Clinical Trial of Combination Chemotherapy With Aflibercept in Patients With Advanced Colorectal Cancer
- Conditions
- Metastatic Colorectal Cancer
- Interventions
- Registration Number
- NCT02129257
- Lead Sponsor
- Hellenic Cooperative Oncology Group
- Brief Summary
The AMALTHEA (Aflibercept MAintenance after first-Line THErapy with FOLFIRI+Aflibercept in metastatic colorectal cancer patients) trial is an investigator-initiated, single arm, open-label, phase II study. Patients with histologically proven metastatic colorectal carcinoma will be treated with a combination of FOLFIRI and aflibercept for 6 months. Both Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type (wt) and mutant (mut) patients wil be enrolled. In the absence of Progressive Disease (PD) after 6 months of the combination of chemotherapy and aflibercept, the patient will be treated with a maintenance therapy with aflibercept alone until PD or unacceptable toxicity, investigator's decision or patient's refusal of further treatment or death, whichever comes first.
- Detailed Description
Statistical hypotheses and sample size calculation:
It is estimated that the progression-free survival (PFS) rate at 1year will be improved from 33% (corresponding to a median PFS of 7.5 months \[null hypothesis\]) to 47% (corresponding to a median PFS of 11 months \[alternative hypothesis\]) with the combination of first-line Folinic acid/5-Fluorouracil/Irinotecan (FOLFIRI) plus aflibercept therapy in patients with metastatic colorectal cancer (mCRC). Using the one-stage Fleming's design, in order to reject the null hypothesis in a one-sided test with a type I error of 5% and power 80%, 73 patients will be needed to enter the study.
Analysis population:
* Intent-to-treat (ITT) population: all patients who will have given their informed consent and who will have been correctly registered to the study
* Evaluable population for tumor response: all treated patients, without major protocol deviation, with at least one tumor evaluation while on treatment (except for early disease progression or death) and evaluable for response
* Safety population: the subset of the ITT population that took at least one dose of study medication
Primary analysis:
The primary efficacy parameter will be PFS rate at 1 year and it will be calculated in the ITT population.
Analysis of secondary endpoints:
Response to treatment will be described in a frequency table along with the corresponding percentages and 95% exact confidence intervals.
Kaplan-Meier method will be used to estimate median PFS and overall survival (OS) values and 95% confidence intervals. All of these analyses will be performed in the ITT population. Analysis for objective response rate (ORR) will additionally be presented in the evaluable population for tumor response.
Adverse Events (AEs) of the safety population for the FOLFIRI-aflibercept treatment part and the maintenance therapy will be presented in frequency tables according to grade, along with the corresponding percentages (N, %).
Exploratory endpoints:
Univariate and multivariate Cox regression analyses will also be performed to explore prognostic factors among basic clinicopathological characteristics and evaluated biomarkers, with respect to PFS and OS. Time-to-event distributions for the expression of examined markers will be estimated by Kaplan-Meier method and compared using log-rank test.
Formalin-fixed embedded tumor tissue blocks will be collected from the primaries or metastases for the immunohistochemical and messenger ribonucleic acid (mRNA) study of key angiogenic effectors and regulators, such as: vascular endothelial growth factor A (VEGF A), vascular endothelial growth factor A-121 (VEGFA-121), vascular endothelial growth factor A121b (VEGFA121b), short and long VEGFA isoforms, metalloproteinase inhibitor 3 (TIMP3), vascular endothelial growth factor B (VEGF-B), placental growth factor (PlGF), vascular endothelial growth factor-C (AVEGF-C), Semaphorins, hypoxia-inducible factor 1 (HIF1), vascular endothelial growth factor receptor 1 (VEGFR1), vascular endothelial growth factor receptor 2 (VEGFR2), neuropilin 1 (NRP1), neuropilin 2 (NRP2), thrombospondin 1 (TSP1), thrombospondin 2 (TSP2), angiopoietin-1 (Ang1), Angiopoietin-2 (Ang2), Tie2, interleukin 8 (IL8), CXC chemokine receptor 1 (CXCR1), CXC chemokine receptor 2 (CXCR2)
Pharmacokinetic(PK)/Pharmacodynamic analyses (PD) PK/PD assessments (plasma analytes, plasma free and VEGF-bound aflibercept) will be performed in all registered and treated patients at specified timepoints during both FOLFIRI-aflibercept induction and aflibercept maintenance therapy, to assess the free/bound aflibercept ratio over cycles and the potential correlation with clinical endpoints (safety and efficacy).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 73
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description FOLFIRI-AFLIBERCEPT AFLIBERCEPT Aflibercept 4 mg/kg administered over 1 hour on Day 1, followed by FOLFIRI regimen. Treatment will be repeated every 2 weeks. FOLFIRI regimen: Irinotecan 180 mg/m² intravenous (IV) infusion and folinic acid 400 mg/m² IV infusion followed by: 5-fluorouracil (5-FU) 400 mg/m² IV bolus followed by: 5-FU 2400 mg/m² continuous IV infusion over 46 hours. FOLFIRI administration will immediately follow the aflibercept one. In the absence of PD after 6 months of the combination of chemotherapy and aflibercept, the patient will be treated with a maintenance therapy with aflibercept alone until PD or unacceptable toxicities, investigator's decision or patient's refusal of further treatment or death, whichever comes first. FOLFIRI-AFLIBERCEPT Irinotecan Aflibercept 4 mg/kg administered over 1 hour on Day 1, followed by FOLFIRI regimen. Treatment will be repeated every 2 weeks. FOLFIRI regimen: Irinotecan 180 mg/m² intravenous (IV) infusion and folinic acid 400 mg/m² IV infusion followed by: 5-fluorouracil (5-FU) 400 mg/m² IV bolus followed by: 5-FU 2400 mg/m² continuous IV infusion over 46 hours. FOLFIRI administration will immediately follow the aflibercept one. In the absence of PD after 6 months of the combination of chemotherapy and aflibercept, the patient will be treated with a maintenance therapy with aflibercept alone until PD or unacceptable toxicities, investigator's decision or patient's refusal of further treatment or death, whichever comes first. FOLFIRI-AFLIBERCEPT Folinic Acid Aflibercept 4 mg/kg administered over 1 hour on Day 1, followed by FOLFIRI regimen. Treatment will be repeated every 2 weeks. FOLFIRI regimen: Irinotecan 180 mg/m² intravenous (IV) infusion and folinic acid 400 mg/m² IV infusion followed by: 5-fluorouracil (5-FU) 400 mg/m² IV bolus followed by: 5-FU 2400 mg/m² continuous IV infusion over 46 hours. FOLFIRI administration will immediately follow the aflibercept one. In the absence of PD after 6 months of the combination of chemotherapy and aflibercept, the patient will be treated with a maintenance therapy with aflibercept alone until PD or unacceptable toxicities, investigator's decision or patient's refusal of further treatment or death, whichever comes first. FOLFIRI-AFLIBERCEPT 5-Fluorouracil Aflibercept 4 mg/kg administered over 1 hour on Day 1, followed by FOLFIRI regimen. Treatment will be repeated every 2 weeks. FOLFIRI regimen: Irinotecan 180 mg/m² intravenous (IV) infusion and folinic acid 400 mg/m² IV infusion followed by: 5-fluorouracil (5-FU) 400 mg/m² IV bolus followed by: 5-FU 2400 mg/m² continuous IV infusion over 46 hours. FOLFIRI administration will immediately follow the aflibercept one. In the absence of PD after 6 months of the combination of chemotherapy and aflibercept, the patient will be treated with a maintenance therapy with aflibercept alone until PD or unacceptable toxicities, investigator's decision or patient's refusal of further treatment or death, whichever comes first.
- Primary Outcome Measures
Name Time Method Progression-Free Survival (PFS) rate at 1 year Up to 1 year
- Secondary Outcome Measures
Name Time Method Evaluation of Objective Response Rate (ORR) defined as the proportion of patients with complete response (CR) or partial response (PR) among all patients, as assessed according to Response Evaluation Criteria for Solid Tumors (RECIST) v1.1 Up to 20 months Response to treatment will be described in a frequency table along with the corresponding percentages and 95% exact confidence intervals.
Evaluation of Overall Survival (OS) Time interval from registration to the date of death due to any cause assessed up to 60 months Evaluation of Progression-Free Survival (PFS) Time interval from registration to the first date of documented progression or death due to any cause assessed up to 60 months Number of participants with Serious and Non-Serious Adverse Events graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 Up to 40 months Adverse Events of the safety population for the FOLFIRI-aflibercept treatment part and the maintenance therapy will be presented in frequency tables according to grade, along with the corresponding percentages (N,%)
Tumor tissue mRNA levels of VEGFA-121, VEGFA121b, VEGF-B, PlGF, VEGF-C, Semaphorins, HIF1, VEGFR1, VEGFR2, Neuropilins 1,2, Thrombospondin, Angiopoietins 1,2. Predictive significance for response rate, PFS, OS. Tumor blocks will be collected at baseline Steady-state concentration of free Aflibercept and VEGF-bound Aflibercept in plasma. Predictive significance for response rate, PFS, OS. On day 1 of cycle 1, on day 1 of cycle 3, on day 1 of week 3 of Aflibercept maintenance monotherapy, at the end of treatment, assessed up to 20 months Enzyme-linked immunosorbent assay (ELISA) plasma concentrations of VEGFA, soluble VEGFR1, soluble VEGFR2, VEGF-B, PlGF, basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF). Predictive significance for response rate, PFS, OS. On day 1 of cycle 1, on day 1 of cycle 3, on day 1 of week 3 of Aflibercept maintenance monotherapy, at the end of treatment, assessed up to 20 months
Trial Locations
- Locations (18)
2nd Dept of Internal Medicine, Agios Savvas Cancer Hospital
🇬🇷Athens, Greece
2nd Dept of Internal Medicine, General Hospital of Athens "Hippokratio"
🇬🇷Athens, Greece
Dept of Medical Oncology, Ioannina University Hospital
🇬🇷Ioannina, Greece
Division of Oncology, Dept of Internal Medicine, University Hospital of Patras
🇬🇷Patras, Greece
2nd Dept of Medical Oncology, Agii Anargiri Cancer Hospital
🇬🇷Athens, Greece
Dept of Medical Oncology, University Hospital of Heraklion
🇬🇷Heraklio, Greece
Thermi Clinic S.A.
🇬🇷Thermi, Greece
251 Airforce Hospital
🇬🇷Athens, Greece
Oncology Dept, University Hospital of Larissa
🇬🇷Larissa, Greece
1st Dept of Medical Oncology, Metropolitan Hospital
🇬🇷Athens, Greece
Oncology Unit, 3rd Dept of Internal Medicine, Athens School of Medicine, Sotiria General Hospital
🇬🇷Athens, Greece
Agios Georgios Chania General Hospital
🇬🇷Chania, Mournies, Greece
Oncology Section, Dept of Clinical Therapeutics, General Hospital of Athens "Alexandra"
🇬🇷Athens, Greece
3rd Dept of Medical Oncology, Agii Anargiri Cancer Hospital
🇬🇷Athens, Greece
3rd Dept of Medical Oncology, Hygeia Hospital
🇬🇷Athens, Greece
Division of Oncology, 2nd Dept of Internal Medicine, University Hospital "Attiko"
🇬🇷Athens, Greece
2nd Dept of Medical Oncology, Metropolitan Hospital
🇬🇷Athens, Greece
Dept of Medical Oncology, Papageorgiou General Hospital
🇬🇷Thessaloniki, Greece