E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced metastatic colorectal cancer (stage IV) |
|
E.1.1.1 | Medical condition in easily understood language |
Colon cancer that has spread to other organs. |
|
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 | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10010035 |
E.1.2 | Term | Colorectal cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 |
The primary objective is: • To characterise the tolerability of Modufolin in Stage IV CRC patients in 1st, 2nd line treatment in terms of toxicity during eight (8) weeks of treatment with one (1) of four (4) dose levels of Modufolin in the given treatment arms. |
|
E.2.2 | Secondary objectives of the trial |
- To characterise all adverse events (AEs) and clinically significant abnormal laboratory test result changes regardless of attribution during the entire study period. - To evaluate tumour response and disease progression by means of Objective Response Rate (ORR) and Early Tumour Shrinkage (ETS) at the end of study participation. - To determine the pharmacokinetic characteristics of methylenetetrahydrofolate (MTHF), methyl-tetrahydrofolate (methyl-THF), and tetrahydrofolate (THF) calculated from plasma samples in each cohort following Modufolin® administration on Day 1 in Cycle #1 and in Cycle #4 in a subset of patients. - To assess the impact on quality of life (QoL) in patients enrolled at Greek sites. |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Follow-up Study of Clinical Study ISO-CC-005: After end of study participation, patients that may benefit from continued treatment with Modufolin® will be offered enrolment in a Follow-up Study, provided they fulfil the eligibility criteria for enrolment. Upon enrolment in the Follow-up Study, patients will continue treatment with Modufolin® in accordance with the assigned Main Study regimen, which may be adapted with additional treatment at the discretion of the Investigator. In this way, the Sponsor aims to meet patients’ specific needs and facilitate investigators the possibility to follow clinical practice. For patients in Cohorts #18b and #19b: The frequency of the CT/MRI scan evaluations will be mandatory and occur every eight (8) to 12 weeks (±3 days) since previous scan was performed. |
|
E.3 | Principal inclusion criteria |
1) Advanced metastatic colorectal (Stage IV) cancer verified by biopsy, eligible for 1st or 2nd line therapy. (For Greek sites: only patients eligible for 2nd line treatment will be allowed in Cohort #1 through Cohort #17) For enrolment in Cohorts #18a and #18b of Treatment Arm #4 and in Treatment Arm #6: only patients eligible for 1st line therapy will be allowed 2) CT-scan or MRI of thorax, abdomen and pelvis; within five (< 5) weeks before start of chemotherapy 3) Evaluable disease and one measurable site of disease according to RECIST 1.1 criteria (at least 10 mm for CT-scan or MRI) 4) Male and female adults, age of 18 years or older 5) WHO performance status 0 < 2, and life expectancy > 3 months 6) Adequate haematological function: a) Haemoglobin (Hb) > 100 g/L, b) Absolute neutrophil count (ANC) > 1.5x109/L, and c) Platelets > 100x109/L 7) Adequate renal and hepatic functions: a) Creatinine clearance > 50 mL/min, b) Total bilirubin < 1.5 times upper limit of normal (ULN), c) Aspartate transaminase (AST) and Alanine transaminase (ALT) < 3 times ULN (and < 5 times ULN in case of liver metastases) 8) Eligible for at least one of the chemotherapy treatment arms in the study protocol which, at the time of enrolment, is currently open for recruitment, according to Investigators judgement 9) Negative pregnancy test for females of child bearing potential 10) Willing and able to provide informed consent 11) Using adequate contraceptive measures Female patients who have been post-menopausal for more than one year or female patients of childbearing potential using a highly efficient method of contraception (i.e. a method with less than 1% failure rate [e.g. sterilisation, hormone implants, hormone injections, some intrauterine devices, or vasectomised partner]). Male patients agreeing to use condoms during the study and for three months after the end of the study/last dose of the investigational medicinal product (IMP), or patients having a partner who is using a highly efficient method of contraception as described above. |
|
E.4 | Principal exclusion criteria |
1) Malign tumours other than colorectal adenocarcinomas (current or within the previous 5 years), with the exception for curatively treated non melanoma skin cancer or in situ carcinoma of the cervix. 2) Fewer than 14 days since start of administration of latest treatment of CRC and first study drug dosing in the Main Study. For enrolment in Cohort #18b of Treatment Arm #4 and Cohort #19b of Treatment Arm #6, only: Less than 6 months between randomization and completion of the last anti cancer treatment (such as chemotherapy/ radiotherapy/immunotherapy). NB: Rectal cancer treatment shorter than 8 weeks of chemo/radiation therapy is allowed. 3) Evidence of central nervous system metastases 4) Unresolved bowel obstruction or sub-obstruction, uncontrolled Crohn’s disease or ulcerative colitis 5) History of cardiac disease with a New York Heart Association (NYHA) Class II or greater congestive heart failure, myocardial infarction or unstable angina in the past six (6) months prior to Day 1 of treatment and serious arrhythmias requiring medication for treatment 6) Current severe chronic diarrhoea 7) Current chronic infection or uncontrolled serious illness causing immunodeficiency 8) Any current uncontrolled serious illness or medical condition 9) Current major psychiatric disorder (e.g. major depression, psychosis) 10) Participation in another clinical study with an IMP within one (1) month prior to inclusion 11) Known intolerance to fluoropyrimidine therapy suggestive of dihydropyrimidine dehydrogenase deficiency 12) Suspicion of hypersensitivity or allergy to the IMP, or to products chemically related to the IMP (i.e. folate derivatives) 13) Female patients: currently pregnant or breast-feeding 14) Previous treatment with Modufolin® at any dose, regardless of indication treated. 15) Suspicion, as per Investigator’s judgement, of forthcoming need of any chemotherapeutic agents, antibodies or biologics other than those included in this protocol. 16) For enrolment in Cohort #18b of Treatment Arm #4 and Cohort #19b of Treatment Arm #6, only: Confirmation of progressive disease within 6 months after completion of prior adjuvant anti-cancer treatment. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
- Number and severity of dose limiting toxicity (DLT) associated with the administration of the chemotherapeutic agents or any other significant AEs at the respective Modufolin® dose level in each treatment arm of the study. - Number of patients with chemotherapeutic agent dose adjusted (including withdrawal of therapy agent) due to presence of related toxicity at the respective Modufolin® dose level in each treatment arm of the study - Number of adjustments required for any administered chemotherapeutic agent due to presence of related toxicity, at the respective Modufolin® dose level in each treatment arm of the study. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
- Number and severity of AEs or clinically significant abnormal laboratory test result changes regardless of causal relationship - Determination of Objective Response Rate (ORR) and Early Tumour Shrinkage (ETS) after four (4) cycles of chemotherapy. - Plasma pharmacokinetics of 5,10- Methylene Tetrahydrofolate (MTHF), 5-Methyl Tetrahydrofolate (5-methyl-THF), and Tetrahydrofolate (THF), directly prior to, and at 10 minutes, at 1, 2, and 4 hours in each cohort following Modufolin® administration on Day 1 in Cycle #1 and in Cycle #4 in a subset of patients. - To assess the impact on quality of life (QoL) in patients enrolled at Greek sites. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
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 | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Modufolin® has been tested before, first time in combination with 5-FU, Oxilaplatin and Irinotecan |
|
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 6 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
|
Last patient, last visit. End of study participation is defined as the date of the patient's last visit in the study by completing End-of-Study Visit in the Main Study. For patients that are enrolled in the Followup Study, the end of study participation is defined as the date when patient completes the End of Follow-up Study |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 28 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 28 |