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

• ClinicalTrials.gov Identifier: NCT03654729
• Recruitment Status: Recruiting
• First Posted: August 31, 2018
• Last Update Posted: November 13, 2019
• Sponsor: PledPharma AB
• Collaborator: Solasia Pharma K.K.
• Information provided by (Responsible Party): PledPharma AB

Study Description

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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)

Eligibility Criteria

• 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.

Contacts and Locations

Contacts

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

  Show 107 Study Locations

Sponsors and Collaborators

PledPharma AB

Solasia Pharma K.K.

Investigators

• Study Director: Stefan Carlsson, MD; Chief Medical Officer

More Information

• Responsible Party: PledPharma AB
• ClinicalTrials.gov Identifier: NCT03654729 History of Changes
• Other Study ID Numbers: PP06490
• First Posted: August 31, 2018
• Last Update Posted: November 13, 2019
• Last Verified: November 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

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