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

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.

Eligibility 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 \[§ 40 Abs. 1 S. 3 Nr. 3a AMG\].