E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chemotherapy induced peripheral neuropathy |
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E.1.1.1 | Medical condition in easily understood language |
Damages to nerves of the peripheral nervous system, induced by chemotherapy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10079545 |
E.1.2 | Term | Chemotherapy induced peripheral neuropathy |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare each dose of PledOx (2 and 5 µmol/kg) vs placebo with respect to the proportion of patients with moderate or severe chronic CIPN |
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E.2.2 | Secondary objectives of the trial |
Compare each dose of PledOx vs placebo
Efficacy • Proportion of patients with mild, moderate or severe chronic CIPN • Sensitivity to touching cold items • Cumulative dose of oxaliplatin during chemotherapy • Vibration sensitivity on the lateral malleolus • Worst pain in hands or feet • Functional impairment (non-dominant hand) • Sustained efficacy on prevention of CIPN during LTFU
Safety • Overall response rate • Progression-free survival • Overall survival • Safety and tolerability
Exploratory • Chronic CIPN by supporting analysis using full FACT/GOG NTX-13 • Cumul. dose of 5-FU during chemo • Both oxaliplatin and 5-FU: number of cycles, dose intensity & reductions (reason for reduction), dose delays (length of delay) • PK profile of PledOx with multiple dosing* • QT/QTc interval using a 12-lead ECG* • QoL/health status • Functional impairment (LTFU) • Worst pain in hand or feet during LTFU • QoL/health status • Health eco impact
*84 pts (28/group) in preselected sites only |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. Non-resectable metastatic (stage IV) CRC, pathologically confirmed adenocarcinoma of the colon or rectum. 4. No prior systemic chemotherapy (within the previous 12 months) and/or biologic/targeted therapy for metastatic CRC. 5. Measurable disease according to RECIST 1.1. 6. Patient indicated for at least 3 months of oxaliplatin-based chemotherapy (without any pre-planned treatment breaks) and without pathological findings of a neurologic exam performed prior to oxaliplatin treatment according to local practice. 7. ECOG performance status of 0 or 1. 8. Adequate hematological parameters: hemoglobin ≥100 g/L, absolute neutrophil count (ANC) ≥1.5 x 10^9/L, platelets ≥100 x 10^9/L. 9. Adequate renal function: creatinine clearance >50 cc/min using the Cockroft and Gault formula or measured. 10. Adequate hepatic function: total bilirubin ≤1.5 times the upper limit of normal (ULN) (except in the case of known Gilbert’s syndrome); AST and ALT ≤3 times ULN (AST and ALT ≤5 times ULN in case of liver metastases). 11. Baseline blood manganese level <2.0 times ULN. 12. For patients with a history of diabetes mellitus, HbA1c ≤7%. 13. Negative pregnancy test for females of child-bearing potential. 14. 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 3 months after completion of study therapy. |
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E.4 | Principal exclusion criteria |
1. 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. 2. Any grade of neuropathy from any cause. 3. Any evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, cardiac, unresolved bowel obstruction, hepatic or renal disease). 4. 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. 5. Any history of seizures 6. A surgical incision that is not healed. 7. 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. 8. 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. 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 manganese exposure is likely. |
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E.5 End points |
E.5.1 | Primary end point(s) |
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). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
9 months after first dose of IMP |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints Efficacy • 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. • 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. • Mean cumulative dose of oxaliplatin administered per patient during mFOLFOX6 chemotherapy, 9 months after the first dose of IMP. • 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. • Mean change from baseline in worst pain in hands or feet in the past week, using a numerical rating scale (NRS), at 9 months after the first dose of IMP. • 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. • Proportion of patients 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, 12, 15, 18, 21 and 24 months after the first dose of IMP.
Safety • ORR • PFS • Time to death (OS) • Safety and tolerability as assessed by adverse events (AEs), laboratory variables and vital signs • Proportion of patients with PledOx toxicities in addition to chemotherapy-related toxicities graded using the NCI-CTCAE v4.03
Exploratory Endpoints • Frequency and proportion of patients with any CIPN scoring 1, 2, 3 or 4, in any 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, at all other timepoints after the first dose of IMP. • Mean score of the first 4 items of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), at 9 months after the first dose of IMP. • Mean score of the 13 items of the FACT/GOG-NTX-13, at 9 months after the first dose of IMP. • Mean cumulative dose of 5-FU administered per patient during mFOLFOX6 chemotherapy, 9 months after the first dose of IMP. • For both oxaliplatin and 5-FU: Dose intensity, mean number of cycles per patient, proportion of patients with any dose reduction, reason(s) for dose reductions, proportion of patients with any dose delay, and mean duration of dose delay. • PK parameters including Cmax, tmax, AUC0-last of PledOx (only at pre-selected sites and in 84 patients in total), at all measured time points. • Mean QT/QTc interval using a 12-lead ECG (only at pre-selected sites and in 84 patients in total), at all measured time points. • Mean health index and mean VAS score, using the EQ-5D-5L, at 9, 12, 15, 18, 21, and 24 months after the first dose of IMP. • Mean health index, using the FACT/GOG, at 9, 12, 15, 18, 21, and 24 months after the first dose of IMP. • Mean time to complete the grooved Pegboard, with the non-dominant hand, at 12, 15, 18, 21, and 24 months after the first dose of IMP. • Mean change from baseline in worst pain in hands or feet in the past week, using a NRS, at 12, 15, 18, 21, and 24 months after the first dose of IMP. • The proportion of patients with a 2-point, 3-point and 4-point increase in worst pain in hands or feet in the past week, using a NRS, at 9, 12, 15, 18, 21, and 24 months after the first dose of IMP. • Health economic impact, measured by the combined impact of medical resource utilization (hospitalizations, outpatient visits, medical procedures and medical use), patient impact (AEs, fall accidents, functional loss) and indirect societal costs (loss of ability to work), at 6, 12, 18 & 24 months after the first dose of IMP. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- FACT/GOG-NTX-13, Grooved pegboard, Grad. Tuning fork, Pain NRS: treat visits V1-12 (D1 of each Cyc), assess visits M3, 6, 9, 12, 15, 18, 21 & 24, EoT (D14 last cycle) - AEs: V1-12, M3 & 6, EoT - PFS & OS: M3, 6, 9, 12, 15, 18, 21 & 24, EoS (OS only) - CT/MRI scan: Screen, V4, 8, 12, M9-24 - Disease assessment: V5, 9, M6-24, EoT - Biochem: V1, 3, 5, 7, 9, 11, EoT - Blood Mn: Screen, V4, 8, 12, EoT - Hemato, Vital sign, ECOG: Screen, V1-12, M3, 6, 9, 12, 15, 18, 21 & 24, EoT - Cold sensitivity: Screen, V2, 4 & 8 days 1, 2, 3 after IMP infusion - QoL/health status: V1, 4, 8 & 12, M9-24 - Physical exam: Screen, M6-24, EoT - MRI of CNS and Blood Mn incl. neuro exam: V1-12, M3, EoT - ECG: Screen - PK patients: PK & ECG: V1, 4 & 8 (EoT for ECG) - HE: V1, M6, 12, 18 & 24 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 80 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Czech Republic |
France |
Germany |
Hong Kong |
Hungary |
Italy |
Japan |
Korea, Republic of |
Spain |
Taiwan |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last patient reaching End of Study: Overall Survival assessment at approximately month 36 (by telephone or any available medical source) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 10 |