Aflibercept and 5-FU vs. FOLFOX as 1st Line Treatment for Elderly or Frail Elderly Patients With Met. Colorectal Cancer (ELDERLY)

Aflibercept and 5-FU vs. FOLFOX as 1st Line Treatment for Elderly or Frail Elderly Patients With Metastatic Colorectal Cancer

This is a controlled, open-label, randomized phase- II trial (1:1 randomization) investigating 5-FU + aflibercept and 5-FU + oxaliplatin in elderly and frail elderly patients with mCRC scheduled to receive first line treatment.

Study Overview

Status

Completed

Conditions

Detailed Description

The current trial seeks to evaluate a new treatment option for elderly / frail elderly patients with mCRC including 5-FU - better tolerated than capecitabine in the FOCUS2 study - in conjunction with aflibercept, a broad active anti-angiogenic drug within a randomized phase-II setting. Patients will be randomized using a 1:1 randomization between 5-FU / aflibercept and 5-FU / oxaliplatin using the oxaliplatin-based regimen established in FOCUS2 trial. Main goal is to estimate the 6-months PFS rate with 5-FU / Aflibercept and the safety of this regimen. The decision to use a randomized phase-II design using the "FOCUS2- FOLFOX" is based on two assumptions; (i) Bias can be better controlled by using a randomized phase-II design (ii) A clear standard regimen in frail elderly cannot be defined, but FOLFOX was superior to 5-FU alone in FOCUS2 and the patient population included in the FOCUS2 study represents the patient population scheduled to be included in the current trial.

Provided the randomized phase-II study shows adequate efficacy of 5-FU / aflibercept and a tolerable safety profile, the study will be carried on to the phase-III part of the trial. Description of the terms and conditions to expand the current trial are not part of this protocol. Briefly, a potential phase-III study should aim at showing non-inferiority of 5-FU / aflibercept regarding 6-months PFS rate as primary endpoint. This would allow to include all patients from the phase-II part in the phase-III study in order to save time and patients.

Study Type

Interventional

Enrollment (Actual)

124

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

      • Aschaffenburg, Germany, 63739
        • Phase Drei
      • Bad Saarow, Germany, 15526
        • Helios Klinikum Bad Saarow
      • Bayreuth, Germany, 95445
        • Klinikum Bayreuth
      • Berlin, Germany, 13347
        • MVZ Seestrasse
      • Bremen, Germany, 28755
        • Klinikum Bremen Nord
      • Essen, Germany, 45136
        • Kliniken Essen-Mitte
      • Frankfurt, Germany, 60431
        • Agaplesion Markus Krankenhaus
      • Frankfurt, Germany, 60488
        • Krankenhaus Nordwest GmbH
      • Garmisch-Partenkirchen, Germany, 82467
        • Klinikum Garmisch-Partenkirchen Gmbh
      • Heidelberg, Germany, 69120
        • Nationales Centrum für Tumorerkrankungen (NCT)
      • Karlsruhe, Germany, 76133
        • Städtisches Klinikum Karlsruhe
      • Kassel, Germany, 34121
        • DRK-Kliniken Nordhessen gGmbH
      • Lahr, Germany, 77933
        • Ortenau Klinikum Lahr
      • Lebach, Germany, 66822
        • Onkologisches Zentrum
      • Ludwigshafen, Germany, 67063
        • Klinikum Ludwigshafen
      • Magdeburg, Germany, 39130
        • Klinikum Magdeburg gGmbH
      • Mannheim, Germany, 68167
        • Tagestherapiezentrum am ITM Universitätsmedizin Mannheim
      • Mutlangen, Germany, 73557
        • Kliniken Ostalb
      • München, Germany, 81377
        • Klinikum der Universität München-Großhadern
      • Neumarkt In Der Oberpfalz, Germany, 92318
        • Kliniken des Landkreises Neumarkt in der Oberpfalz
      • Ravensburg, Germany, 88212
        • Studienzentrum Onkologie Ravensburg
      • Stolberg, Germany, 52222
        • Clinical Research Stolberg GmbH
      • Trier, Germany, 54290
        • Klinikum Mutterhaus Trier
      • Tübingen, Germany, 72076
        • Universitätsklinikum Tübingen
      • Wilhelmshaven, Germany, 26389
        • Klinikum Wilhelmshaven

