TWICE-IRI: Optimization of Second-line Therapy With Aflibercept, Irinotecan (Day 1 or Day 1,3), 5-Fluorouracile and Folinic Acid in Patients With Metastatic Colorectal Cancer. A Randomized Phase III Study.

Optimization of second-line therapy with aflibercept, irinotecan (day1 or day 1,3), 5fluorouracile and folinic acid in patients with metastatic colorectal cancer. A randomized Phase III study.

Background - Rationale Aflibercept The addition of aflibercept to the standard FOLFIRI regimen as second-line therapy was evaluated in a large phase III study (EFC10262-VELOUR). This combination significantly improved both PFS (4.7 to 6.9 months, HR=0.76; P=\<0.001) and OS (12.1 to 13.5 months, HR=0.82; P=0.003). In the evaluable population (86.5%), the tumor response rate was also improved when adding aflibercept (ORR=19.8% \[16.4-23.2\]) to the FOLFIRI regimen (ORR=11.1% \[8.5-13.8\]).

Irinotecan The combination of aflibercept with FOLFIRI3, an optimized irinotecan-based regimen, was evaluated in 65 patients in a French multicentric retrospective cohort. (Carola C et al, WJCO 2018) In the cohort of irinotecan-naïve patients (n=30), the objective response rate was 43.3%, and the disease control rate 76.7%. Median PFS and OS were 11.3 months (95% CI 6.1-29.0) and 17.0 months (95% CI 13.0-17.3). The most common (\>5%) grade 3-4 adverse events were diarrhea (37.9%), neutropenia (14.3%), stomatitis and anemia (10.4%), hypertension (6.7%).

In the cohort of patients previously treated with irinotecan (n=35), the objective response rate was 34.3%, and the disease control rate 60.0%. Median PFS and OS were 5.7 months (95% CI 3.9-10.4) and 14.3 months (95% CI 12.8-19.5).

Table. FOLFIRI-aflibercept vs. FOLFIRI3-aflibercept: a cross-trial comparison FOLFIRI-aflibercept (VELOUR) FOLFIRI3-aflibercept (Irinotecan-naïve) N = 612 N = 30 Efficacy RR, % 19.3 vs 43.3 PFS, months 6.9 vs 11.3 OS, months 13.5 vs 17.0 Grade 3-4 AEs, % Any 83.4 vs 56.7 Neutropenia 36.7 vs 14.3 Diarrhea 19.3 vs 37.9 Mucositis 13.8 vs 10.4 Hypertension 19.3 vs 6.9 Discontinuation, % Progression 49.8 vs 36.7 Adverse event 26.6 vs 46.7

Study Objectives

Primary:

•To compare once (day 1) or twice (day 1, day 3) administration of irinotecan in combination with 5-fluorouracile and aflibercept as second-line therapy in patients with metastatic colorectal cancer in terms of overall response rate (ORR)

Secondary:

* To evaluate disease control rate (DRC) and Early Response Rate (ERR)
* To evaluate progression-free survival (PFS) and overall survival (OS),
* to evaluate the conversion rate to locoregional therapy, surgery of metastasis, the quality of resection (R0, R1, R2) and the pathological response in patients with resected metastatic disease,
* To assess the impact on health-related quality of life (HRQOL) using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 (QLQ-C30),
* To assess Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) on using the National Cancer Institute Common Toxicity Criteria (NCI-CTC version 5.0).

Exploratory:

* To assess the impact on selected circulating biomarkers (angiogenic and exosomal)
* To assess the impact on selected tumor biomarkers

Eligibility Criteria:
Inclusion Criteria:

