E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
metastatic colorectal cancer |
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E.1.1.1 | Medical condition in easily understood language |
metastatic colorectal cancer |
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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 | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052358 |
E.1.2 | Term | Colorectal cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 assess the rates of progression-free survival at six months calculated from the start of treatment in elderly / frail elderly patients with metastatic colorectal cancer undergoing a 1st line treatment. |
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E.2.2 | Secondary objectives of the trial |
To compare the treatment arms with respect to: Safety - Dose intensities of study medication - Type, incidence and severity of AEs and SAEs - Laboratory parameters
Efficacy - Response rate assessed by the local investigators - Overall and progression-free survival
Patient reported outcomes - Quality of life - Geriatric assessment - Overall treatment utility
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. To enter this trial, the oncologist has to confirm that the reason for entering the trial was advanced age alone or age and frailty. As an operational definition for frailty the G8 screening tool will be used upon inclusion of the patient in a standardized manner. Briefly, G8 is an established screening tool that includes seven items from the Mini Nutritional Assessment (MNA) and an age-related item (<80, 80 to 85, or 85 years). The total score can range from 0 to 17. The result on the G8 is considered abnormal if the score is ≤14, indicating a geriatric risk profile. Due to age or frailty, the patient might not be a candidate for standard full-dose combination therapy. 2. Patients have to have histologically confirmed mCRC with unidimensionally measurable inoperable metastatic disease 3. ECOG performance status of 2 or better. 4. Life expectancy of 3 months or longer at enrolment 5. Patients ≥70 years with no upper age limit 6. Previous adjuvant chemotherapy is allowed if completed more than 6 months before randomisation 7. Previous rectal (chemo)radiotherapy is allowed if completed more than 6 months before randomisation 8. Hematological status: • Neutrophils (ANC) ≥ 1.5 x 109/L • Platelets ≥ 100 x 109/L • Hemoglobin ≥ 9 g/dL 9. Adequate renal function: • Serum creatinine level ≤ 1.5 x upper limit normal (ULN) 10. Adequate liver function: • Serum bilirubin ≤ 1.5 x upper limit normal (ULN) • Alkaline phosphatase ≤ 2.5 x ULN (unless liver metastases are present, then < 5 x ULN in that case) • AST and ALT < 3 x ULN (unless liver metastases are present then < 5 x ULN in that case) 11. Proteinuria < 2+ (dipstick urinalysis) or ≤ 2 g/24hour 12. Signed and dated informed consent, and willing and able to comply with protocol requirements 13. Regular follow-up feasible 14. Male patients with a partner of childbearing potential must agree to use effective contraception (Pearl Index < 1) during the course of the trial and at least 3 months after last administration of the study drug.
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E.4 | Principal exclusion criteria |
1. Prior systemic chemotherapy for mCRC 2. Other concomitant or previous malignancy, except: • Adequately treated in-situ carcinoma of the uterine cervix • Basal or squamous cell carcinoma of the skin • Cancer in complete remission for >3 years 3. Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days before start of study treatment. 4. History or evidence upon physical examination of CNS metastasis unless adequately treated (irradiation and no seizure with appropriate treatment) 5. Uncontrolled hypercalcemia 6. Pre-existing peripheral neuropathy (NCI grade ≥2) resulting from previous therapy 7. Concomitant protocol unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy), 8. Treatment with any other investigational medicinal product within 28 days prior to study treatment. 9. Significant cardiovascular disease: • Cardiovascular accident or myocardial infarction or unstable angina ≤6 months before start of study treatment • Severe cardiac arrhythmia • New York Heart Association grade ≥2 congestive heart failure • Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy. • History of stroke or transient ischemic attack ≤6 months before start of study treatment • Coronary/peripheral artery bypass graft ≤6 months before start of study treatment. • Deep vein thrombosis or thromboembolic events ≤1 month before start of study treatment 10. Patients with known allergy to any excipient to study drugs, 11. Any of the following within 3 months prior to randomization: Grade 3-4 gastrointestinal bleeding/hemorrhage, treatment resistant peptic ulcer disease, erosive oesophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic event. 12. Bowel obstruction before start of study treatment. 13. Treatment with CYP3A4 inducers unless discontinued > 7 days prior to randomization 14. Known dihydropyrimidine dehydrogenase (DPD) deficiency 15. Involvement in the planning and/or conduct of the study (applies to both Sanofi staff and/or staff of sponsor and study site) 16. Patient who might be dependent on the sponsor, site or the investigator 17. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG. 18. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].
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E.5 End points |
E.5.1 | Primary end point(s) |
Rate of patients free of progression at the time point of 6 months calculated from the start of treatment. Response assessment will be done in a standardized manner using CT scan.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at 6 months calculated from the start of treatment. |
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E.5.2 | Secondary end point(s) |
Safety • Dose intensities of study medication • Type, incidence and severity of AEs, SAEs (CTCAE version 4.03) • Dose reduction or discontinuation of study drug due to adverse events • Rate of treatment discontination due to toxicity • Type, incidence and severity of laboratory abnormalities
Efficacy • Response rates (response will be assessed by the local investigator using RECIST criteria v. 1.1; CT scans are conducted at 2, 4 and 6 months and every two months thereafter) • Overall and progression-free survival (OS)
Patient reported outcomes • Quality of life using EQ5D • Geriatric assessment using G8, ADL and IADL • Overall treatment utility (as defined in FOCUS2 trial)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Safety and tolerability: continuously - Response Rate (ORR): at 2, 4 and 6 months and every two months thereafter - Overall survival (OS) and Progression-free Survival (PFS): continuously - Patient reported outcomes: QoL baseline and every 4 weeks; geriatric assessment: baseline, after 3 and 6 months; OTU: after 3 and 6 months
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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 | 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 | 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) | 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 | Yes |
E.8.1.1 | Randomised | Yes |
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) | Yes |
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 | 40 |
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
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Database closure is defined as the end of the trial: Sites need to collect survival data of patients and are involved in the data cleaning process actively (e.g. additional source data may be requested and additonal monitoring visits may be neccessary). Therefore, database closure is considered the end of the trial. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |