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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.
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| Name | Class |
|---|---|
| Solasia Pharma K.K. | INDUSTRY |
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This study evaluates the investigational drug PledOx in the prevention of chronic chemotherapy induced peripheral neuropathy (CIPN) induced by the drug oxaliplatin.
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:
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PledOx (2 µmol/kg) | Experimental | Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. |
|
| PledOx (5 µmol/kg) | Experimental | Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. |
|
| Placebo | Placebo Comparator | Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Calmangafodipir (2 µmol/kg) | Drug | Solution in 20 mL single dose glass vials |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Stefan Carlsson, MD | Chief Medical Officer | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| California Cancer Associates | Fresno | California | 93720 | United States | ||
| Mid Florida Hematology and Oncology Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36308441 | Derived | Pfeiffer P, Lustberg M, Nasstrom J, Carlsson S, Persson A, Nagahama F, Cavaletti G, Glimelius B, Muro K. Calmangafodipir for Prevention of Oxaliplatin-Induced Peripheral Neuropathy: Two Placebo-Controlled, Randomized Phase 3 Studies (POLAR-A/POLAR-M). JNCI Cancer Spectr. 2022 Nov 1;6(6):pkac075. doi: 10.1093/jncics/pkac075. |
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386 patients were screened in the 28 days before the start of treatment, 291 were randomised and 285 were treated.
Patients were recruited in the US, EU and Asia between 2018 and 1 March 2020. The Sponsor placed recruitment/dosing in the POLAR program on hold following interactions with the French regulatory authority and a US clinical hold of the study on 23 January 2020. As of 2 March 2020, no more patients were enrolled or IMP administered. Enrolled patients were followed until the data cut-off date of 31 August 2020 and these patients have been assigned as "completed" in the disposition.
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| ID | Title | Description |
|---|---|---|
| FG000 | PledOx (2 µmol/kg) | Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial |
| FG001 | PledOx (5 µmol/kg) |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 15, 2020 | Jul 22, 2021 |
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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:
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| Calmangafodipir (5 µmol/kg) | Drug | Solution in 20 mL single dose glass vials |
|
|
| Placebo | Drug | Solution in 20 mL single dose glass vials |
|
| 9 months |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| Orange City |
| Florida |
| 32763 |
| United States |
| Cancer Center of Kansas | Wichita | Kansas | 67214 | United States |
| Willis-Knighton Cancer Center | Shreveport | Louisiana | 71103 | United States |
| Mercy Clinic - Cancer & Hematology | Springfield | Missouri | 65804 | United States |
| Mercy Clinic Oncology and Hematology | St Louis | Missouri | 63141 | United States |
| CHI St Francis Cancer Treatment Center | Grand Island | Nebraska | 68803 | United States |
| Hunterdon Hematology Oncology | Flemington | New Jersey | 08822 | United States |
| Monter Cancer Center | Lake Success | New York | 11042 | United States |
| Montefiore Medical Research | The Bronx | New York | 10461 | United States |
| Scott & White Vasicek Cancer Treatment Center | Temple | Texas | 76508 | United States |
| Onze-Lieve-Vrouwziekenuis Aalst | Aalst | Belgium |
| Imelda GI Clinical Research Center | Bonheiden | Belgium |
| Cliniques Universitaires St-Luc | Brussels | Belgium |
| UZ Gent | Ghent | Belgium |
| CHU Liège | Liège | Belgium |
| AZ Sint Maarten | Mechelen | Belgium |
| AZ Delta | Roeselare | Belgium |
| CHU UCL Namur - Site Godinne | Yvoir | Belgium |
| Nemocnice Benesov | Benešov | Czechia |
| Nemocnice Horovice | Hořovice | Czechia |
| Nemocnice Na Pleši | Nová Ves pod Pleší | Czechia |
| General University Hospital | Prague | Czechia |
| Hospital Na Bulovce | Prague | Czechia |
| Onkologická Klinika 1. Lf Uk A Tn | Prague | Czechia |
| CHRU de Brest - Hôpital Morvan | Brest | France |
| Clinique Pasteur-Lanroze | Brest | 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 | France |
| Hôpital Nord Franche-Comté Site du Mittan | Montbéliard | France |
| Institut de Cancérologie de l'Ouest | Nantes | France |
| Hopital l'Archet, CHU de Nice | Nice | France |
| Hôpital Robert Debré | Reims | France |
| Centre Hospitalier Privé Saint-Grégoire | Saint-Grégoire | France |
| Clinique Ste Anne | Strasbourg | France |
| Hopitaux Universitaires de Strasbourg | Strasbourg | France |
| 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 | Germany |
| Queen Mary Hospital | Hong Kong | Hong Kong |
| 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-Rendelőintézet | Szolnok | Hungary |
| 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 | Naples | 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 | Italy |
| Osaka International Cancer Institute | Osaka-shi, Osaka | Osaka | 541-8567 | Japan |
| Fujita Health University Hospital | Aichi | 470-1192 | Japan |
| Kyushu University Hospital | Fukuoka-shi, Fukuoka | 812-8582 | Japan |
| Fukuoka University Hospital | Fukuoka-shi, Fukuoka | 814-0133 | Japan |
| Kansai Rosai Hospital | Hyōgo | Japan |
| St. Marianna University School of Medicine Hospital | Kanagawa | 216-8511 | Japan |
| Aichi Cancer Center Hospital | Nagoya-shi, Aichi | 464-8681 | Japan |
| Osaka University Hospital | Osaka | 565-0871 | Japan |
| National Hospital Organization Osaka National Hospital | Osaka-shi, Osaka | 540-0006 | Japan |
| Sapporo Medical University Hospital | Sapporo-shi, Hokkaido | 065-0033 | Japan |
| Shizuoka Cancer Center | Shizuoka | 411-8777 | Japan |
| The Cancer Institute Hospital Of JFCR | Tokyo | 135-8550 | Japan |
| Hallym University Sacred Heart Hospital | Anyang-si | South Korea |
| Dong-A University Hospital | Busan | South Korea |
| Chonnam National University Hwasun Hospital | Gwangju | South Korea |
| Seoul National University Bundang Hospital | Seongnam-si | South Korea |
| Korea University Guro Hospital | Seoul | South Korea |
| Seoul National University Hospital | Seoul | South Korea |
| 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 | Seville | Spain |
| Hospital Quironsalud Valencia | Valencia | Spain |
| Hospital Miguel Servet | Zaragoza | Spain |
| KMUH: Kaohsiung Medical University Chung-Ho Memorial Hospital | Kaohsiung City | Taiwan |
| CMMC: Chi Mei Medical Center | Tainan | Taiwan |
| NCKUH: National Cheng Kung University Hospital | Tainan | Taiwan |
