Chemotherapy induced peripheral neuropathy MedDRA version: 20.1 Level: LLT Classification code 10079545 Term: Chemotherapy induced peripheral neuropathy System Organ Class: 100000004852
Conditions
Sponsors
PledPharma AB
Eligibility
Sex/Gender
All
Inclusion criteria
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 =65 years) yes F.1.3.1 Number of subjects for this age range 210
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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;Secondary Objective: 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;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).;Timepoint(s) of evaluation of this end point: 9 months after first dose of IMP | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 | — |
Countries
Belgium, Czech Republic, France, Germany, Hong Kong, Hungary, Italy, Japan, Korea, Republic of, Spain, Taiwan, United Kingdom, United States
Contacts
Public ContactChief Medical Officer
PledPharma AB
Outcome results
None listed