| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Second-Line Therapy in Patients with Metastatic Colorectal Cancer. |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients who have advanced colorectal cancer, who have failed on their first, oxaliplatin containing, chemotherapy regimen. |
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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 | 17.0 |
| 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 |
|
| 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 compare progression-free survival (PFS) between patients treated with Regorafenib plus standard chemotherapy (FOLFIRI) versus patients treated with placebo plus the same standard chemotherapy (FOLFIRI). (PFS: time from randomization until the patient’s cancer gets worse or death).
This study will be conducted in patients with metastatic colorectal cancer (mCRC) who were previously treated with a standard chemotherapy regimen that included oxaliplatin. |
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| E.2.2 | Secondary objectives of the trial |
• To compare overall response (OR) rates (Patients who experience complete recovery or partial recovery) between ARM A and ARM B as defined via Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
• To compare disease control (DC) rates (Patients who experience complete recovery, partial recovery or stabilisation of their disease) between ARM A and ARM B as defined via RECIST 1.1
• To compare overall survival (OS) between ARM A and ARM B (OS: time from randomization until death).
• To evaluate the effect of regorafenib on the Pharmacokinetic profile of irinotecan and SN-38. (PK profiling will not be perfomed at the UK sites in this study).
• To further evaluate the safety and tolerability of regorafenib in combination with FOLFIRI.
• In tissue and blood samples donated from participating patients, is there any correlation between the markers found in the tissue and the patients' response to treatment? |
|
| 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 |
| Optional sub-study: Collect a tumour biopsy in a subset of patients in order to compare genetic alterations in KRAS, BRAF, and PI3K and other genes from fresh biopsies versus primary or metastatic archival tumour samples, to determine if any new genetic alterations are detected. |
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| E.3 | Principal inclusion criteria |
• Age ≥18 years of age (no upper age limit)
• Histological or cytological documentation of adenocarcinoma of the colon or rectum
• Archived, paraffin-embedded tissue block (primary or metastatic) available for genomic studies required
• Metastatic disease not amenable to surgical resection with curative intent
• Progression during or within 6 months following administration of a standard regimen for the treatment of metastatic disease that included oxaliplatin with any of the following agents with or without bevacizumab:
- 5-fluorouracil (F-FU) with or without leucovorin or levoleucovorin
- Capecitabine
NOTE: In patients receiving FOLFOX, oxaliplatin is sometimes discontinued due to toxicity or as part of maintenance therapy strategy. If such patients progress while on 5-FU alone, they are eligible for this trial. As an example, a patient who is begun on FOLFOX or CapeOx (with or without bevacizumab), whose oxaliplatin is held for neurotoxicity and who is switched to capecitabine monotherapy or capecitabine with bevacizumab, would be considered to have had ONE prior therapy.
OR
Patients who develop metastatic disease within 9 months of adjuvant FOLFOX for stage II or III colon cancer
• Measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
• Life expectancy of at least 3 months
• Adequate bone marrow, renal, and hepatic function, as evidenced by the following:
o absolute neutrophil count (ANC) ≥1,500/mm3
o platelets ≥100,000/mm3
o haemoglobin ≥9.0 g/dL
o serum creatinine ≤1.5 x upper limit of normal (ULN)
o Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2
o AST and ALT ≤3 x ULN ( ≤5.0 × ULN for patients with liver involvement of their cancer)
o Bilirubin ≤1.5 X ULN
o Alkaline phosphatase ≤3 x ULN (≤5 x ULN with liver involvement of their cancer)
o Amylase and lipase ≤1.5 x ULN
o Spot urine must not show 1+ or more protein in urine or the patient will require a repeat urine analysis. If repeat urinalysis shows 1+ protein or more, a 24-hour urine collection will be required and must show total protein excretion <1000 mg/24 hours
o INR/PTT ≤1.5 x ULN
Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care.
• Women of childbearing potential and male subjects must agree to use adequate contraception for the duration of study participation and up to 6 months following completion of therapy. Adequate contraception is defined as any medically recommended method (or combination of methods) as per standard of care. Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with fluorouracil and irinotecan.
• The subject is capable of understanding and complying with parameters as outlined in the protocol
• Signed, IRB-approved written informed consent |
|
| E.4 | Principal exclusion criteria |
• Prior treatment with regorafenib
• More than 1 prior chemotherapy regimen for mCRC. Previous adjuvant FOLFOX based chemotherapy is allowed. Prior FOLFIRI or single agent irinotecan is prohibited.
