preventive Treatment of Oxaliplatin Induced Peripheral Neuropathy in Metastatic Colorectal Cancer (POLAR-M) (POLAR-M)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03654729
Recruitment Status : Recruiting
First Posted : August 31, 2018
Last Update Posted : November 13, 2019
Sponsor:
Collaborator:
Solasia Pharma K.K.
Information provided by (Responsible Party):
PledPharma AB

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

Condition or disease Intervention/treatment Phase
Colorectal Cancer Chemotherapy-induced Peripheral Neuropathy Drug: Calmangafodipir (2 µmol/kg) Drug: Calmangafodipir (5 µmol/kg) Drug: Placebo Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 420 participants
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.

Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Official Title: A Phase 3, Double-blind, Multicenter, Placebo-controlled Study of PledOx Used on Top of Modified FOLFOX6 (5-FU/FA and Oxaliplatin) to Prevent Chemotherapy Induced Peripheral Neuropathy (CIPN) in Patients With First-line mCRC
Actual Study Start Date : October 1, 2018
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Oxaliplatin

Arm Intervention/treatment
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 Name: 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 Name: 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




Primary Outcome Measures :
  1. Moderate or severe chronic chemotherapy induced peripheral neuropathy (CIPN) [ Time Frame: 9 months ]
    Proportion of patients (with moderate or severe chronic CIPN) scoring 3 or 4 in at least 1 of the first 4 items of the FACT/GOG-NTX-13 (i.e., FACT/GOG-NTX-4), targeting numbness, tingling or discomfort in hands and/or feet, 9 months after the first dose of IMP (i.e. PledOx or placebo administered on Day 1, Cycle 1 of mFOLFOX6 chemotherapy).


Secondary Outcome Measures :
  1. Mild, moderate or severe chronic chemotherapy induced peripheral neuropathy (CIPN) [ Time Frame: 9 months ]
    Proportion of patients (with mild, moderate or severe chronic CIPN) scoring 2, 3, or 4, in at least 1 of the first 4 items of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), targeting numbness, tingling or discomfort in hands and/or feet, 9 months after the first dose of IMP.

  2. Sensitivity to touching cold items [ Time Frame: 6 weeks ]
    Mean change from baseline in sensitivity to touching cold items on day 2, Cycle 4 of mFOLFOX6 chemotherapy, as assessed by the Cold Sensitivity Questionnaire (measuring sensitivity when touching or swallowing cold objects/fluid). 10 point scale from 0 meaning no sensitivity/discomfort at all to 10 meaning sensitivity/discomfort as bad as it can be.

  3. Cumulative dose of oxaliplatin during chemotherapy [ Time Frame: 9 months ]
    Mean cumulative dose of oxaliplatin administered per patient during mFOLFOX6 chemotherapy, 9 months after the first dose of IMP.

  4. Vibration sensitivity on the lateral malleolus [ Time Frame: 9 months ]
    Mean change from baseline in vibration sense, on the lateral malleolus (left and right), using a graduated tuning fork, at 9 months after the first dose of IMP.

  5. Worst pain in hands or feet [ Time Frame: 9 months ]
    Mean change from baseline in worst pain in hands or feet in the past week, using the Pain Assessment (Numerical Rating Scale (NRS)), at 9 months after the first dose of IMP. The NRS is a 10 point scale with 0 as no pain at all and 10 as pain as bad as you can imagine and evaluates the intensity of pain in hands and feet during the past week. A higher value means worse outcome.

  6. Functional impairment (in the non-dominant hand) [ Time Frame: 9 months ]
    Mean change from baseline in the time to complete the grooved Pegboard with the non-dominant hand, at 9 months after the first dose of IMP.

  7. Sustained efficacy on prevention of CIPN during long-term follow-up [ Time Frame: 12, 15, 18, 21 and 24 months ]
    Proportion of patients scoring 3 or 4 in at least 1 of the first 4 items of the FACT/GOGNTX-13 (i.e. FACT/GOG-NTX-4), targeting numbness, tingling or discomfort in hands and/or feet, 12, 15, 18, 21 and 24 months after the first dose of IMP.

  8. Overall response rate (ORR) [ Time Frame: 12 and 24 months ]
    ORR, according to RECIST v1.1

  9. Progression-free survival (PFS) [ Time Frame: 12 and 24 months ]
    PFS

  10. Overall survival (OS) [ Time Frame: 36 months ]
    Time to death (OS)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03654729


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

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Sponsors and Collaborators
PledPharma AB
Solasia Pharma K.K.
Investigators
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Study Director: Stefan Carlsson, MD Chief Medical Officer

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Responsible Party: PledPharma AB
ClinicalTrials.gov Identifier: NCT03654729     History of Changes
Other Study ID Numbers: PP06490
First Posted: August 31, 2018    Key Record Dates
Last Update Posted: November 13, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by PledPharma AB:
Metastatic
Colorectal
Cancer
Metastatic Colorectal Cancer
Oxaliplatin induced CIPN
CIPN
Oxaliplatin
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Colonic Diseases
Peripheral Nervous System Diseases
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Neuromuscular Diseases
Nervous System Diseases
Pyridoxal Phosphate
Oxaliplatin
Edetic Acid
Antineoplastic Agents
Anticoagulants
Calcium Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs