## Protocol Section
### Identification Module
**NCT ID:** NCT04392479

**Acronym:** TWICE-IRI

**Brief Title:** 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.

**Official Title:** 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.

#### Organization Study ID Info
**ID:** FBH-002
#### Organization
**Class:** OTHER
**Full Name:** Hôpital Franco-Britannique-Fondation Cognacq-Jay
### Status Module
#### Completion Date
**Date:** 2024-06

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2023-10-23

**Type:** ACTUAL

**Last Update Submit Date:** 2023-10-19

**Overall Status:** ACTIVE_NOT_RECRUITING

#### Primary Completion Date
**Date:** 2023-06-15

**Type:** ACTUAL

#### Start Date
**Date:** 2020-09-02

**Type:** ACTUAL

**Status Verified Date:** 2023-10

#### Study First Post Date
**Date:** 2020-05-18
**Type:** ACTUAL
**Study First Submit Date:** 2020-05-13
**Study First Submit QC Date:** 2020-05-13
### Sponsor Collaborators Module

#### Collaborators

**Class:** UNKNOWN

**Name:** Fondation ARCAD

#### Lead Sponsor

**Class:** OTHER

**Name:** Hôpital Franco-Britannique-Fondation Cognacq-Jay

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** 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.

**Detailed Description:** 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

### Conditions Module

**Conditions:**

- Cancer Colorectal

- Metastasis

**Keywords:**

- Aflibercept

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 202

**Type:** ESTIMATED

**Phases:**

- PHASE3

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** * Aflibercept (D1) H0: 4mg/kg IV infusion over 60min (+ 2-minute window),
* Folinic acid (D1) H+1: 400mg/m² IV infusion over 120min (+ 2-minute window),
* Irinotecan (D1) H+1: 180mg/m² IV infusion over 60min (+ 2-minute window),
* 5-fluorouracile (D1) H+3: 400mg/m² IV infusion over 15min (+ 2-minute window),
* 5-fluorouracile (D1 to D3): H+3.5: 2400mg/m² IV infusion over 46 hours (+ 1hour window)
* H+49.5: End of treatment administration

**Intervention Names:**

- Drug: Aflibercept-FOLFIRI

**Label:** Aflibercept-FOLFIRI (arm 1)

**Type:** ACTIVE_COMPARATOR

#### Arm Group 2

**Description:** * Aflibercept (D1) H0: 4mg/kg IV infusion over 60min (+ 2-minute window),
* Folinic acid (D1) H+1: 400mg/m² IV infusion over 120min (+ 2-minute window),
* Irinotecan (D1 and D3) H+1 and H+49: 75mg/m² IV infusion over 60min (+ 2-minute window) on cycles 1 and 2, then 90mg/m² at cycle 3 and furthers in absence of AEs grade ≥2,
* 5-fluorouracile (D1 to D3) H+3: 2400mg/m² IV infusion over 46 hours (+ 1hour window)
* H+50: End of treatment administration

**Intervention Names:**

- Drug: Aflibercept-mFOLFIRI3

**Label:** Aflibercept-mFOLFIRI3 (arm 2)

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Aflibercept-FOLFIRI (arm 1)

**Description:** Aflibercept-FOLFIRI

**Name:** Aflibercept-FOLFIRI

**Other Names:**

- ZALTRAP-FOLFIRI

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Aflibercept-mFOLFIRI3 (arm 2)

**Description:** Aflibercept-mFOLFIRI3

**Name:** Aflibercept-mFOLFIRI3

**Other Names:**

- ZALTRAP- mFOLFIRI3

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** Tumor measurements will be obtained using CT-scans (or MRIs) of the thorax, abdomen, and pelvis at baseline then every 8 weeks (+/- one week) according to RECIST v1.1. At the investigator's discretion, tumor assessments may be repeated at any time if progressive disease is suspected.

It is preferred that the scans for a patient are taken with the same technique (CT or MRI) throughout the study.

**Measure:** Overall response rate (ORR).

**Time Frame:** 2 months

#### Secondary Outcomes

**Description:** The disease control rate is the sum of patients with tumor response (either CR or PR) or stabilization (SD) as best response.

**Measure:** Disease control rate (DCR)

**Time Frame:** 2 months

**Description:** The early response rate will be evaluated at the first tumor evaluation at 8 weeks (+/- 1 week).

**Measure:** Early response rate

**Time Frame:** 2 months

**Description:** PFS is defined as the time interval from randomization to the date of first documented disease progression or death from any cause, whichever occurs first. Alive patients without progression will be censored at the last tumor assessment, either during study treatment period or during follow-up period.

**Measure:** Progression-free survival (PFS)

**Time Frame:** 2 months

**Description:** OS is defined as the time interval from randomization to the date of death from any cause. Alive patients will be censored at the last date known to be alive, either during study treatment period or during follow-up period. Survival status will be assessed by telephone, ordinary visits, hospital records or other means found suitable until death or the end of the study, whichever occurs first. Information regarding post-study anti-cancer therapies will be collected if new treatment is initiated.

