E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic colorectal cancer resistanct to standard chemotherapy with evidence of deficiency of the mismatch repair gene MSH2, either on immunohistochemistry of tumour histology or on testing of peripheral blood for a germline mutation in MSH2 |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
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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 determine the efficacy (by response rate using RECIST criteria) of methotrexate in patients with metastatic colorectal cancer and evidence of MSH2 deficiency previously treated with standard chemotherapy. |
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E.2.2 | Secondary objectives of the trial |
To determine tumour stabilisation rates of patients receiving study treatment To determine survival of patients receiving study treatment. To determine the tolerability of study treatment in this patient population by quality of life and toxicity analysis. To identify biomarkers that may predict for a response to treatment
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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 |
1) Tumour biopsy substudy - patients who have metastatic disease that is readily accessible for a biopsy sample to be taken without significant risks may optionally consent for a further histology sample to be taken. Gene expression profiling on this sample will be compared to gene expression profiling on the original (diagnostic) sample 2) PET and MRI substudies - patients in selected centres can optionally consent to having PET (positron emission tomography) and MRI scans performed before, during and after treatment |
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E.3 | Principal inclusion criteria |
1) Confirmed diagnosis of metastatic or locally recurrent colorectal carcinoma 2) Paraffin embedded histological material available for analysis 3) Either confirmed loss of expression of MSH2 on IHC or confirmed mutation in MSH2 on gene sequencing 4) Life expectancy of > 3 months 5) ECOG Performance Status of 0-2 6) Willingness and ability to comply with scheduled study visits and tests 7) Radiologically and/ or clinically documented measurable disease (RECIST criteria) 8) Adequate bone marrow function, renal function and hepatic function 9) Metastatic disease refractory to standard chemotherapy with 5-fluorouracil, irinotecan and oxaliplatin containing regimens, or intolerant of standard chemotherapy, or other patient factors why standard treatment cannot be given 10) Age 18 years or older 11) Patients must be willing to undertake appropriate contraceptive methods or remain sexually abstinent for the duration of study treatment and for at least three months after receiving the last dose of chemotherapy
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E.4 | Principal exclusion criteria |
1) Previous treatment with methotrexate, either for malignant or non-malignant disease, except when methotrexate was given as a chemomodulator with 5-fluorouracil for colorectal cancer in the adjuvant setting 2) Concomitant uncontrolled medical conditions 3) Concomitant metastatic malignancy apart from non-melanotic skin cancers and carcinoma in situ of the uterine cervix in the last 10 years (Previous treatment for cancers associated with the Lynch syndrome is acceptable) 4) Pregnant or breast feeding 5) Medical or psychiatric conditions impairing ability to give informed consent 6) Any contraindication to treatment with methotrexate 7) Prior radiotherapy to a lesion that will be used as a marker lesion to assess disease response, unless there has been evidence of clear documented progression of that lesion since radiotherapy 8) Consideration should be given to treating significant 3rd compartment fluid collections (ascites, pleural effusions) before treatment commences
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be the objective response rate to treatment (ORR) (to include radiological evidence of confirmed complete response and partial response), as defined by RECIST criteria on CT scans. |
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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 | Yes |
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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
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.8.3 |
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 | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 close to recruitment when the specified number of patients have enrolled. The study will officially be considered ended when all patients enrolled have either had disease progression, died, or survived 1 year after treatment without disease progression. |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |