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Clinical Trial of Combination Chemotherapy With Aflibercept in Patients With Advanced Colorectal Cancer (AMALTHEA)

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ClinicalTrials.gov Identifier: NCT02129257
Recruitment Status : Completed
First Posted : May 2, 2014
Last Update Posted : October 24, 2017
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Drug: AFLIBERCEPT Drug: Irinotecan Drug: 5-Fluorouracil Drug: Folinic Acid Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 73 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Single-arm Phase II Study of Maintenance Therapy With Aflibercept After First-line Treatment With FOLFIRI Plus Aflibercept in Metastatic Colorectal Cancer Patients
Actual Study Start Date : May 26, 2014
Actual Primary Completion Date : January 2017
Actual Study Completion Date : September 25, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: FOLFIRI-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.
Drug: AFLIBERCEPT
Other Names:
  • Zaltrap
  • AVE005

Drug: Irinotecan
Other Name: Campto

Drug: 5-Fluorouracil
Drug: Folinic Acid



Primary Outcome Measures :
  1. Progression-Free Survival (PFS) rate at 1 year [ Time Frame: Up to 1 year ]

Secondary Outcome Measures :
  1. 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 [ Time Frame: Up to 20 months ]
    Response to treatment will be described in a frequency table along with the corresponding percentages and 95% exact confidence intervals.

  2. Evaluation of Overall Survival (OS) [ Time Frame: Time interval from registration to the date of death due to any cause assessed up to 60 months ]
  3. Evaluation of Progression-Free Survival (PFS) [ Time Frame: Time interval from registration to the first date of documented progression or death due to any cause assessed up to 60 months ]
  4. 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 [ Time Frame: 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,%)

  5. 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. [ Time Frame: Tumor blocks will be collected at baseline ]
  6. Steady-state concentration of free Aflibercept and VEGF-bound Aflibercept in plasma. Predictive significance for response rate, PFS, OS. [ Time Frame: 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 ]
  7. 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. [ Time Frame: 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 ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Histologically proven adenocarcinoma of the colon and/or rectum
  • Metastatic disease confirmed clinically/radiologically
  • Signed written informed consent
  • No prior therapy for metastatic disease
  • Duly documented inoperable metastatic disease, ie not suitable for complete curative surgical resection
  • At least one measurable or evaluable lesion as assessed by Computed Tomography (CT) scan or MRI (Magnetic Resonance Imaging) according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1
  • Age ≥18 years
  • Eastern Cooperative Oncology Group (ECOG) Performance status (PS) 0-2
  • Adequate hematological status:

    • neutrophils (ANC) ≥1.5x109/L
    • platelets ≥100x109/L
    • haemoglobin ≥9g/dL
  • Adequate renal function: serum creatinine level <1.5 mg/dl and Glomerular Filtration Rate>50 ml/min by Cockroft/Gault formula
  • Adequate liver function:

    • serum bilirubin ≤1.5 x upper normal limit (ULN)
    • alkaline phosphatase
    • aspartate aminotransferase (AST)
    • alanine aminotransferase (ALT) < 5 x ULN
  • Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour
  • Regular follow-up feasible
  • Baseline evaluations performed before registration: clinical and blood evaluations no more than 2 weeks (14 days) prior to registration, tumor assessment (chest X-ray, CT-scan or MRI, evaluation of non-measurable lesions) no more than 3 weeks (21 days) prior to registration
  • First course of treatment planned less than 1 week (7 days) after registration
  • For female patients of childbearing potential, negative serum pregnancy test within 1 week (7 days) prior of starting study treatment
  • Female patients must commit to using reliable and appropriate methods of contraception until at least three months after the end of study treatment (when applicable). Male patients with a partner of childbearing potential must agree to use contraception in addition to having their partner use another contraceptive method during the trial.

