Colorectal Cancer Metastatic, Colorectal Carcinoma, Colorectal Neoplasms, Neoplasm Metastasis
Conditions
Keywords
Clinical Trial, Phase II, Elderly, Aged, Disease-Free Survival, Safety, Tolerability, Chemotherapy regimen, Monoclonal antibody, FOLFIRI, Panitumumab, RAS/BRAF Wild-type
Brief summary
To estimate progression-free survival at one year in elderly patients with RAS/BRAF wild-type unresectable mCRC and good performance status treated with FOLFIRI + panitumumab as first-line therapy. The clinical hypothesis of this study is that the combination of panitumumab and FOLFIRI is a good treatment option in elderly patients with good performance status and RAS/BRAF wild-type unresectable mCRC. Another purpose of this clinical trial is to determine the RAS/BRAF mutation status in liquid biopsies at baseline and at the time of disease progression.
Detailed description
Phase II, multicentre, single-arm trial. Elderly patients with good performance status and RAS/BRAF wild-type unresectable mCRC will be evaluated before being included in this trial. Eligible patients will receive panitumumab plus FOLFIRI for disease control until disease progression, unacceptable toxicity, investigator decision or the patient's withdrawal of consent. Tumour response will be evaluated by investigators using RECIST criteria (Response Evaluation Criteria in Solid Tumours) version 1.1. Tumour response will be evaluated every 8 weeks until disease progression is documented. Disease response will be confirmed no less than 28 days after the criteria for response are first met. Radiographic progression of subjects with symptoms indicating disease progression will be evaluated at the time of symptom onset. Following disease progression, information will be collected on the subsequent lines of treatment chosen by the investigator and survival at follow-up visits held every 12 weeks (± 4 weeks) until completion of the trial (approximately 24 months after inclusion of the last patient in the trial). A blood sample will be taken at baseline and at the time of disease progression in order to determine the RAS/BRAF mutation status.
Interventions
DRUGPanitumumab
Panitumumab 6 mg/kg will be administered by intravenous (IV) infusion over 60 min on days 1 and 14 of every cycle just before administration of chemotherapy
DRUGIrinotecan
Irinotecan 150 mg/m2 will be administered as IV infusion over 90 min on day 1of first treatment cycle. If tolerance of this first dose is good, it will be scaled to a full dose of 180 mg/m2 starting from the second treatment cycle
DRUGFolinic acid
Folinic acid 200-400 mg/m2 will be administered as IV infusion over 2 hours on day 1
DRUG5-FU
5-FU will be administered IV 400 mg/m2 bolus followed by 2400 mg/m2 IV continuous infusion over 46-48 hours on days 1 and 2
Sponsors
Amgen
Pivotal S.L.
Grupo Espanol Multidisciplinario del Cancer Digestivo
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
70 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males or females ≥ 70 years, 2. Able to understand, sign and date an informed consent form approved by the IEC, 3. Histologically confirmed colorectal carcinoma with metastatic disease, 4. RAS/BRAF wild-type status in solid biopsy confirmed prior to inclusion of the study, 5. No previous treatment for metastatic disease, 6. Patients starting therapy with FOLFIRI + panitumumab with a treatment aim other than achieving potential resectability of the disease, 7. Independence in activities of daily living (ADL) based on the Katz Index and in instrumental activities of daily living (IAL) based on the Lawton Index, 8. Having no or only one comorbidity according to the Charlson Comorbidity Index. The following ones are not considered comorbidities as long as it is provided they are adequately controlled with medication: gastroduodenal ulcer, diabetes without target organs' damage, chronic respiratory disease and connective tissue disease. 9. Presence of at least one unidimensional measurable lesion ≥ 10 mm according to RECIST criteria (version 1.1), 10. ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, 11. Adequate bone marrow function: neutrophils ≥ 1.5 x 10\^9/l; platelets ≥ 100 x 10\^9/l; haemoglobin ≥ 9 g/dl, 12. Hepatic, renal and metabolic function as follows: 1. Total bilirubin count ≤ 1.5 x ULN; ALT and AST \< 5 x ULN; 2. Renal function, calculated creatinine clearance or 24-hour creatinine clearance ≥ 50 ml/min; 3. Magnesium \> LLN
Exclusion criteria
