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

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ClinicalTrials.gov Identifier: NCT03530267
Recruitment Status : Recruiting
First Posted : May 21, 2018
Last Update Posted : April 19, 2021
Sponsor:
Collaborators:
STABIL - Statistische und Biometrische Lösungen
Trium Analysis Online GmbH
Sanofi
Information provided by (Responsible Party):
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Drug: Aflibercept + mLV5FU2 Drug: mFOLFOX7 Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 196 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Aflibercept and 5-FU vs. FOLFOX as 1st Line Treatment for Elderly or Frail Elderly Patients With Metastatic Colorectal Cancer
Actual Study Start Date : September 28, 2018
Estimated Primary Completion Date : March 15, 2022
Estimated Study Completion Date : September 15, 2022

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Arms and Interventions
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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.

 Drug: mFOLFOX7
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.

 Drug: Aflibercept + mLV5FU2
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).


Outcome Measures
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Primary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: 6 months ]
    Rate of patients free of progression


Secondary Outcome Measures :
  1. Safety: Dose intensities of study medication [ Time Frame: 6 months ]
    As calculated over the whole treatment duration and summarized descriptively by summary statistics.

  2. Safety: Adverse events (AE) [ Time Frame: 7 months ]
    AE's will be summarized by presenting the number and percentages of patients having any AE

  3. 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

  4. Safety: Rate of treatment discontinuation due to toxicitiy [ Time Frame: 6 months ]
    Rate of treatment discontinuations during the study

  5. Safety: Laboratory abnormalities [ Time Frame: 6 months ]
    Summary of lab abnormalities as assessed in the documentation

  6. Efficacy: Response rates [ Time Frame: 2 years ]
    As measured by RECIST criteria v. 1.1

  7. Efficacy: Overall survival (OS) [ Time Frame: 2 years ]
    OS according to Kaplan-Meier

  8. Efficacy: PFS [ Time Frame: 2 years ]
    PFS according to Kaplan-Meier

  9. 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.

  10. PRO: Geriatric assessment [ Time Frame: 6 months ]
    Geriatric assessment as measured by using G8, ADL and IADL

  11. 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.


Eligibility Criteria
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Ages Eligible for Study:   70 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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].
Contacts and Locations
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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): NCT03530267


Contacts
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Contact: Ralf-Dieter Hofheinz, Prof. Dr. +49621383 ext 2855 ralf.hofheinz@umm.de
Contact: Claudia Pauligk, Dr. +49697601 ext 3906 elderly@ikf-khnw.de

Locations
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Sponsors and Collaborators
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
STABIL - Statistische und Biometrische Lösungen
Trium Analysis Online GmbH
Sanofi
Investigators
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Study Chair: Salah-Eddin Al-Batran, Prof. Dr. Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
More Information
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Publications:

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Responsible Party: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
ClinicalTrials.gov Identifier: NCT03530267    
Other Study ID Numbers: ELDERLY
First Posted: May 21, 2018    Key Record Dates
Last Update Posted: April 19, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No IPD will be shared

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest:
colorectal cancer
5-FU
Aflibercept
Oxaliplatin
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