| Royal Marsden Hospital | London | SW3 6JJ | United Kingdom |
| North Tyneside General Hospital | North Shields | NE29 8NH | United Kingdom |
| Mount Vernon Cancer Centre | Northwood | HA6 2RN | United Kingdom |
| The Royal Marsden Hospital (Surrey) | Sutton | SM2 5PT | United Kingdom |
| York Teaching Hospital | York | YO61 8HE | United Kingdom |
Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial |
| FG002 | Placebo | Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial |
| Treated |
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
Safety analysis set consisting of all randomized patients who received at least one dose of IMP. Patients were analyzed according to the study treatment they actually received.
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| ID | Title | Description |
|---|---|---|
| BG000 | PledOx (2 µmol/kg) | Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial |
| BG001 | PledOx (5 µmol/kg) | Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial |
| BG002 | Placebo | Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Body Mass Index | Median | Full Range | kg/m^2 |
| |||||||||||||||
| ECOG performance status | The ECOG performance scale is a six point functional scale (0 to 5) rating the extent of effect on daily living with higher scores representing a worse outcome. A score 0 represents "fully active, able to carry on all pre-disease performance without restriction" and a score 1 represents "restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work". | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria:
| Posted | Count of Participants | Participants | 9 months |
|
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| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria:
| Posted | Count of Participants | Participants | 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. | Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria:
| Posted | Least Squares Mean | 95% Confidence Interval | Scores on a scale | 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. | Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria:
| Posted | Least Squares Mean | 95% Confidence Interval | mg/m^2 | 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) | Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria:
| Posted | Mean | Standard Deviation | Scores on a scale | 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. | Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria:
| Posted | Least Squares Mean | 95% Confidence Interval | Scores on a scale | 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. | Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria:
| Posted | Least Squares Mean | 95% Confidence Interval | seconds | 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. | The safety analysis set consisting of all randomized patients who received at least one dose of IMP. The overall number analyzed represents the total in the safety population treated at the start of the study. ORR was assessed throughout the study when varying numbers of patients in each group remained on study | Posted | Count of Participants | Participants | 12, 15 and 18 months |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Progression-free Survival (PFS) | Patients with progression-free survival | Safety analysis set consisting of all randomized patients who received at least one dose of IMP. Patients were analyzed according to the study treatment they actually received. | Posted | Number | participants | 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 | Safety analysis set consisting of all randomized patients who received at least one dose of IMP. Patients were analyzed according to the study treatment they actually received. | Posted | Number | participants | 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 |
|
From screening until 30 days after the end of treatment visit which occurred after up to 6 months of treatment
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | PledOx (2 µmol/kg) | Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial | 9 | 96 | 27 | 96 | 93 | 96 |
| EG001 | PledOx (5 µmol/kg) | Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial | 9 | 93 | 21 | 93 | 91 | 93 |
| EG002 | Placebo | Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial | 16 | 96 | 24 | 96 | 95 | 96 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Neutropenia | Blood and lymphatic system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Cardiogenic shock | Cardiac disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Colitis | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Enterocolitis | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Haemorrhoids | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Ileus | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Inguinal hernia | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Intestinal obstruction | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Neutropenic colitis | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Pancreatitis acute | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Parotitis | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Stomatitis | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Death | General disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Euthanasia | General disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Generalised oedema | General disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Malaise | General disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Bile duct obstruction | Hepatobiliary disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Cholecystitis | Hepatobiliary disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Anaphylactic shock | Immune system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Drug hypersensitivity | Immune system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Hypersensitivity | Immune system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Infusion related reaction | Immune system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Urticaria | Immune system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Cellulitis | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
| |
| Corona virus infection | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
| |
| Device related infection | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
| |
| Diverticulitis | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
| |
| Enteritis infectious | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
| |
| Necrotising fasciitis | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
| |
| Neutropenic infection | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
| |
| Peritonitis | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
| |
| Pneumonia | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