Exclusion Criteria

  • Exclusive presence of bone metastasis only
  • Uncontrolled hypercalcemia
  • Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg despite medical therapy), or history of hypertensive crisis, or hypertensive encephalopathy
  • Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy)
  • Treatment with any other investigational medicinal product within 28 days prior to study entry
  • Other serious and uncontrolled non-malignant chronic disease
  • History or presence of Central Nervous System (CNS) metastasis unless adequately treated (e.g. non irradiated CNS metastasis, seizures not controlled with standard medical therapy)
  • Gilbert's syndrome
  • Intolerance to atropine sulfate or loperamide
  • Known dihydropyrimidine dehydrogenase deficiency
  • Treatment with Cytochrome P450 3A4 (CYP3A4) inducers unless discontinued > 7 days prior to randomization
  • Any of the following in 3 months prior to inclusion: grade 3-4 gastrointestinal bleeding (unless due to resected tumor), treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, or diverticulitis
  • Other concomitant or previous malignancy, except:

    • adequately treated in-situ carcinoma of the uterine cervix
    • basal or squamous cell carcinoma of the skin
    • cancer in complete remission for >5 years
  • Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days
  • Pregnant or breastfeeding women
  • Patients with known allergy to any excipients to study drugs
  • History of myocardial infarction and/or stroke or other arterial thrombotic events or pulmonary embolism or unstable angina pectoris within 6 months prior to registration
  • Poorly controlled cardiac arrhythmias
  • Bowel obstruction
  • History of severe tumour bleeding or bleeding disorders
  • Poorly controlled anti-coagulation therapy (INR>3.0 on coumadin or heparin compounds)
  • Palliative radiation therapy within 4 weeks prior to registration

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02129257


Locations
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Greece
Agios Georgios Chania General Hospital
Chania, Mournies, Greece, 73300
2nd Dept of Internal Medicine, Agios Savvas Cancer Hospital
Athens, Greece, 11522
251 Airforce Hospital
Athens, Greece, 11525
2nd Dept of Internal Medicine, General Hospital of Athens "Hippokratio"
Athens, Greece, 11527
Oncology Unit, 3rd Dept of Internal Medicine, Athens School of Medicine, Sotiria General Hospital
Athens, Greece, 11527
Oncology Section, Dept of Clinical Therapeutics, General Hospital of Athens "Alexandra"
Athens, Greece, 11528
Division of Oncology, 2nd Dept of Internal Medicine, University Hospital "Attiko"
Athens, Greece, 12462
2nd Dept of Medical Oncology, Agii Anargiri Cancer Hospital
Athens, Greece, 14564
3rd Dept of Medical Oncology, Agii Anargiri Cancer Hospital
Athens, Greece, 14564
3rd Dept of Medical Oncology, Hygeia Hospital
Athens, Greece, 15123
1st Dept of Medical Oncology, Metropolitan Hospital
Athens, Greece, 18547
2nd Dept of Medical Oncology, Metropolitan Hospital
Athens, Greece, 18547
Dept of Medical Oncology, University Hospital of Heraklion
Heraklio, Greece, 71110
Dept of Medical Oncology, Ioannina University Hospital
Ioannina, Greece, 45500
Oncology Dept, University Hospital of Larissa
Larissa, Greece, 41334
Division of Oncology, Dept of Internal Medicine, University Hospital of Patras
Patras, Greece
Thermi Clinic S.A.
Thermi, Greece, 57001
Dept of Medical Oncology, Papageorgiou General Hospital
Thessaloniki, Greece, 56429
Sponsors and Collaborators
Hellenic Cooperative Oncology Group
Sanofi
Investigators
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Study Chair: George Pentheroudakis, MD, Ass.Prof Dept of Medical Oncology, Ioannina University Hospital

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Responsible Party: Hellenic Cooperative Oncology Group
ClinicalTrials.gov Identifier: NCT02129257     History of Changes
Other Study ID Numbers: HE 6A/13
2013-002567-26 ( EudraCT Number )
First Posted: May 2, 2014    Key Record Dates
Last Update Posted: October 24, 2017
Last Verified: October 2017

Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Folic Acid
Irinotecan
Fluorouracil
Levoleucovorin
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antimetabolites
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antidotes
Protective Agents
Vitamin B Complex
Vitamins