E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic colorectal cancer with Acquired Resistance to Anti-EGFR Monoclonal Antibodies |
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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 | 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 |
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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 efficacy of 2 different weekly dosing regimens (9 mg/kg
loading dose followed by 6 mg/kg/week dose versus 12 mg/kg/week) of Sym004 compared with investigator`s choice in terms of overall survival time in subjects with metastatic colorectal cancer (mCRC). |
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E.2.2 | Secondary objectives of the trial |
- To assess the efficacy of the 2 different weekly dosing regimens of Sym004 in subjects with mCRC in terms of best overall response and progression-free survival time and time to treatment failure;
- To determine the safety profile of the 2 different weekly dosing regimens;
- To evaluate the dose intensity for the 2 different weekly dosing regimens;
- To determine the pharmacokinetic (PK) profile;
- To evaluate the occurrence of antidrug antibody (ADA);
- To identify potential predictive biomarkers of response to treatment in blood and tumor tissue;
- To evaluate quality of life |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Written informed consent obtained before undergoing any study-related activities
- Male or female, at least 18 years of age
- Subjects with histologically or cytologically confirmed mCRC, KRAS WT at initial diagnosis
- Failure of or intolerance to 5-FU, Oxaliplatin, and Irinotecan
- Acquired resistance to marketed anti-EGFR mAbs as defined in the protocol
- Measurable disease defined as one or more target lesions according to Response Evaluation Criteria in Solid Tumors (RECIST)
- Life expectancy of at least 3 months
- ECOG performance status ≤ 1
- Other predefined inclusion criteria may apply |
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E.4 | Principal exclusion criteria |
- Pretreatment with regorafenib
- Subjects who in the opinion of the subject and investigator would benefit more from regorafenib treatment (except where regorafenib is not reimbursed in the country)
- Skin rash Common Terminology Criteria for Adverse Events (CTCAE) Grade > 1 from previous anti-EGFR
therapy at time of randomization
- Magnesium < 0.9mg/dL
- Known hypersensitivity to any of the treatment ingredients. Known previous Grade 3-4 infusion related
reactions with anti-EGFR mABs
- Other predefined exclusion criteria may apply |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is overall survival (OS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
OS will be evaluated when 181 events of randomized patients are reported; expected in 2.5 years |
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E.5.2 | Secondary end point(s) |
- Best overall response according to RECIST v1.1
- Progression-free survival time
- Time to treatment failure
- number of subjects with AEs, serious AEs, treatment emergent AEs, AEs leading to death, and AEs with Grade >= 3 NCI-CTCAE (V.4.03)
- Relative dose intensity
- Pharmacokinetic profile (area under curve AUC 0-t, half-life, clearance, volume of distribution, C max, C trough, t max)
- Host immune response, number of subjects with anti-drug antibodies (ADA)
- Biomarkers: RAS pathway mutations, HER2 and MET status, EGFR and HER3 ligand levels
- Quality of life by subject reporting questionnaires using EORTC QLQ-C30 (version 3)
- Quality of life by subject reporting questionnaires using EORTC QLQ-CR29
- Quality of life by subject reporting questionnaires using FACT-EGFR18 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy endpoints:
- from randomization until first event, where an event can be a progression [radiologically confirmed or clinical progression] or death due to any cause, where death will only be considered as an event if it occurs within 12 weeks after last tumor response assessment without progression
Biomarkers:
- as defined in the protocol
Pharmacokinetics:
- as defined in the protocol
Quality of life:
- every 3/6 weeks during the Treatment Period
Safety endpoints:
- until 28 days after the last IMP administration or up to 21 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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
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 |
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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 | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 51 |
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 | No |
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 |
Austria |
Belgium |
France |
Germany |
Hungary |
Italy |
Poland |
Russian Federation |
Spain |
United States |
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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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28 days after the last subject received the last dose of trial treatment |
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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 | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |