E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061451 |
E.1.2 | Term | 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 |
phase 1
To evaluate the maximum tolerated dose in a selected group of patients with good performance status with metastatic disease who have progressed on at least first line therapy.
phase 2
To establish safety and tolerability of recommended phase II treatment dose of aflibercept and capecitabine in patients not suitable for doublet/triplet cytotoxic chemotherapy |
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E.2.2 | Secondary objectives of the trial |
phase 1
To evaluate the overall treatment toxicity profile in this group.
Overall response rate in this group
phase 2
To establish the overall response rate (ORR) in this group
To assess the overall treatment utility of this combination via the use of a comprehensive health assessment tool.
To evaluate the overall treatment toxicity profile according to the CTC v4.03.
To assess progression free survival in this group
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Histologically confirmed colorectal cancer with evidence of metastatic disease
Adequate medical fitness to undergo fluoropyrimidine-based chemotherapy.
No known dihydropyrimidine dehydrogenase deficiency.
Adequate bone marrow function with:
platelets > 100 x 109/l; WBC > 3 x 109/l; neutrophils > 1.5 x 109/l; Hb > 9 g/dl
Serum bilirubin < 1.5 x upper limit of institutional normal range (ULN), alkaline phosphatase < 5 x ULN and transaminases < 3 x ULN unless liver metastasis then < 5 x ULN.
Serum creatinine ≤ 1.5 x ULN or creatinine clearance > 50ml/min
Proteinuria < 2+ (dipstick urinalysis) or ≤ 1g/24hour.
For female patients of childbearing potential, negative serum pregnancy test within 1 week (7 days) prior of starting study treatment,
Female patients must commit to using reliable and appropriate methods of contraception until at least three months after the end of study treatment (when applicable). Male patients with a partner of childbearing potential must agree to use contraception in addition to having their partner use another contraceptive method during the trial.
Recovery from any treatment related grade 3/4 non-haematological toxicity (except alopecia and fatigue) to baseline or ≤ grade 1
Absence of pre-existing liver dysfunction of Childs-Pugh B or worse
Written informed consent
Life expectancy > 3 months
Age ≥ 18 years
Phase I study specific criteria
WHO performance status 0 – 1
Progressive disease after at least first line chemotherapy treatment
Previous fluoropyrimidine therapy has not required dose reduction of greater than 25%, significant delay (≥ 7 days) or stopped treatment due to fluoropyrimidine toxicity
Phase 2 specific criteria
WHO performance status 0 – 2
Patients not deemed suitable for doublet/triplet combination chemotherapy.
No previous treatment for mCRC. |
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E.4 | Principal exclusion criteria |
Known evidence of brain metastases
o Liver-only metastatic disease deemed to be resectable
o LVEF <50%
o Patients who did not previously tolerate IV 5-FU or capecitabine (required dose reduction, significant delay (≥ 7days) or stopped treatment due to fluoropyrimidine toxicity
Any of the following within 3 months prior to inclusion: grade 3-4 gastrointestinal bleeding/haemorrhage (unless due to resected tumour), treatment resistant peptic ulcer disease, erosive oesophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thrombo-embolic event.
o Any of the following within 6 months prior to inclusion: myocardial infarction, acute coronary syndrome, unstable angina pectoris, coronary revascularisation (PCI or CABG), NYHA class III or IV congestive heart failure, stroke or transient ischaemic attack.
o Any patient who has undergone major surgery <1month prior to trial entry.
o Uncontrolled hypertension (grade 3 /4)
o Significant proteinuria (≥2+ on dipstick or ≥1g/24hour)
o Significant bleeding diathesis or significant underlying coagulopathy (INR>1.5) in the absence of vitamin K antagonist therapy.
o Intolerance to loperamide
o Previous history of gastrointestinal fistula or perforation
o Evidence of bowel obstruction
o Clinically relevant history of drug or alcohol abuse
o Serious uncontrolled inter current illness including poorly controlled diabetes mellitus
o HIV, HBV or HCV infection.
o Pregnancy or lactation. Men and women of child-bearing potential must use adequate contraception
Any psychological, familial, sociological or geographic condition potentially hampering compliance with the study protocol and follow-up schedule. |
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E.5 End points |
E.5.1 | Primary end point(s) |
phase 1
o To establish the maximum tolerated dose and dose-limiting toxicities in this group
phase 2
o Tolerability and feasbility of treatment (no dose reduction, significant treatment delay or stopping treatment early due to toxicity). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Toxicity will be assessed prior to each cycle of treatment |
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E.5.2 | Secondary end point(s) |
phase 1
o To evaluate the overall treatment toxicity profile in this group
phase 2
o Overall response rate
o Progression free survival
o Dose limiting toxicities.
o Quality of life
o Overall treatment utility via the use of comprehensive health assessment tool
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.5 | Efficacy | No |
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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 10 |
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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The trial will be closed when all participants have made their final follow-up visit, the data entered into the database and all queries resolved and the database locked. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |