| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Histologically or cytologically confirmed carcinoma of the colon and/or rectum with
evidence of metastases.
Diagnosis of metastatic disease according to RECIST not more than 3 months prior to enrolment
No prior chemotherapeutic treatment for metastatic colorectal carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients have to be diagnosed with bowel cancer, a cancer characterized by neoplasia in the colon, rectum, or vermiform appendix. This cancer can metastasizes to distant sites. |
|
| 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 | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010028 |
| E.1.2 | Term | Colorectal cancer Duke's D |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| Determine the efficacy of modified XELIRI (Capecitabine and Irinotecan) in combination with bevacizumab followed by XELOX (Capecitabine and Oxaliplatin) in combination with bevacizumab at progression in comparison with the reverse sequence based on duration of disease control (DDC) . |
|
| E.2.2 | Secondary objectives of the trial |
-Determine
• first line progression free survival (PFS)
• second line PFS
• overall response rate
• time to response
• duration of response
• overall survival of XELIRI plus bevacizumab and XELOX plus bevacizumab
-Tumour assessments (based on RECIST criteria) using CT scans, MRI scans, X-ray, bone scan, clinical examination
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Written informed consent
2) Age ≥ 18 years
3) Patient must be able to comply with the protocol
4) Histologically or cytologically confirmed carcinoma of the colon and/or rectum with evidence of metastases.
5 )Diagnosis of metastatic disease according to RECIST not more than 3 months prior to enrolment.
6) Life Expectancy of at least 3 months
7) At least one measurable metastatic lesion (as per RECIST criteria)
8) Prior adjuvant or neo-adjuvant chemotherapy /radiotherapy allowed if completed more than 6 months before inclusion. Patients who received
Oxaliplatin for neoadjuvant or adjuvant treatment should receive XELIRI for 1st line treatment, patients who received Irinotecan for
neoadjuvant or adjuvant treatment should receive XELOX for 1st line treatment for their metastatic disease.
9) ECOG performance score of 0 or 1
10) Adequate haematological function: ANC ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L, Hb ≥ 9 g/dL
11) INR ≤ 1.5 and aPTT ≤ 1.5 x ULN within 7 days prior to starting study treatment
12) Adequate liver function: Serum bilirubin ≤ 1.5 x ULN; alkaline phosphatase and transaminases ≤ 2.5 x ULN (in case of liver metastases < 5 x ULN)
13) Serum Creatinine ≤ 1.5 x ULN
14) Urine dipstick for proteinuria < 2+. If urine dipstick is ≥ 2+, 24- hour urine must demonstrate ≤ 1 g of protein in 24 hours
15) Negative serum pregnancy test within 7 days of starting study treatment in pre- menopausal women and women < 2 years after the onset of menopause. This test has to be reconfirmed by a urine test, should the 7 days window be exceeded. Fertile women (<2 years after last menstruation) and men must use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile).
|
|
| E.4 | Principal exclusion criteria |
1) Prior chemotherapeutic treatment for metastatic CRC
2) Symptomatic CNS metastases
3) Significant vascular disease (e.g. aortic aneurysm potentially requiring surgical intervention, pulmonary embolism or recent peripheral arterial thrombosis) within 6 months prior start of study treatment.
4) History of haemoptysis (≥ ½ teaspoon of bright red blood per episode) within 1 month prior start of study treatment
5) Past or current history (within the last 2 years prior to treatment start) of other malignancies (Patients with curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible).
6) Clinically significant cardiovascular disease, for example CVA (≤ 6 months before treatment start), myocardial infarction (≤ 6 months before treatment start), unstable angina, NYHA ≥ grade 2 CHF, arrhythmia requiring medication, or uncontrolled hypertension.
7) Prior history of hypertensive crisis or hypertensive encephalopathy
8) Treatment with any other investigational agent or any other biological agent (e.g.cetuximab), or participation in another clinical trial within 30 days prior to entering this study.
9) Known hypersensitivity to any of the study drugs
10) Current or recent (within 10 days of first dose of study treatment) chronic use of aspirin (> 325 mg/day)
11) Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic (as opposed to prophylactic) purposes.
12) Evidence of bleeding diathesis or coagulopathy.
13) Serious, non healing wound, ulcer, or bone fracture.
14) Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to treatment, or anticipation of the need for major surgery during the course of the study. If CVAD is required for chemotherapy administration, it should be inserted within 2 days prior to study treatment cycle.
15) Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior start of study therapy
16) History of abdominal fistula, tracheo-oesophageal fistula or any grade 4 non gastrointestinal fistula, gastrointestinal perforation or intraabdominal abscess before 1st line therapy.
17) History or evidence upon physical/neurological examination of CNS disease (unrelated to cancer) (unless adequately treated with standard medical therapy) e.g. uncontrolled seizures
18) Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications
19) Patients with contraindication for cross over chemotherapy (e.g. patients treated with irinotecan based first line therapy and serious polyneuropathy > grade 1, not feasible for oxaliplatin based cross over second line therapy, or patients treated with oxaliplatin based first line therapy and hereditary fructose intolerance not feasible for Irinotecan based cross over second line therapy)
20) Pregnancy or lactation
21) Fertile women (<2 years after last menstruation) and men not willing to use effective means of contraception. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is to determine the efficacy of modified XELIRI (Capecitabine and Irinotecan) in combination with bevacizumab followed by XELOX (Capecitabine and Oxaliplatin) in combination with bevacizumab at progression in comparison with the reverse sequence based on DDC. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
64 months from first patient entered (first patient in 12-April-2012)
(accrual time was 33 months from 1st patient entered, projected analysis of the primary endpoint will be 64 months from first patient entered).
|
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints are:
To determine
• first line PFS
• second line PFS
• the overall response rate
• time to response
• duration of response
• overall survival of Xeliri plus bevacizumab and Xelox plus bevacizumab
- Tumour assessments (based on RECIST criteria) using CT scans, MRI scans, X-ray, bone scan, clinical examination.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
64 months from first patient entered (first patient in 12-April-2012)
(accrual time was 33 months from 1st patient entered, projected analysis of the primary endpoint will be 64 months from first patient entered). |
|
| 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Sequence of treatment XELOX than XELIRI |
|
| 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 | 12 |
| 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
|
The end of the ML25153 is defined as the last patient last visit at the end of the follow up period.
The clinical cut-off date for the final analysis of progression free survival is the date at which the last data point from the last patient was captured to reach the 100% information. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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