**Measure:** Overall survival (OS)

**Time Frame:** time interval from randomization to the date of death from any cause. Assessed up to 13 months after the beginning of the study

**Description:** Salvage surgery rate (%) corresponding to the number of patients amenable to surgery of metastasis during study treatment. The number of patients with R0 or R1 resection will be evaluated.

**Measure:** Salvage surgery rate

**Time Frame:** 2 months

**Description:** The pathological tumor response will be assessed in patients having primary and/or metastasis resection using Tumor Regression Grade (TRG), modified TRG and Blazer grade. (Rubbia-Brandt L et al, Ann Oncol 2007 ; Blazer 3rd DG et al, J Clin Oncol 2008)

**Measure:** Pathological response rate

**Time Frame:** 2 months

**Description:** frequency of AEs and SAEs per patient and per cycle of treatment using NCI CTCAE v5.0.

**Measure:** Tolerance

**Time Frame:** 2 weeks

**Description:** The time until definitive HRQoL score deterioration (TUDD), (Bonnetain F et al, Eur J Cancer 2010) The survival without HRQoL deterioration-free survival (QFS). HRQoL will be assessed with EORTC QLQ-C30 questionnaire

**Measure:** HRQoL

**Time Frame:** 2 months

**Description:** Blood : (PlGF, VEGF-A, VEGF-B, VEGF-C, VEGF-D, sVEGFR1, sVEGFR2, sVEGFR3, Ang2, sTie2, Syndecan) .Exosomal biomarkers assessments (CEA, HSP70, VEGFR-2)

Tumor: Analyses will be performed according to the knowledge on potential markers at that time

**Measure:** Exploratory biomarkers

**Time Frame:** 2 months

### Eligibility Module

**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.

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Levallois-Perret

**Country:** France

**Facility:** Franco-British Hospital - GCS IHFB Cognacq-Jay

**Zip:** 92300

#### Overall Officials

**Official 1:**

**Affiliation:** Franco-British Hospital GCS IHFB Cognacq-Jay

**Name:** Benoist CHIBAUDEL, MD

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

### References Module

#### References

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## Derived Section

### Condition Browse Module - Ancestors

- ID: D000007414

- Term: Intestinal Neoplasms

- ID: D000005770

- Term: Gastrointestinal Neoplasms

- ID: D000004067

- Term: Digestive System Neoplasms

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000009369

- Term: Neoplasms

- ID: D000004066

- Term: Digestive System Diseases

- ID: D000005767

- Term: Gastrointestinal Diseases

- ID: D000003108

- Term: Colonic Diseases

- ID: D000007410

- Term: Intestinal Diseases

- ID: D000012002

- Term: Rectal Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC06

- Name: Digestive System Diseases

### Condition Browse Module - Browse Leaves

- ID: M12307

- Name: Neoplasm Metastasis

- Relevance: LOW

- As Found: Unknown

- ID: M17890

- Name: Colorectal Neoplasms

- Relevance: HIGH

- As Found: Colorectal Cancer

- ID: M10448

- Name: Intestinal Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M8886

- Name: Gastrointestinal Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M7256

- Name: Digestive System Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M7255

- Name: Digestive System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M8883

- Name: Gastrointestinal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M6336

- Name: Colonic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M10444

- Name: Intestinal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M14844

- Name: Rectal Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000015179

- Term: Colorectal Neoplasms

### Intervention Browse Module - Ancestors

- ID: D000020533

- Term: Angiogenesis Inhibitors

- ID: D000043924

- Term: Angiogenesis Modulating Agents

- ID: D000006133

- Term: Growth Substances

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000006131

- Term: Growth Inhibitors

- ID: D000000970

- Term: Antineoplastic Agents

### Intervention Browse Module - Browse Branches

- Abbrev: Micro

- Name: Micronutrients

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: Hemat

- Name: Hematinics

- Abbrev: Vi

- Name: Vitamins

### Intervention Browse Module - Browse Leaves

- ID: M6191

- Name: Leucovorin

- Relevance: LOW

- As Found: Unknown

- ID: M29233

- Name: Levoleucovorin

- Relevance: LOW

- As Found: Unknown

- ID: M257727

- Name: Aflibercept

- Relevance: HIGH

- As Found: Magnetic Resonance Imaging

- ID: M1671

- Name: Irinotecan

- Relevance: LOW

- As Found: Unknown

- ID: M8618

- Name: Folic Acid

- Relevance: LOW

- As Found: Unknown

- ID: M22318

- Name: Angiogenesis Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M9231

- Name: Growth Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: T447

- Name: Folinic Acid

- Relevance: LOW

- As Found: Unknown

- ID: T446

- Name: Folic Acid

- Relevance: LOW

- As Found: Unknown

- ID: T448

- Name: Folate

- Relevance: LOW

- As Found: Unknown

- ID: T475

- Name: Vitamin B9

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: C000533178

- Term: Aflibercept

### Misc Info Module

- Version Holder: 2024-05-24
