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

Colorectal Cancer Clinical Trial

— POLAR-M  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03654729
• Other study ID #: PP06490
• Status: Terminated
• Phase: Phase 3
• Start date: November 7, 2018
• Est. completion date: August 31, 2020

Study information

• Verified date: November 2021
• Source: Egetis Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 291
• Est. completion date: August 31, 2020
• Est. primary completion date: August 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chemotherapy-induced Peripheral Neuropathy
• Colorectal Cancer
• Colorectal Neoplasms
• Peripheral Nervous System Diseases

Intervention

Drug:
• Calmangafodipir (2 µmol/kg)
Solution in 20 mL single dose glass vials
• Calmangafodipir (5 µmol/kg)
Solution in 20 mL single dose glass vials
• Placebo
Solution in 20 mL single dose glass vials

Locations

Country	Name	City	State
Belgium	Onze-Lieve-Vrouwziekenuis Aalst	Aalst
Belgium	Imelda GI Clinical Research Center	Bonheiden
Belgium	Cliniques Universitaires St-Luc	Brussels
Belgium	UZ Gent	Gent
Belgium	CHU Liège	Liege
Belgium	AZ Sint Maarten	Mechelen
Belgium	AZ Delta	Roeselare
Belgium	CHU UCL Namur - Site Godinne	Yvoir
Czechia	Nemocnice Benesov	Benešov
Czechia	Nemocnice Horovice	Horovice
Czechia	Nemocnice Na Pleši	Nová Ves Pod Pleší
Czechia	Hospital Na Bulovce	Prague
Czechia	Onkologická Klinika 1. Lf Uk A Tn	Prague
Czechia	General University Hospital	Prague 2
France	CHRU de Brest - Hôpital Morvan	Brest
France	Clinique Pasteur-Lanroze	Brest Cedex 2
France	Centre Hospitalier Départemental de Vendée - Unité de recherche clinique	La Roche-sur-Yon
France	Centre Oscar Lambret	Lille
France	Hôpital Edouard Herriot - HCL	LYON Cedex 03
France	Hôpital Nord Franche-Comté Site du Mittan	Montbéliard Cedex
France	Institut de Cancérologie de l'Ouest	Nantes
France	Hopital l'Archet, CHU de Nice	NICE Cedex 3
France	Hôpital Robert Debré	Reims
France	Centre Hospitalier Privé Saint-Grégoire	Saint-Grégoire
France	Clinique Ste Anne	Strasbourg
France	Hopitaux Universitaires de Strasbourg	Strasbourg
Germany	Hämatolgisch-onkologische Praxis Augsburg	Augsburg
Germany	Onkozentrum Dresden	Dresden
Germany	Universitätsklinikum Carl Gustav Carus	Dresden
Germany	Agaplesion Markus Krankenhaus	Frankfurt
Germany	Onkodok GmbH	Gütersloh
Germany	Klinikum Neuperlach	München
Hong Kong	Queen Mary Hospital	Hong Kong
Hungary	Országos Onkológiai Intézet	Budapest
Hungary	Semmelweis Egyetem	Budapest
Hungary	Borsod-Abaúj-Zemplén Megyei Központi Kórház és Egyetemi Oktatókórház	Miskolc
Hungary	Tolna Megyei Balassa Janos Korhaz	Szekszárd
Hungary	Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház-Rendelointézet	Szolnok
Italy	IRCCS Candiolo	Candiolo
Italy	Oncologia Istituti Ospitalieri	Cremona
Italy	Irccs Irst	Meldola - FC
Italy	Azienda Ospedaliero - Universitaria di Modena Policlinico	Modena
Italy	Hospital San Gerardo	Monza
Italy	Istituto Nazionale Tumori	Napoli
Italy	IRCCS Policlinico San Matteo	Pavia
Italy	Ospedale degli infermi	Ponderano
Italy	Ospedale S. Maria delle Croci - Ravenna	Ravenna
Italy	IRCCS azienda Ospedaliera S Maria Nuova	Reggio Emilia
Italy	San Camillo Forlanini Hospital	Rome
Italy	Casa Sollievo della Sofferenza	San Giovanni Rotondo
Japan	Fujita Health University Hospital	Aichi
Japan	Fukuoka University Hospital	Fukuoka-shi, Fukuoka
Japan	Kyushu University Hospital	Fukuoka-shi, Fukuoka
Japan	Kansai Rosai Hospital	Hyogo
Japan	St. Marianna University School of Medicine Hospital	Kanagawa
Japan	Aichi Cancer Center Hospital	Nagoya-shi, Aichi
Japan	Osaka University Hospital	Osaka
Japan	National Hospital Organization Osaka National Hospital	Osaka-shi, Osaka