1. Provision of signed and dated informed consent and stated willingness to comply with all study procedures and availability for the duration of the study, Signed, written Informed Consent Form (ICF),
2. Willing and able to comply with the protocol,
3. Age 18-75 years,
4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1,
5. Life expectancy ≥ 3 months,
6. Histologically proven carcinoma of colon and/or rectum,
7. Confirmed unresectable metastatic disease,
8. At least one measurable and/or evaluable tumor metastasis on CT-scan or MRI per RECIST criteria version 1.1,
9. Prior oxaliplatin-based first-line therapy for metastatic disease (the use of prior bevacizumab or anti-EGFR mabs is allowed but not mandatory) - Less than 6 months from completion of any prior oxaliplatin-based adjuvant therapy can be considered as first-line therapy. Prior use of irinotecan in combination with oxaliplatin and 5FU as first-line therapy is allowed if the interval between the last administration of irinotecan and disease progression is at least 6 months (ie, irinotecan-free interval ≥6 months).
10. Negative urine and/or serum pregnancy test within 7 days before inclusion if female subject is of childbearing potential,
11. Clinical laboratory parameters adequate as follows:

    * Serum total bilirubin level ≤ 1.5 x upper normal limit (UNL),
    * Neutrophil count ≥ 1.5x109/L,
    * Platelet count ≥ 100x109/L,
    * Hemoglobin ≥ 9 g/dL,
    * Serum creatinine level ≤ 150µM,
    * Serum albumin ≥ 25 g/L,
    * Calcium ≥ 1 x ULN
    * Alkaline phosphatase (ALP) \< 3 x ULN, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 3 x ULN (in the case of liver metastases, \<5 x ULN),
    * Proteinuria \<2+ (dipstick urinalysis) or ≤1g/24hour,
12. For women of childbearing potential and for men, agreement to use an effective contraceptive method from the time of screening throughout the study until 6 months after administration of the last dose of any study medication. Highly effective contraceptive method consist of prior sterilization, inter-uterine device, intrauterine hormone-releasing system, oral or injectable contraceptives barrier methods, and/or true sexual abstinence),
13. Affiliation to French health care system.

Exclusion Criteria:

1. History of arterial thrombotic event in the last 6 months (eg., myocardial infarction, cerebrovascular accident or transient ischemic attack),
2. Uncontrolled hypertension (defined as systolic blood pressure \> 140 mmHg and/or diastolic blood pressure \> 90 mmHg despite optimal medical therapy), or history of hypertensive crisis, or hypertensive encephalopathy,
3. Prior use of aflibercept,
4. Adverse events from prior anticancer therapy grade ≥2 (National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI-CTCAE\] version 5.0), except for neuropathy and alopecia,
5. Bowel obstruction, inflammatory bowel disease
6. Known DPD deficiency. If not known for the patient, testing for DPD should be done during the screening period (patients with uracilemia ≥16ng/mL are not eligible),
7. Known UGT1A1 deficiency (eg, Gilbert syndrome, Crigler-Najjar syndrome). If not known for the patient, genetic testing for UGT1A1 should be done during the screening period for patients with hyperbilirubinemia (ie, total bilirubin level \>1xULN),
8. Active infection requiring intravenous antibiotics at the start of study treatment,
9. Known active infection with human immunodeficiency virus (HIV), hepatitis B (HBV), or hepatitis C (HCV),
10. Known allergy or hypersensitivity to the active substance or ingredients of any study drug,
11. Women currently pregnant or breastfeeding,
12. Inability to comply with study and follow-up procedures as judged by the Investigator,
13. Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy)
14. Concomitant use of Saint John Wort herb (millepertuis), Yellow Fever vaccine, Live Attenuated Vaccines (LAV) and phenytoine
15. Treatment with any other investigational medicinal product within 28 days or 5 investigational agent half-lives (whichever is longer) prior to the start of study treatment,
16. Any other disease, active, uncontrolled bacterial, viral or fungal infection requiring systemic therapy, metabolic dysfunction, physical examination finding or clinical laboratory finding that leads to reasonable suspicion of a disease or condition that contraindicates the use of study drugs that may affect the interpretation of the results, or that may render the subject at high risk for treatment complications.
17. Previous or concurrent malignancy, except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for three years prior to study entry,
18. Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to start of study treatment, or anticipation of need for major surgical procedure during the course of the study.
19. Minor surgical procedure including placement of a vascular access device, within 2 days of start of study treatment,
20. History of abdominal fistula, gastrointestinal (GI) perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to start study treatment.
21. Clinically significant active cardiac disease (including NYHA class III or IV congestive heart failure)
22. Venous thromboembolic event (including pulmonary embolism) grade 3 or 4 within 6 months prior to start study treatment.