| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Histologically or cytologically confirmed UICC stage IV carcinoma of colon or rectum with metastasis (metastatic colorectal cancer) with need for treatment due to progression |
|
| E.1.1.1 | Medical condition in easily understood language |
| metastatic colorectal cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 evaluate the effect of treatment with FTD/TPI on HRQoL as measured by EORTC QLQ-C30 (global health status/quality of life scale)
|
|
| E.2.2 | Secondary objectives of the trial |
• To assess HRQoL measured by the EORTC QLQ-C30 (all scales and items) and the EQ-5D-5L questionnaire under FTD/TPI and under BSC
• To evaluate time-to event measures under treatment with FTD/TPI and in those only being observed and given BSC
• To evaluate safety of treatment with FTD/TPI
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Patients had provided written informed consent prior to any procedure
• Patients of ≥ 18 years of age at the time of signing the informed consent
• Histologically or cytologically confirmed UICC stage IV carcinoma of colon or rectum with metastasis (metastatic colorectal cancer) with need for treatment due to progression
• At least one measurable or non-measurable lesion as defined by RECIST version 1.1 32
• Patients who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents
• Patients able to take medications orally (ie, no feeding tube)
• mCRC patients independent from their ECOG performance status at study enrolment
• Adequate organ function as defined by the following laboratory values obtained within 7 days prior to first administration of FTD/TPI on Day 1 of Cycle 1 (haematology and laboratory values for patients who are administered only BSC need not be obtained within 7 days prior to observation Cycle 1)
a. Absolute neutrophil count of ≥ 1.5 × 109/L,
b. Platelet count ≥ 75 × 109/L,
c. Total serum bilirubin of ≤ 1.5 upper limit of normal (ULN),
d. Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3.0 × ULN; if liver function abnormalities are due to underlying liver metastasis, AST and ALT ≤ 5 × ULN
e. Calculated creatinine clearance (CrCl) ≥ 30 mL/min
• Only applicable for females who receive treatment with FTD/TPI (Group A):
Females of childbearing potential (FCBPs) must have a negative pregnancy test (urine or serum) within 7 days prior to enrolment. FCBPs must agree to use highly effective contraceptive measures with a failure rate of less than 1% per year when used consistently and correctly as defined in Section 4.1 of the CTFG guidance “Recommendations related to contraception and pregnancy testing in clinical trials” during the entire study treatment with FTD/TPI and up to 6 months after the discontinuation of study drug FTD/TPI. Complete sexual abstinence is acceptable as a highly effective contraceptive method only if the subject is refraining from heterosexual intercourse during the entire study treatment with FTD/TPI and up to 6 months after the discontinuation of study drug FTD/TPI and the reliability of sexual abstinence is in line with the preferred and usual lifestyle of the subject.
Women using hormonal contraceptives should agree to add a barrier contraceptive method.
A woman will be considered as being of childbearing potential unless she has gone through menopause for at least 1 year (i.e. minimum of one year without menses) or unless she has a history of tubal ligation, bilateral oophorectomy or hysterectomy that is clearly documented in the patient’s source documents.
• Only applicable for males who receive treatment with FTD/TPI (Group A):
Males must agree to use effective contraceptive measures or to practice complete abstinence during the study treatment with FTD/TPI and up to 6 months after the discontinuation of study drug FTD/TPI
• Patients capable to understand the purposes and risks of the study, who are willing and able to participate in the study, who are able to understand and to fill in the questionnaire and from whom written and dated informed consent to participate in the study has been obtained. |
|
| E.4 | Principal exclusion criteria |
• Patients requesting not to be treated with FTD/TPI but considering other tumour treatment (e.g. palliative radiotherapy)
• Concurrently active malignancies other than mCRC excluding malignancies that are disease free for more than 5 years, adequately treated basal cell or squamous cell skin cancer or carcinoma-in-situ deemed cured by adequate treatment, e.g. in situ cervical, breast or prostate cancer.
• Brain or leptomeningeal metastases not controlled through surgery or radiotherapy
• Active infection (i.e, body temperature ≥38°C due to infection)
• Intestinal obstruction
• Uncontrolled diarrhea
• Uncontrolled diabetes
• Pulmonary fibrosis or interstitial pneumonitis
• Renal failure with CrCl <30 ml/min
• Hepatic failure ≥ CTCAE version 4 Grade 3
• Cerebrovascular accident within the last 6 months
• Myocardial infarction within the last 6 months, severe/unstable angina, symptomatic congestive heart failure New York Heart Association (NYHA) class III or IV
• Gastrointestinal hemorrhage within last 3 months
• Autoimmune disorders or history of organ transplantation that require immunosuppressive therapy.
• Psychiatric disease that may increase the risk associated with study participation or study drug administration, or may interfere with the generation of QoL results.
• Any other severe concomitant disease or disorder, including the presence of laboratory abnormalities, which places the subject at unacceptable risk or which could influence patient’s ability to participate in the study and his/her safety during the study or interfere with interpretation of study results
• Treatment with any of the following within the specified time frame prior to first administration of FTD/TPI or Day 1 of observation cycle 1 (if no administration of FTD/TPI):
a. Major surgery within prior 4 weeks (the surgical incision should be fully healed prior to study drug administration).
b. Any anticancer therapy within prior 2 weeks.
c. Extended field radiation within prior 4 weeks or limited field radiation within prior 2 weeks.
