Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy in Adjuvant Colorectal Cancer

Colorectal Cancer Clinical Trial

— POLAR-A  

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 the Adjuvant Treatment of Patients With Stage III or High-risk Stage II Colorectal Cancer

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04034355
• Other study ID #: PP06489
• Secondary ID: 2017-004707-43
• Status: Terminated
• Phase: Phase 3
• Start date: January 7, 2019
• 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 is to evaluate PledOx for prevention of chronic chemotherapy induced peripheral neuropathy induced by oxaliplatin in patients with Stage III or high-risk Stage II colorectal cancer (CRC).

Description:

This is a Phase 3, multicenter, double-blind, placebo-controlled study with PledOx for prevention of chronic CIPN induced by oxaliplatin in patients with Stage III or high-risk Stage II colorectal cancer (CRC). Patients with CRC, who are indicated for adjuvant modified FOLFOX6 (mFOLFOX6) chemotherapy for up to 6 months, will be randomized in a 1:1 ratio to 1 of 2 treatment arms: - Arm A: PledOx (5 µmol/kg) + mFOLFOX6 chemotherapy - Arm B: Placebo + mFOLFOX6 chemotherapy Before March 2nd., 2020, the investigational medicinal product (IMP; i.e. PledOx or placebo) was administered by an intravenous (i.v.) infusion on the first day of each chemotherapy 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 and IMP may be continued. As of March 2nd., all patients have to stop IMP but may continue mFOLFOX6.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 301
• 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:

1. Signed informed consent form before any study related assessments and willing to follow all study procedures.

2. Male or female aged =18 years.

3. Pathologically confirmed adenocarcinoma of the colon or rectum including: Stage III carcinoma (any T N1,2 M0) or Stage II carcinoma (T3,4 N0 M0).

4. The patient has undergone curative (R0) surgical resection performed within 12 weeks prior to randomization

5. The patient has a postsurgical carcinoembryonic antigen (CEA) level =1.5 x upper limit of normal (ULN, in current smokers, CEA level =2.0 x ULN is allowed).

6. No prior anti-cancer therapy for CRC except radiotherapy or concomitant chemo-radiotherapy using a fluoropyrimidine alone for locoregional rectal cancer.

7. Patient indicated for up to 6 months of oxaliplatin-based chemotherapy and without pathological findings of a neurologic exam performed prior to oxaliplatin treatment according to local practice.

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

9. Adequate hematological parameters: hemoglobin =100 g/L, absolute neutrophil count =1.5 x 109 /L, platelets =100 x 109 /L.

10. Adequate renal function: creatinine clearance >50 cc/min using the Cockcroft and Gault formula or measured.

11. Adequate hepatic function: total bilirubin =1.5 x ULN (except in the case of known Gilbert's syndrome); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =3 x ULN.

12. Baseline blood manganese (Mn) level <2.0 x ULN.

13. For patients with a history of diabetes mellitus, HbA1c =7%.

14. Negative pregnancy test for women of child-bearing potential (WOCBP).

15. For men and WOCBP, use of adequate contraception (oral contraceptives, intrauterine device or surgically sterile) while on study drug and for at least 6 months after completion of study therapy.

Exclusion Criteria:

1. Any evidence of metastatic disease.

2. Any unresolved toxicity by National Cancer Institute-Common Terminology Criteria for Adverse Events Version (NCI-CTCAE) v.4.03 >Grade 1 from previous anti-cancer therapy (including radiotherapy), except alopecia.

3. Any grade of neuropathy from any cause.

4. Any evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, cardiac, unresolved bowel obstruction, hepatic or renal disease).

5. Chronic infection or uncontrolled serious illness causing immunodeficiency. Patients with known history of chronic hepatitis B can be enrolled if they are asymptomatic and an acute and active HBV infection can be excluded.

6. Any history of seizures.

7. A surgical incision that is not healed.

8. Known hypersensitivity to any of the components of mFOLFOX6 and, if applicable, therapies to be used in conjunction with the chemotherapy regimen or any of the excipients of these products.

9. 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.

10. Known dihydropyrimidine dehydrogenase deficiency.

11. 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).

