| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic colorectal cancer, KRAS wild-type (WT) or mutant, with disease progression after first line treatment with an oxaliplatin-containing regimen. |
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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 | 10052358 |
|
| 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 gather preliminary evidence of superior activity, of RO5083945 added to FOLFIRI versus FOLFIRI + cetuximab in terms of progression free survival (PFS) in patients with KRAS WT colorectal cancer • to gather preliminary evidence of superior activity, of RO5083945 added to FOLFIRI versus FOLFIRI alone in terms of progression free survival (PFS) in patients with KRAS mutant colorectal cancer |
|
| E.2.2 | Secondary objectives of the trial |
| to evaluate best overall response rate (ORR) • to evaluate duration of response • to evaluate clinical benefit rate (CBR) • to evaluate overall survival • to evaluate the safety profile of patients treated with RO5083945 in combination with FOLFIRI versus FOLFIRI + cetuximab or FOLFIRI alone • to assess the effect of concomitant FOLFIRI on the pharmacokinetics of RO5083945 and vice versa • to evaluate the relationship between immune effector cells (in blood and tumor) and clinical outcome parameters (e.g. responders vs. non responders, PFS) • to evaluate the relationship between key upstream (e.g. ligands) and downstream EGFR markers (in tumor) and clinical outcome parameters (e.g. responders vs. non responders, PFS) • to compare fresh (new) vs. archival tumor biopsies (e.g. for EGFR expression) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1.Signed informed consent,and willing and able to comply with protocol requirements (including tumor biopsies) - 2.Age≥18 years - 3. Histologically or cytologically confirmed carcinoma of the colon and/or rectum with evidence of at least one measurable lesion as per RECIST criteria 1.1 - 4. The pt has received first-line combination therapy of an oxaliplatin containing regimen (re-challenge after drug holiday with same regimen is allowed) for metastatic disease and a)experienced radiographic disease progression during first-line therapy, or b)experienced radiographic disease progression within 6 months after the last dose of first-line therapy, or c) discontinued part or all of first-line therapy due to toxicity and experienced radiographic disease progression within 6 months after the last dose of first line therapy. - 5. Fresh (new) tumor biopsy (24 hour formalin fixed and shipped wet in 70% Ethanol) must be shipped to the central laboratory prior to randomization.A minimum of 11 evaluable slides must be available for analysis.Only KRAS and EGFR data generated from the fresh (new) tumor biopsy will be considered for the inclusion and stratification of the pt respectively. - 6. ECOG performance status 0-1 - 7. Life expectancy >12 weeks - 8. Adequate hematological function:platelet count of ≥ 100 x109/L, Hb ≥ 9 g/dL, granulocyte ≥ 1500x106/L 9. Adequate liver function:serum bilirubin ≤ 1.2xULN; transaminases ≤ 2.5xULN (in case of liver metastases < 5xULN) - 10. Adequate renal function:creatinine clearance ≥60 mL/min (Cockcroft and Gault formula) - 11. Negative serum pregnancy test within 7 days (+7 days for pts receiving FOLFIRI alone) prior of starting study treatment. The test must be repeated prior to first dosing if NOT done within 7 days (+7 days for pts receiving FOLFIRI alone) in pre-menopausal women and women < 2 years after the onset of menopause - 12. Female pts of childbearing potential must commit to using a reliable and appropriate methods of contraception until at least three months after the end of study treatment. Male pts with a partner of childbearing potential must agree to use a barrier method of contraception (condom) in addition to having their partner use another contraceptive method during the trial and for three months after the last dose. Reliable and appropriate methods of contraception include hormonal implants, oral contraceptives, intrauterine devices or a barrier method used in conjunction with spermicidal jelly. Specific country requirements: United Kingdom: male subjects who have been sterilized must also agree to use a barrier method of contraception. Male subjects must also commit to use a barrier method of contraception until at least 3 months after the end of study treatment. |
|
| E.4 | Principal exclusion criteria |
| 1.Pts who received prior treatment with a monoclonal antibody/small molecule against the EGFR - 2.Pts who received prior treatment with irinotecan - 3. Radiotherapy within the last 4 weeks before start of study drug treatment with the exception of limited field palliative radiotherapy for bone pain relief - 4. Treatment with any other investigational agent, or participation in another therapeutic clinical trial within 4 weeks prior to starting study treatment - 5. Suspected or known CNS metastasis - 6. Dementia or altered mental status that would prohibit informed consent - 7. Gilbert’s Syndrome - 8. Hypersensitivity to the active substance or to any of the excipients to any of the study drugs including premedication (corticosteroids, anti-histamine, paracetamol, hydroxytryptamine3 (5-HT3) receptor antagonist) - 9. Pregnant or breastfeeding women - 10. Chronic use of steroids and/or inhaled steroids will not be allowed. Use of steroids as premedication or as treatment for AEs is allowed. - 11. Active or history of autoimmune disorders/ conditions, including ulcerative colitis or active diverticulitis. Chronic diabetes mellitus, vitiligo or stable hypothyroidism will not be considered exclusion criteria - 12. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of any study drug (including contraindications described in the label of 5-FU (e.g. concomitant use of brivudine, sortivudine and analogues) and irinotecan (e.g., chronic inflammatory bowel disease), major surgery or significant traumatic injury within the last 4 weeks prior to first dose of study treatment or anticipation of the need for major surgery during study treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary variable is PFS defined as the time between randomization and date of first documented disease progression or death, whichever occurs first. |
|
| 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 | Yes |
| 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 | Yes |
| 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.8.3 |
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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 66 |
| 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 |
|
| 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
|
| Lo studio terminera` quando avra` avuto luogo l`aggiornamento della sopravvivenza o ultimo pt avra` completato visita di fup di sicurezza o si sara` ritirato dallo studio prima di tale momento (a seconda di quale evento si verifichera` per primo). |
|
| 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 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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