Japan	Osaka International Cancer Institute	Osaka-shi, Osaka	Osaka
Japan	Sapporo Medical University Hospital	Sapporo-shi, Hokkaido
Japan	Shizuoka Cancer Center	Shizuoka
Japan	The Cancer Institute Hospital Of JFCR	Tokyo
Korea, Republic of	Hallym University Sacred Heart Hospital	Anyang-si
Korea, Republic of	Dong-A University Hospital	Busan
Korea, Republic of	Chonnam National University Hwasun Hospital	Gwangju
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Spain	Hospital de La Santa Creu I Sant Pau	Barcelona
Spain	L´Hospitalet de Llobregat (Barcelona)	Barcelona
Spain	Vall d'hebron university hospital	Barcelona
Spain	Complejo Hospitalario de Jaén	Jaén
Spain	Centro Integral Oncologico Clara Campal	Madrid
Spain	H.G.U.Gregorio Marañón	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Puerta de Hierro	Majadahonda
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Hospital Quironsalud Valencia	València
Spain	Hospital Miguel Servet	Zaragoza
Taiwan	KMUH: Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	CMMC: Chi Mei Medical Center	Tainan
Taiwan	NCKUH: National Cheng Kung University Hospital	Tainan
United Kingdom	Royal Marsden Hospital	London
United Kingdom	North Tyneside General Hospital	North Shields
United Kingdom	Mount Vernon Cancer Centre	Northwood
United Kingdom	The Royal Marsden Hospital (Surrey)	Sutton
United Kingdom	York Teaching Hospital	York
United States	Montefiore Medical Research	Bronx	New York
United States	Hunterdon Hematology Oncology	Flemington	New Jersey
United States	California Cancer Associates	Fresno	California
United States	CHI St Francis Cancer Treatment Center	Grand Island	Nebraska
United States	Monter Cancer Center	Lake Success	New York
United States	Mid Florida Hematology and Oncology Center	Orange City	Florida
United States	Mercy Clinic Oncology and Hematology	Saint Louis	Missouri
United States	Willis-Knighton Cancer Center	Shreveport	Louisiana
United States	Mercy Clinic - Cancer & Hematology	Springfield	Missouri
United States	Scott & White Vasicek Cancer Treatment Center	Temple	Texas
United States	Cancer Center of Kansas	Wichita	Kansas

Sponsors (2)

Lead Sponsor	Collaborator
Egetis Therapeutics	Solasia Pharma K.K.

Countries where clinical trial is conducted

United States,  Belgium,  Czechia,  France,  Germany,  Hong Kong,  Hungary,  Italy,  Japan,  Korea, Republic of,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN)	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.	9 months
Secondary	Mild, Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN)	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.	9 months
Secondary	Sensitivity to Touching Cold Items	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.	Baseline and 8 weeks
Secondary	Cumulative Dose of Oxaliplatin During Chemotherapy	Mean cumulative dose of oxaliplatin administered per patient during mFOLFOX6 chemotherapy, 9 months after the first dose of IMP.	9 months
Secondary	Vibration Sensitivity on the Lateral Malleolus	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)	Baseline and 9 months
Secondary	Worst Pain in Hands or Feet	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.	Baseline and 9 months
Secondary	Functional Impairment (in the Non-dominant Hand)	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.	Baseline and 9 months
Secondary	Overall Response Rate (ORR)	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.	12, 15 and 18 months
Secondary	Progression-free Survival (PFS)	Patients with progression-free survival	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
Secondary	Overall Survival (OS)	Patients with overall survival	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