E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic colorectal cancer |
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E.1.1.1 | Medical condition in easily understood language |
Metastatic colorectal cancer |
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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 | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052358 |
E.1.2 | Term | Colorectal cancer metastatic |
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 |
Comparison of overall survival in the Regorafenib and REGIRI combination (Regorafenib + Irinotecan) arms in mCRC patients of Cyclin D1 A/A genotype. |
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E.2.2 | Secondary objectives of the trial |
Study of:
-Progression-free survival
-Objective response rate
-Disease control rate according to Recist criteria (version 1.1)
-Toxicity (according to the NCI-CTCAE v5.0)
-Quality of life (EORTC QLQ-C30)
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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 |
Investigation any association between cyclin D1 protein expression and response to treatment. |
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E.3 | Principal inclusion criteria |
1. Signed informed consent obtained before any study specific procedures
2. Male or female ≥ 18 years of age
3. Histological or cytological documentation of adenocarcinoma of the colon or rectum
4. Patients with metastatic colorectal cancer
5. Progression during or within 3 months following the last administration of approved standard therapies, which must include a fluoropyrimidine (or raltitrexed), oxaliplatin, irinotecan, anti VEGF therapy and an anti EGFR therapy (for RAS wild-type tumors)
6. ECOG performance status ≤1
7. Life expectancy of at least 3 months
8. Patients with A/A CCND1 genotype of rs603965 CCND1
9. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment:Amylase and lipase ≤1.5 x ULN, Total bilirubin ≤ 1.5 x ULN, Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN (≤ 5 x ULN for patients with liver involvement of their cancer), Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN for patients with liver involvement for their cancer and/or have bone metastases), Platelet count ≥ 100,000/mm3; Hemoglobin (Hb) ≥ 9 g/dL; Absolute neutrophil count (ANC) ≥ 1,500/ mm3. Transfusion to meet the inclusion criterion, Serum creatinine ≤ 1.5 x ULN
10. International normalized ratio (INR) ≤ 1.5 x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless receiving treatment with therapeutic anticoagulation. Patients being treated with anticoagulant, e.g., heparin, will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care
11. Women of childbearing potential must have a blood or urine pregnancy test performed a maximum of 7 days before start of study treatment, and a negative result must be documented before start of study treatment
12. Women of childbearing potential and men must agree to use adequate contraception before entering the study until at least 8 weeks after the last study drug administration of Regorafenib and 12 weeks after the last study drug administration of Irinotecan. The investigator or a designated associate is requested to advise the patient on how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care.
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E.4 | Principal exclusion criteria |
1. Patients with A/G or G/G CCND1 genotype of rs603965 CCND1
2. Prior treatment with regorafenib or sorafenib
3. Prior treatment with TAS 102
4. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study drug
5. Pregnant or breast-feeding subjects. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of study drug
6. Congestive heart failure ≥ New York Heart Association (NYHA) class 2
7. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months)
8. Myocardial infarction less than 6 months before start of study drug
9. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
10. Uncontrolled hypertension. (Systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management)
11. Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE V5.0 Grade 2 dyspnea)
12. Ongoing infection > Grade 2 NCI-CTCAE V5.0
13. Known history of human immunodeficiency virus (HIV) infection
14. Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy
15. Patients with seizure disorder requiring medication
16. History of organ allograft
17. Patients with evidence or history of any bleeding diathesis, irrespective of severity
18. Any hemorrhage or bleeding event ≥ NCI-CTC V5.0 Grade 3 within 4 weeks prior to the start of study medication
19. Non-healing wound, ulcer, or bone fracture
20. Dehydration NCI-CTCAE V5.0 Grade ≥ 1
21. Substance abuse, medical, psychological or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results
22. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
23. Any illness or medical conditions that are unstable or could
jeopardize the safety of the subject and his/her compliance in the study
24. Persistent proteinuria of NCI-CTCAE V5.0 Grade 3 (> 3.5g/24 hours)
25. Patients unable to swallow oral medications
26. Any malabsorption condition
27. Chronic inflammatory bowel disease and / or bowel obstruction
28. Unresolved toxicity higher than NCI-CTCAE V.5.0 Grade 1 attributed to any prior therapy/procedure excluding alopecia, hypothyroidism and oxaliplatin induced neurotoxicity ≤ Grade 2
29. Concomitant participation or participation within the last 30 days in another clinical trial
30. Systemic anticancer therapy during this trial or within 4 weeks before randomization
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival presented with its median and confidence interval at 95%, estimated from randomization date to the date of death, whatever the cause, using the Kaplan-Meier method |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoint include:
- Progression-free survival (PFS), defined as the time (days) from date of randomization to date of first observed disease progression (investigator’s radiological or clinical assessment) or death due to any cause, if death occurs before progression is documented. Patients without tumor progression or death at the time of analysis will be censored at their last date of tumor assessment.
- Disease control rate (DCR), defined as the rate of patients, whose best response was not progressive disease (i.e., CR, PR or SD), to all randomized patients in the treatment group
- Objective response rate (OOR), defined as the rate of patients with CR or PR, to all randomized patients in the treatment group. Patients prematurely discontinuing without an assessment will be considered non-responders for the analysis.
- Safety will be evaluated using the NCI-CTCAE version 5.0 scale; at each visit for the duration of the treatment.
-Quality of life will be evaluated, using the EORTC QLQ-C30 questionnaire.
The expected benefit is an overall survival improvement of this treatment in patients with metastatic colorectal cancer who have received all standard treatments except TAS-102 and Regorafenib.
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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) | 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 | 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 | 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 last visit of the last subject undergoing the trial |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |