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Trial record 1 of 1 for:    PP06490
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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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03654729
Recruitment Status : Terminated (On 23 January 2020, the Sponsor announced that the United States (US) Food and Drug Administration (FDA) had issued a clinical hold in the US of the POLAR program.)
First Posted : August 31, 2018
Results First Posted : December 17, 2021
Last Update Posted : December 17, 2021
Sponsor:
Collaborator:
Solasia Pharma K.K.
Information provided by (Responsible Party):
Egetis Therapeutics

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 ([Ca0.8,Mn0.2]Na3DPDP) are efficacious inhibitors of CIPN and other conditions caused by cellular oxidative stress, without interfering negatively with the tumoricidal activity of chemotherapy.

This is a Phase 3, multicenter, double-blind, placebo-controlled study to establish the efficacious dose of PledOx in prevention of chronic 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 region (Asia, non-Asia) and PK sub-study (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

Before March 2nd., 2020, the Investigational Medicinal Product, (IMP; i.e. PledOx or placebo) was administered by an intravenous infusion on the first day of each chemotherapy (mFOLFOX6) cycle. IMP was not to be administered if mFOLFOX6 was not given to the patient.

If a patient later discontinues oxaliplatin, treatment with 5-FU/folinate may be continued.

The addition of an appropriate biologic therapy (bevacizumab, panitumumab, cetuximab) will be left to the discretion of the Investigator.

As of March 2nd., all patients have to stop IMP but may continue mFOLFOX 6

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 291 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 region (Asia, non-Asia) and PK sub-study (yes, no) to one of three treatment arms:

  • Arm A: PledOx (2 µmol/kg) + mFOLFOX6 chemotherapy
  • Arm B: PledOx (5 µmol/kg) + m
  • Arm C: Placebo + mFOLFOX6 chemotherapy
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 : November 7, 2018
Actual Primary Completion Date : August 31, 2020
Actual Study Completion Date : August 31, 2020

Resource links provided by the National Library of Medicine


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)
Solution in 20 mL single dose glass vials
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)
Solution in 20 mL single dose glass vials
Other Name: PledOx

Placebo Comparator: Placebo
Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy.
Drug: Placebo
Solution in 20 mL single dose glass vials




Primary Outcome Measures :
  1. Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN) [ Time Frame: 9 months ]
    Percentage of patients (with moderate or severe chronic CIPN) scoring 3 or 4 in at least 1 of the first 4 items of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity-13-item subscale (FACT/GOG-NTX-13; i.e., FACT/GOG-NTX-4) 9 months after the first dose of IMP (i.e. PledOx or placebo administered on Day 1, Cycle 1 of mFOLFOX6 chemotherapy). The FACT/GOG-13 questionnaire includes 13 items that measure the severity and impact of symptoms of neurotoxicity over the past 7 days. Patients rate each item as 0 ("not at all"), 1 (" a little bit"), 2 ("somewhat"), 3 ("quite a bit") or 4 ("very much"). These 13 items are summed to create a total score, ranging from 0 to 52, with a higher score representing a worse outcome. The FACT/GOG-NTX-4 is a 4 item subscale targeting numbness, tingling or discomfort in hands and/or feet.


Secondary Outcome Measures :
  1. Mild, Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN) [ Time Frame: 9 months ]
    Percentage 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 Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity-13-item subscale (FACT/GOG-NTX-13; i.e., FACT/GOG-NTX-4) 9 months after the first dose of IMP (i.e. PledOx or placebo administered on Day 1, Cycle 1 of mFOLFOX6 chemotherapy). The FACT/GOG-13 questionnaire includes 13 items that measure the severity and impact of symptoms of neurotoxicity over the past 7 days. Patients rate each item as 0 ("not at all"), 1 (" a little bit"), 2 ("somewhat"), 3 ("quite a bit") or 4 ("very much"). These 13 items are summed to create a total score, ranging from 0 to 52, with a higher score representing a worse outcome. The FACT/GOG-NTX-4 is a 4 item subscale targeting numbness, tingling or discomfort in hands and/or feet.

  2. Sensitivity to Touching Cold Items [ Time Frame: Baseline and 8 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: Baseline and 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. When the tuning fork was struck against the ball of the thumb, the base of the tuning fork was placed over the appropriate bony surface (i.e., lateral malleolus left and right) and the patient was asked to indicate the moment when the vibration was no longer detected. The intensity at which the patient no longer detected the vibration is reported on a scale of 0 (minimum score, representing the maximum vibration amplitude) to 8 (maximum score, representing the minimum vibration amplitude)

  5. Worst Pain in Hands or Feet [ Time Frame: Baseline and 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: Baseline and 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. Overall Response Rate (ORR) [ Time Frame: 12, 15 and 18 months ]
    Percentage of patients with an overall response (complete response or partial response) according to RECIST v1.1 for target lesions and assessed by CT (preferred) or MRI. Complete response=disappearance of all target lesions; partial response >=30% decrease in the sum of the longest diameter of target lesions.

  8. Progression-free Survival (PFS) [ Time Frame: Analyses at 12 and 24 months were planned; the analysis was performed once based on available data at cut-off 31 August 2020 as the study was terminated early by the Sponsor ]
    Patients with progression-free survival

  9. Overall Survival (OS) [ Time Frame: An analysis at 36 months was planned. The analysis was performed based on available data at cut-off 31 August 2020 as the study was terminated early by the Sponsor ]
    Patients with overall survival



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 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.
  • Any history of seizures.
  • 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


Locations
Show Show 98 study locations
Sponsors and Collaborators
Egetis Therapeutics
Solasia Pharma K.K.
Investigators
Layout table for investigator information
Study Director: Stefan Carlsson, MD Chief Medical Officer
  Study Documents (Full-Text)

Documents provided by Egetis Therapeutics:
Study Protocol  [PDF] May 15, 2020
Statistical Analysis Plan  [PDF] September 2, 2020

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Egetis Therapeutics
ClinicalTrials.gov Identifier: NCT03654729    
Other Study ID Numbers: PP06490
First Posted: August 31, 2018    Key Record Dates
Results First Posted: December 17, 2021
Last Update Posted: December 17, 2021
Last Verified: November 2021
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 Egetis Therapeutics:
Metastatic
Colorectal
Cancer
Metastatic Colorectal Cancer
Oxaliplatin induced CIPN
CIPN
Oxaliplatin
Additional relevant MeSH terms:
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Colorectal Neoplasms
Peripheral Nervous System Diseases
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neuromuscular Diseases
Nervous System Diseases
Pyridoxal Phosphate
Edetic Acid
Anticoagulants
Calcium Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex
Vitamins
Micronutrients
Physiological Effects of Drugs