| |
| Pyelonephritis | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
| |
| Sepsis | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
| |
| Wound infection | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
| |
| Fall | Injury, poisoning and procedural complications | MedDRA 23.0 | Systematic Assessment |
| |
| Femoral neck fracture | Injury, poisoning and procedural complications | MedDRA 23.0 | Systematic Assessment |
| |
| Femur fracture | Injury, poisoning and procedural complications | MedDRA 23.0 | Systematic Assessment |
| |
| Toxicity to various agents | Injury, poisoning and procedural complications | MedDRA 23.0 | Systematic Assessment |
| |
| Urinary tract stoma complication | Injury, poisoning and procedural complications | MedDRA 23.0 | Systematic Assessment |
| |
| Wound dehiscence | Injury, poisoning and procedural complications | MedDRA 23.0 | Systematic Assessment |
| |
| Wound haemorrhage | Injury, poisoning and procedural complications | MedDRA 23.0 | Systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | MedDRA 23.0 | Systematic Assessment |
| |
| Blood bilirubin increased | Investigations | MedDRA 23.0 | Systematic Assessment |
| |
| Cachexia | Metabolism and nutrition disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Dehydration | Metabolism and nutrition disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Hyperkalaemia | Metabolism and nutrition disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Metastases to spine | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 23.0 | Systematic Assessment |
| |
| Tumour perforation | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 23.0 | Systematic Assessment |
| |
| Altered state of consciousness | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Cerebral infarction | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Presyncope | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Syncope | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Completed suicide | Psychiatric disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Renal failure | Renal and urinary disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Ovarian vein thrombosis | Reproductive system and breast disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Pulmonary artery thrombosis | Respiratory, thoracic and mediastinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Respiratory distress | Respiratory, thoracic and mediastinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Embolism | Vascular disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Hypertension | Vascular disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Hypotension | Vascular disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Thrombosis | Vascular disorders | MedDRA 23.0 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Leukopenia | Blood and lymphatic system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Neutropenia | Blood and lymphatic system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Constipation | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Dyspesia | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Stomatitis | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Asthenia | General disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Malaise | General disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Oedema peripheral | General disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Drug hypersensitivity | Immune system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
| |
| Paronychia | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | MedDRA 23.0 | Systematic Assessment |
| |
| Aspartate aminotransferase increased | Investigations | MedDRA 23.0 | Systematic Assessment |
| |
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Hypoalbuminaemia | Metabolism and nutrition disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Hypomagnesaemia | Metabolism and nutrition disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Dysgeusia | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Neuropathy peripheral | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Paraesthesia | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Peripheral sensory neuropathy | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Insomnia | Psychiatric disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Proteinuria | Renal and urinary disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Hiccups | Respiratory, thoracic and mediastinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Dermatitis acneiform | Skin and subcutaneous tissue disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Palmar-plantar erythrodysaesthesia syndrome | Skin and subcutaneous tissue disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Rash | Skin and subcutaneous tissue disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Skin fissures | Skin and subcutaneous tissue disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Hypertension | Vascular disorders | MedDRA 23.0 | Systematic Assessment |
| |
| Weight decreased | Investigations | MedDRA 23.0 | Systematic Assessment |
|
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Kristina Sjoblom Nygren | Egetis Therapeutics AB | +46732344698 | kristina.sjoblom@egetis.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 2, 2020 | Jul 21, 2021 | SAP_001.pdf |
Not provided
| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| D009362 | Neoplasm Metastasis |
| D009369 | Neoplasms |
| ID | Term |
|---|---|
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
| D009385 | Neoplastic Processes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
Not provided
Not provided
| ID | Term |
|---|---|
| C060076 | N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid |
Not provided
Not provided
Not provided
| Male |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| 1 |
|
| Unknown |
|
| Cochran-Mantel-Haenszel |
| 0.7434 |
| Risk Ratio (RR) |
| 1.0951 |
| 2-Sided |
| 95 |
| 0.6356 |
| 1.8870 |
| Superiority |
| OG001 | PledOx (5 µmol/kg) | Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial |
| OG002 | Placebo | Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial |
|
|
| OG002 |
| Placebo |
Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial |
|
|
|
|
Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy.
Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial
| OG002 | Placebo | Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial |
|
|
| OG002 |
| Placebo |
Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial |
|
|
|
|
Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy.
Placebo: Solution in 20 mL single dose glass vial
|
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Units | Counts |
|---|---|
| Participants |
|
|
| No |
|
| Yes |
|
| No |
|
| Yes |
|