1. Diagnosed or suspected central nervous system (CNS) metastasis, 2. Patients with initially resectable metastases at the time of diagnosis of metastatic disease. 3. History or presence of another malignancy, with the exception of curatively treated in situ carcinoma of the cervix or non-melanoma skin cancer or any curatively treated solid tumour, with no active disease or administration of treatment within 5 years prior to inclusion in the study, 4. Prior treatment with irinotecan, 5. Prior adjuvant chemotherapy for colorectal cancer terminated less than 6 months before metastatic disease was diagnosed, 6. Prior anti-epidermal growth factor receptor (EGFR) antibody therapy (eg, cetuximab), anti- vascular endothelial growth factor (VEGF) or treatment with small molecule EGFR inhibitors (eg, erlotinib), 7. Unresolved toxicities from prior systemic treatment that, in the investigator's opinion, make the patient unsuitable for inclusion, 8. Hormone therapy, immunotherapy with experimental or approved antibodies/proteins (e.g. bevacizumab) ≤ 30 days prior to inclusion, 9. Evidence of previous acute hypersensitivity reaction of any grade to any of the components of the treatment, 10. History of interstitial lung disease or pulmonary fibrosis or signs of interstitial lung disease or pulmonary fibrosis on baseline CT, 11. Presence of geriatric syndromes, defined as dementia, repeated falls, fecal incontinence or urinary incontinence, 12. Acute or subacute bowel obstruction and/or active bowel disease or another bowel disease causing chronic diarrhoea (defined as diarrhoea of grade ≥ 2 according to the NCI (National Cancer Institute) Common Terminology Criteria for Adverse Events (CTCAE version 4.03), 13. Significant cardiovascular disease, including unstable angina pectoris or myocardial infarction within 12 months prior to inclusion in the study, 14. History of Gilbert's syndrome or dihydropyrimidine dehydrogenase deficiency, 15. Positive test result for human immunodeficiency virus, hepatitis C virus, chronic active hepatitis B infection, 16. Treatment for systemic infection within 14 days prior to the start of the study treatment, 17. Clinically significant sensory peripheral neuropathy, 18. Any concurrent disease that may increase the risk associated with study participation or may interfere with the interpretation of study results, 19. Any investigational product within 30 days prior to inclusion, 20. Surgery (not including diagnostic biopsy or the placement of a central line) and/or radiotherapy within 28 days prior to inclusion in the study, 21. Males whose partner is of child-bearing age and who does not agree to use adequate contraceptive precautions, i.e. double-barrier methods (e.g. diaphragm plus condom) or abstinence for the duration of the study and for 1 month after the last administration of the study drug, 22. Subjects who do not agree or are unable to meet the study requirements, 23. Psychological, familial, sociological or geographical conditions potentially hampering compliance with the study protocol and the follow-up schedule. Such conditions should be discussed with the patient before enrolment in the clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival at one year | 12 months after inclusion | Percentage of subjects still alive and progression free 12 months after inclusion in the study |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | 42 months | Time (months) from inclusion in the trial until disease progression or death |
| Objective response rate | 42 months | Proportion of patients with an objective response (complete or partial response) according to RECIST 1.1 criteria |
| Disease control rate | 42 months | Proportion of patients with disease control (complete response, partial response or stable disease) |
| Duration of response | 42 months | Time (months) from the first confirmation of objective response according to RECIST 1.1 criteria until disease progression or death |
| Time to response | 18 months | Time (months) from inclusion in the trial until the date of the first confirmation of objective response according to RECIST 1.1 criteria |
| Overall survival (OS) | 42 months | Time (months) from inclusion in the trial until death of the patient |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | 42 months | Incidence and severity of adverse events. AEs description according to the NCI (National Cancer Institute) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 |
| Combined analysis of prognostic factors in metastatic disease | 42 months | To analyse the number of lesions in liver and lung disease (1-3 vs 4-9 or ≥10), and the size of the largest lesion (\<5 cm or ≥ 5 cm), in correlation with the analytical values, mainly LDH and AP values. |
| Time to treatment failure | 18 months | Time (months) from inclusion in the trial until progression, death or discontinuation due to toxicity |
| Proportion of patients with early tumour shrinkage (ETS) | 2 months | Defined as tumour shrinkage ≥ 30% at the first tumour assessment based on RECIST 1.1 criteria |
| Depth of response (DpR) | 18 months | Measured as the maximum reduction ratio (percentage) of the tumour compared with baseline measurement (sum of diameters of the lesions) at the different assessments based on RECIST 1.1 criteria |
Other
| Measure | Time frame | Description |
|---|---|---|
| RAS/BRAF conversion proportion | At treatment initiation and at the time of PD (42 months) | Conversion rate of RAS/BRAF status at first-line treatment initiation and at the time of disease progression |
| RAS/BRAF mutations' detection proportion | At baseline | Detection rate of RAS/BRAF mutations in liquid biopsies at baseline in subjects with RAS/BRAF wild-type mCRC according to the solid biopsy analysis |
Countries
Spain
Outcome results
None listed