• Known history of or concomitant malignancy likely to affect life expectancy in the judgment of the investigator
• Pregnant or breastfeeding patients. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of FOLFIRI treatment, and a negative result must be documented before start of treatment.
• History of Gilbert’s syndrome
• Known DPD deficiency
• Pernicious anaemia or other anaemias due to vitamin B12 deficiency (due to potential masking of deficiency with leucovorin)
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of Day 1 of treatment with FOLFIRI
• Radiotherapy within 4 weeks prior to first dose of FOLFIRI
• Active cardiac disease including any of the following:
o Congestive heart failure (New York Heart Association [NYHA]) ≥Class 2
o Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of Day 1 of FOLFIRI
o Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
o Uncontrolled hypertension. (Systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg despite optimal medical management)
• Patients with pheochromocytoma
• Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within the 6 months before start of FOLFIRI
• Ongoing infection >Grade 2 according to NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0)
• Known history of human immunodeficiency virus (HIV) infection
• Known history of chronic hepatitis B or C
• Patients with seizure disorder requiring medication
• Symptomatic metastatic brain or meningeal tumours unless the patient is >6 months from definitive therapy, has a negative imaging study within 4 weeks of FOLFIRI initiation, and is clinically stable with respect to the tumour at the time of study entry. Also, the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies)
• History of organ allograft
• Evidence or history of bleeding diathesis. Any haemorrhage or bleeding event > Grade 4 within 4 weeks of start of FOLFIRI
• Non-healing wound, ulcer, or bone fracture
• Renal failure requiring hemo- or peritoneal dialysis
• Dehydration according to NCI-CTC v 4.0 Grade >1
• Substance abuse, medical, psychological, or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results
• Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
• Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
• Inability to swallow oral medications
• Any mal-absorption condition
• Unresolved toxicity higher than CTCAE v. 4.0 Grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin-induced neurotoxicity (which must be ≤Grade 2)
• Patients unable or unwilling to discontinue (and substitute if necessary) use of prohibited drugs for at least 30 days prior to Day 1 of FOLFIRI initiation
• Any chronic inflammatory bowel disease and/or chronic bowl obstruction
• Unwilling to provide consent for genetic studies of tumour, whole blood, or plasma specimens
• Unwilling to avoid vaccinations with live vaccine and concomitant use of attenuated live vaccines’ |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To compare PFS between regorafenib + FOLFIRI chemotherapy (ARM A) versus placebo + FOLFIRI (ARM B) in patients failing one prior oxaliplatin-containing regimen for mCRC. PFS is defined as the time from randomization until progression or death as a result of any cause. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 2 treatment cycles during treatment (1 cycle = 28 days). After treatment follow up assessments are performed at 30 days post treatment and then every 3 months for the next 2 years and then every 6 months for the following 3 years. |
|
| E.5.2 | Secondary end point(s) |
• To compare overall response (OR) rates (RECIST: CR+PR).
• To compare disease control (DC) rates (RECIST: CR+PR+SD).
• To compare overall survival (OS) (OS: time from randomization until death).
• To evaluate the effect of regorafenib on the PK profile of irinotecan and SN-38.
• To further evaluate the safety and tolerability of regorafenib in combination with FOLFIRI.
• To explore potential correlations between blood and tissue biomarkers and clinical benefit. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Overall Response: Tumour assessments performed every 2 treatment cycles (1 cycle = 28 days) and at treatment discontinuation.
• Disease Control: Tumour assessments performed every 2 treatment cycles (1 cycle = 28 days) and at treatment discontinuation.
• Overall survival: Every 2 treatment cycles during treatment (1 cycle = 28 days) and at treatment discontinuation. After treatment, follow up assessments are performed at 30 days post treatment and then every 3 months for the next 2 years and then every 6 months for the following 3 years.
• PK profiling: Samples drawn at - Cycle 1: Day 1, Day 2 and Cycle 2: Day 1, Day 2.
• Safety and tolerability: All timepoints.
• Correlative studies: Samples drawn at baseline, cycle 2 day 21 and treatment discontinuation. |
|
| 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 | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
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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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| 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 | 1 |
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