12. Major psychiatric disorder (major depression, psychosis), alcohol and/or drug abuse.

13. Patients with a history of second or third degree atrioventricular block or a family heredity.

14. A history of a genetic or familial neuropathy.

15. Treatment with any investigational drug within 30 days prior to randomization.

16. Pregnancy, lactation or reluctance to using contraception.

17. Any other condition that, in the opinion of the Investigator, places the patient at undue risk.

18. Previous exposure to mangafodipir or calmangafodipir.

19. Welders, mine workers or other workers in occupations (current or past) where high Mn exposure is likely.

Related Conditions & MeSH terms

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

Intervention

Drug:
• Calmangafodipir (5 µmol/kg)
PledOx will be given to patients as an i.v. infusion, on top of mFOLFOX6 chemotherapy. PledOx is a solution in 20 mL single dose glass vials.

Other:
• Placebo
Placebo will be administered via the same route as PledOx (i.v. infusion). Placebo is a 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	Liège
Belgium	AZ Sint Maarten	Mechelen
Belgium	AZ Delta	Roeselare
Belgium	CHU UCL Namur - Site Godinne	Yvoir
Czechia	Nemocnice Benesov	Benesov
Czechia	Nemocnice Horovice	Horovice
Czechia	Nemocnice Na Pleši	Nová Ves pod Plesi
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
France	CHU Nice L'Archet 2	Nice
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	Onkodok GmbH / Onkologische Schwerpunktpraxis	Gütersloh
Germany	Klinikum Neuperlach	Munchen
Italy	Oncologia Istituti Ospitalieri	Cremona
Italy	Irccs Irst	Meldola - FC
Italy	Hospital San Gerardo	Monza
Italy	Istituto Nazionale Tumori	Napoli
Italy	IRCCS Policlinico San Matteo	Pavia
Italy	Ospedale degli infermi	Ponderano
Italy	IRCCS azienda Ospedaliera S Maria Nuova	Reggio Emilia
Italy	Casa Sollievo della Sofferenza	San Giovanni Rotondo
Japan	Fukuoka University Hospital	Fukuoka
Japan	Kyushu University Hospital	Fukuoka
Japan	St. Marianna University School of Medicine Hospital	Kawasaki
Japan	Aichi Cancer Center Hospital	Nagoya
Japan	National Hospital Organization Osaka National Hospital	Osaka
Japan	Osaka International Cancer Institute	Osaka
Japan	Osaka University Hospital	Osaka
Japan	Sapporo Medical University Hospital	Sapporo
Japan	Shizuoka Cancer Center	Shizuoka
Japan	The Cancer Institute Hospital of JFCR	Tokyo
Japan	Fujita Health University Hospital	Toyoake
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	Granvia de L´Hospitalet 199-203	Barcelona
Spain	Hospital de La Santa Creu I Sant Pau	Barcelona
Spain	Vall d'hebron university hospital	Barcelona
Spain	Centro Integral Oncologico	Madrid
Spain	H.G.U.Gregorio Marañón	Madrid
Spain	Hospital Universitario Puerta de Hierro	Majadahonda
Spain	Hospital Univ Virgen Macarena	Sevilla
Spain	Hospital Quironsalud Valencia	Valencia
Taiwan	KMUH: Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
United Kingdom	Mid Essex Hospital Services NHS Trust - Broomfield Hospital	Chelmsford
United Kingdom	North Tyneside General Hospital	North Shields
United Kingdom	Mount Vernon Cancer Centr	Northwood
United Kingdom	The Royal Marsden Hospital (Surrey)	Sutton

Sponsors (2)

Lead Sponsor	Collaborator
Egetis Therapeutics	Solasia Pharma K.K.

Countries where clinical trial is conducted

Belgium,  Czechia,  France,  Germany,  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	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 (cycle is 14 days) of mFOLFOX6 chemotherapy, as assessed by the Cold Sensitivity questionnaire. Cold sensitivity was rated 0 (not at all) to 10 (as bad as you can imagine).	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 Investigational Medicinal Product	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 Investigational Medicinal Product. 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 a numerical rating scale (Numeric Rating Scale; Scale range of 0-10;0 = no pain, 10= pain as bad as you can imagine), at 9 months after the first dose of Investigational Medicinal Product	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 Investigational Medicinal Product	Baseline and 9 months
Secondary	Patients With Disease Free Survival	Patients with disease free survival.	Analysis was planned at 24 months but performed based on available data at cut-off 31 August 2020 as the study was terminated early by the Sponsor