• Participation in any other clinical trial or treatment with any experimental drug or other experimental therapy within 28 days prior to first administration of FTD/TPI or Day 1 of observation cycle 1 (if no administration of FTD/TPI); participation in a non-interventional study is permitted.
• Patients who have already received FTD/TPI
• Unresolved non-haematological toxicity of ≥ CTCAE version 4 Grade III attributed to prior therapies excluding anemia, alopecia, skin pigmentation and platinum induced neurotoxicity
• Hypersensitivity to trifluridine, tipiracil or any of the excipients
• Hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
• Pregnant or breast-feeding female
• Inappropriate for entry into this study in the judgment of the investigator
• Patient has been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
• Patients possibly dependent from the investigator including the spouse, children and close relatives of any investigator
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Rate of responders with continued unchanged or improved HRQoL.
Response is calculated as mean of the score of the EORTC QLQ-C30, global health status/quality of life scale [QL2] at all scheduled time points of QoL analysis in the time interval from two days before start of Cycle 2 until the end of treatment /end of close observation compared to the baseline score of the global health status /quality of life scale.
Response will be defined as improvement (≥ 10 scores) or stabilization (> -10 and < 10 scores) compared to the baseline score of the global health status/quality of life scale.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- day 1 of each treatment cycle bevor Administration of FTD/TPI / start o the observation cycle
- end of treatment visit/ end of close observation
- month 1-6 of Follow-up, therafter after month 9 and 12 follow-up for a max. Duration of 1 year after the date od first application of FTD/TPI or cycle 1 D1 of close observation (exception: questioning with EORTC QLQ-30 and EQ-5D-5L of patients who receive FTD/TPI treatment for more than 1 year (Group A) for the duration of treatment as described above, at the end-of-treatment visit and at Month 1 of follow up). |
|
| E.5.2 | Secondary end point(s) |
Quality of life
• Rate of responders in the QoL analysis (measured by the EORTC QLQ-C30, global health status/quality of life scale) at every scheduled time point for EORTC QLQ-C30 separately in the time interval from two days before start of Cycle 2 until the end of treatment/end of close observation, at every time point compared to the baseline score of the global health status/quality of life scale.
Response will be defined as improvement (≥ 10 scores) or stabilization (> -10 and < 10 scores) compared to the baseline score of the global health status/quality of life scale at the specified time point.
• HRQoL analysis measured by the EORTC QLQ-C30 questionnaire (all scales/single items; all time points from baseline until end of follow up)
• HRQoL analysis measured by the questionnaire EQ-5D-5L descriptive system; all time points from baseline until end of follow up
• Scores of the EQ VAS as a measure of overall self-rated health status compared to baseline EQ VAS score; all time points until end of follow up
• Time to health-related QoL deterioration measured by EORTC QLQ-C30; global health status/quality of life scale; deterioration defined as a first change of score to < -10 compared to baseline score
• Time to health-related QoL deterioration measured by EQ VAS score; deterioration compared to baseline VAS score
• Disease-specific symptoms of the mCRC measured by the respective subdomains of the EORTC QLQ-C30 (symptom scales fatigue, nausea and vomiting, appetite loss, pain, dyspnoea, constipation, diarrhoea)
• HRQoL analysis measured by the EORTC QLQ-C30 questionnaire (all scales/single items; all time points from baseline until follow up, analysis of response) for following comparisons (if applicable):
• During treatment/close observation vs. after treatment/close observation
• Treatment with FTD/TPI vs. close observation with BSC
• During treatment/close observation (patients with 2 cycles) vs. during treatment/close observation (patients with < 2 cycles and early progression in Cycle 1)
• HRQoL analysis measured by the questionnaire EQ-5D-5L and the EQ VAS (all timepoints from baseline to follow up) for following comparisons (if applicable):
- During treatment/close observation vs. after treatment/close observation
- Treatment with FTD/TPI vs. close observation with BSC
- During treatment/close observation (patients with < 2 cycles) vs. during treatment/close observation (patients with < 2 cycles and early progression in Cycle 1)
Efficacy
• Progression-free survival (clinical or radiological progression) [PFS]
• Overall survival ([OS], calculated from start of treatment/close observation on study)
• Exploratory analysis of objective response rate (ORR)
Safety
• Type, incidence, and severity of FTD/TPI-related adverse reactions (severity evaluated according to CTCAE version 4)
• Tumour-related symptoms and adverse events
• Treatment duration/exposure to FTD/TPI (Group A) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Quality of life:
- day 1 of each treatment cycle bevor Administration of FTD/TPI / start o the observation cycle
- end of treatment visit/ end of close observation
- month 1-6 of Follow-up, therafter after month 9 and 12 follow-up for a max. Duration of 1 year after the date od first application of FTD/TPI or cycle 1 D1 of close observation (exception: questioning with EORTC QLQ-30 and EQ-5D-5L of patients who receive FTD/TPI treatment for more than 1 year (Group A) for the duration of treatment as described above, at the EOT-Visit and at Month 1 of follow up).
Efficacy:
- Restaging: after every second treatment / observation cycle, end of treatment/Observation, Follow-up
- monthly
Safety:
- monthly
- end of treatment visit/ end of close observation |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 45 |
| E.8.5 | The trial involves multiple Member States | No |
| 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
|
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
Print