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

70 years and older (Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. To enter this trial the oncologist has to confirm, that the patient was in his or her opinion not a candidate for standard full-dose combination therapy. Moreover, the oncologist has to state the reason for entering the trial (Advanced age alone versus both age and frailty). As an operational definition for frailty the G8 screening tool will be used upon inclusion of the patient in a standardized manner. Briefly, G8 is an established screening tool that includes seven items from the Mini Nutritional Assessment (MNA) and an age-related item (<80, 80 to 85, or 85 years). The total score can range from 0 to 17. The result on the G8 is considered abnormal if the score is ≤14, indicating a geriatric risk profile.
  2. Patients have to have histologically confirmed mCRC with unidimensionally measurable inoperable advanced or metastatic disease
  3. ECOG performance status of 2 or better.
  4. Life expectancy of 3 months or longer at enrolment
  5. Patients >70 years with no upper age limit
  6. Previous adjuvant chemotherapy is allowed if completed more than 6 months before randomisation
  7. Previous rectal (chemo)radiotherapy is allowed if completed more than 6 months before randomisation
  8. Hematological status:

    • Neutrophils (ANC) ≥ 1.5 x 109/L
    • Platelets ≥ 100 x 109/L
    • Hemoglobin ≥ 9 g/dL
  9. Adequate renal function:

    • Serum creatinine level ≤ 1.5 x upper limit normal (ULN)

  10. Adequate liver function:

    • Serum bilirubin ≤ 1.5 x upper limit normal (ULN)
    • Alkaline phosphatase ≤ 2.5 x ULN (unless liver metastases are present, then < 5 x ULN in that case)
    • AST and ALT < 3 x ULN (unless liver metastases are present then < 5 x ULN in that case)
  11. Proteinuria < 2+ (dipstick urinalysis) or ≤ 1 g/24hour
  12. Signed and dated informed consent, and willing and able to comply with protocol requirements
  13. Regular follow-up feasible
  14. Male patients with a partner of childbearing potential must agree to use effective contraception (Pearl Index < 1) during the course of the trial and at least 3 months after last administration of the study drug.

Exclusion Criteria:

  1. Prior systemic chemotherapy for mCRC
  2. 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
  3. Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 Days
  4. History or evidence upon physical examination of CNS metastasis unless adequately treated (irradiation and no seizure with appropriate treatment)
  5. Uncontrolled hypercalcemia
  6. Pre-existing peripheral neuropathy (NCI grade ≥2)
  7. Concomitant protocol unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy),
  8. Treatment with any other investigational medicinal product within 28 days prior to study entry.
  9. Significant cardiovascular disease:

    • Cardiovascular accident or myocardial infarction or unstable angina ≤6 months before start of study treatment
    • Severe cardiac arrhythmia
    • New York Heart Association grade ≥2 congestive heart failure
    • Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy.
    • History of stroke or transient ischemic attack ≤6 months before start of study treatment
    • Coronary/peripheral artery bypass graft ≤6 months before start of study treatment.
    • Deep vein thrombosis or thromboembolic events ≤1 month before start of study treatment
  10. Patients with known allergy to any excipient to study drugs,
  11. Any of the following within 3 months prior to randomization: Grade 3-4 gastrointestinal bleeding/hemorrhage, treatment resistant peptic ulcer disease, erosive oesophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic event.
  12. Bowel obstruction.
  13. Treatment with CYP3A4 inducers unless discontinued > 7 days prior to randomization
  14. Known dihydropyrimidine dehydrogenase (DPD) deficiency
  15. Involvement in the planning and/or conduct of the study (applies to both Sanofi staff and/or staff of sponsor and study site)
  16. Patient who might be dependent on the sponsor, site or the investigator
  17. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
  18. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Arm A (mFOLFOX7)

Patients in the 5-FU / oxaliplatin arm receive modified (m) FOLFOX 7: Folinic acid 350 mg/m² and oxaliplatin 68 mg/m² by concurrent 2-h intravenous infusion, 5-fluorouracil 1920 mg/m² 46-h intravenous infusion every 2 weeks (qd15).

This regimen represents the 80% dosage reduced mFOLFOX 7. The 80% dose reduction was shown to be a tolerable regimen in frail elderly patients in the FOCUS 2 study.

Patients in this arm receive modified (m) FOLFOX 7: Folinic acid 350 mg/m² and oxaliplatin 68 mg/m² by concurrent 2-h intravenous infusion, 5-FU 1920 mg/m² 46-h intravenous infusion every 2 weeks (qd15).
Experimental: Arm B (Aflibercept + mLV5FU2)

Patients in the 5-FU / aflibercept arm receive aflibercept 4mg/kg as 1-h infusion followed by folinic acid 350 mg/m² by 2-h intravenous infusion, 5-fluorouracil 1920 mg/m² 46-h intravenous infusion (mLV5FU2) every 2 weeks (qd15).

The decision to use reduced doses of 5-FU and folinic acid was made to have comparable doses to the reduced FOLFOX 7.

Patients receive aflibercept 4mg/kg as 1-h infusion followed by folinic acid 350 mg/m² by 2-h intravenous infusion, 5-fluorouracil 1920 mg/m² 46-h intravenous infusion (mLV5FU2) every 2 weeks (qd15).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-free survival (PFS)
Time Frame: 6 months
Rate of patients free of progression
6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety: Dose intensities of study medication
Time Frame: 6 months
As calculated over the whole treatment duration and summarized descriptively by summary statistics.
6 months
Safety: Adverse events (AE)
Time Frame: 7 months
AE's will be summarized by presenting the number and percentages of patients having any AE
7 months
Safety: Dose modification of study drug due to adverse events
Time Frame: 6 months
Dose modifications, including discontinuations, will be summarized by presenting the number and percentages of patients having any dose modification
6 months
Safety: Rate of treatment discontinuation due to toxicitiy
Time Frame: 6 months
Rate of treatment discontinuations during the study
6 months
Safety: Laboratory abnormalities
Time Frame: 6 months
Summary of lab abnormalities as assessed in the documentation
6 months
Efficacy: Response rates
Time Frame: 2 years
As measured by RECIST criteria v. 1.1
2 years
Efficacy: Overall survival (OS)
Time Frame: 2 years
OS according to Kaplan-Meier
2 years
Efficacy: PFS
Time Frame: 2 years
PFS according to Kaplan-Meier
2 years
Patient reported outcomes (PRO): Quality of life
Time Frame: 6 months
Quality of life (QoL) as measured by EQ-5D-5L at d1 of each cycle and on EOT.
6 months
PRO: Geriatric assessment
Time Frame: 6 months
Geriatric assessment as measured by using G8, ADL and IADL
6 months
PRO: Overall treatment utility
Time Frame: 6 months
Overall treatment utility is evaluated according to the principles used in the FOCUS2 trial. Cf. Seymour et al. Geriatric oncol 2013.
6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Study Chair: Salah-Eddin Al-Batran, Prof. Dr., Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 28, 2018

Primary Completion (Actual)

February 1, 2024

Study Completion (Actual)

February 1, 2024

Study Registration Dates

First Submitted

May 8, 2018

First Submitted That Met QC Criteria

May 8, 2018

First Posted (Actual)

May 21, 2018

Study Record Updates

Last Update Posted (Actual)

February 23, 2024

Last Update Submitted That Met QC Criteria

February 22, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

No IPD will be shared

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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