Dose Finding Study in Colorectal Cancer Patients Receiving 5-FU-based Chemotherapy to Assess the Efficacy of Elsiglutide in the Prevention of Chemotherapy Induced Diarrhea (CID)

This is a randomized, stratified, double-blind, double-dummy, parallel group, placebo-controlled, dose finding, multicentre, multinational, phase II study in patient with colorectal cancer receiving 5- Fluorouracil (5-FU)-based chemotherapy (FOLFOX or FOLFIRI). Patients will receive, starting from the day of chemotherapy administration, a single daily dose subcutaneously (s.c.) of elsiglutide 10, 20 or 40 mg or placebo for 4 consecutive days. Each patient will be in the study for 3 consecutive chemotherapy cycles. The treatment period for each patient will be 4 consecutive days at each of the first 2 chemotherapy cycles.

The primary objective is to compare the efficacy of 3 s.c. doses of elsiglutide versus (vs.) placebo and vs. each other dose in the prevention of CID in colorectal cancer patients treated with 5-FU based chemotherapy (FOLFOX or FOLFIRI) with no addition of a monoclonal antibody.

This is a randomized, stratified, double-blind, double-dummy, parallel group, placebo-controlled, dose finding, multicentre, multinational, phase II study in patient with colorectal cancer receiving 5- Fluorouracil (5-FU)-based chemotherapy (FOLFOX -FOLinic acid, Fluorouracil, OXaliplatin chemotherapy regimen - or FOLFIRI - FOLinic acid, Fluorouracil, IRInotecan chemotherapy regimen). Patients will receive, starting from the day of chemotherapy administration, a single daily dose subcutaneously (s.c.) of elsiglutide 10, 20 or 40 mg or placebo for 4 consecutive days. Each patient will be in the study for 3 consecutive chemotherapy cycles. The treatment period for each patient will be 4 consecutive days at each of the first 2 chemotherapy cycles.

Randomization will be performed with a 1:1:1:1 treatment allocation and will be stratified by chemotherapy regimen and country. Two populations are planned for this study.

The population receiving FOLFOX or FOLFIRI without monoclonal antibody is defined as the Target population, while the population concomitantly receiving monoclonal antibody is defined as the Additional population.

Randomization in Target and Additional population are handled independently.

Primary Objective:

To compare the efficacy of 3 s.c. doses of elsiglutide versus (vs.) placebo and vs. each other dose in the prevention of CID in colorectal cancer patients treated with 5-FU based chemotherapy (FOLFOX or FOLFIRI) with no addition of a monoclonal antibody.

Secondary Objectives:

* As a secondary objective, the efficacy of 3 s.c. doses of elsiglutide vs. placebo and vs. each other dose in the prevention of CID in colorectal cancer patients treated with 5-FU based chemotherapy (FOLFOX or FOLFIRI) given in combination with a monoclonal antibody will be explored.
* Safety and tolerability of the administered repeated doses of elsiglutide will be evaluated.

Additionally the following secondary objectives will be explored:

* The pharmacokinetics (PK) of elsiglutide, and its metabolites in each patient who consents to undergo an exposure assessment after the first administration and at steady state. The influence of possible demographic and therapeutic covariates on the PK parameters and their variability will also be investigated. The possible relationship between exposure of elsiglutide and its metabolites and efficacy measures in the target and overall population will be explored.
* The economic impact of the 3 doses of elsiglutide vs. placebo and each other dose in the treatment of CID.
* The impact on patient's QoL (quality of life) of the different dosages vs. placebo.

Eligibility Criteria:
Inclusion Criteria:

1. Written informed consent
2. Male or female \> 18 years of age;
3. Histologically or cytologically confirmed diagnosis of colorectal cancer

   * Inclusion in the Target Population: Scheduled to receive at least 3 consecutive cycles of the same regimen of FOLFOX or FOLFIRI without monoclonal antibody;
   * Inclusion in the Additional Population: Scheduled to receive at least 3 consecutive cycles of the same regimen of FOLFOX or FOLFIRI in combination with monoclonal antibody;
4. A performance status of ≤ 2 according to the Eastern Cooperative Oncology Group (ECOG) scale;
5. Non-childbearing female patient or female patient of childbearing potential using reliable contraceptive measures and having negative pregnancy test before treatment administration;
6. Able to read, understand, follow the study procedure and complete patient diary.

Inclusion criteria will be checked during the screening visit. Inclusion criteria 4 and 6 will be re-checked as applicable on Day 1 of Cycle 1 and Cycle 2.

Exclusion Criteria:

1. Any investigational drugs within 30 days before enrollment or foreseen use of investigational agents during the study;
2. Treatment with chemotherapy of any type within 12 months before enrollment;
3. Patient with any type of ostomy (temporary ostomy should be closed at least 6 months prior to enrollment);
4. Patient who underwent total colectomy;
5. Patient who had abdominal-perineal resection or surgery leaving the patient without a functioning rectum;
6. Any radiotherapy to the abdomen or pelvis in the 6 months prior to enrollment;
7. Scheduled to receive radiotherapy to abdomen or pelvis during the study;
8. a) Exclusion from the Target population Scheduled to receive any concomitant chemotherapeutic agent, other than FOLFOX or FOLFIRI agents; any type of monoclonal antibodies;

8. b) Exclusion from the Additional population Scheduled to receive any concomitant chemotherapeutic agent, other than FOLFOX or FOLFIRI agents;

9. Any type of condition leading to diarrhea, including but not limited to inflammatory bowel diseases (e.g. ulcerative colitis and Crohn's disease), diarrhea of presumed or confirmed infectious origin and irritable bowel syndrome, celiac disease, lactose intolerance, pancreas, liver or diverticular disease, alcohol abuse;

10. History of chronic (≥ 30 consecutive days) use of laxatives;

11. Active and ongoing systemic infection;

12. Lactating woman;

13. History of hypersensitivity or allergies to drugs or compounds potentially related to this investigational drug class;

14. Previous exposure to Glucagon-like peptide-2 (GLP-2) or other compounds in this investigational drug class;

15. Patient who participated in a previous study with elsiglutide;

16. Patient with abnormalities in selected laboratory parameters, including:

* Aspartate aminotransferase (AST) ≥ 5 x upper limit of normal
* Alanine aminotransferase (ALT) ≥ 5 x upper limit of normal
* Bilirubin \> 1.5 x upper limit of normal
* Creatinine \> 2 mg/dL (177 μmol/L)
* Albumine \< 2 g/dL (20 g/L)
* Neutrophils \< 1.5 x109/L
* Platelet count \< 100 x109/L ;

  17. Any illness or condition that, in the opinion of the investigator, may confound the results of the study or pose unwarranted risk in administering the investigational product to the patient;

  18. Any medical condition that precludes the administration of chemotherapy;

  19. Use of laxatives within 7 days prior to study Day 1;

  20. Use of antibiotics within 7 days prior to study Day 1;

  21. Any diarrhea in the 48 hours preceding study drug administration on Day 1;

  22. Major surgery within the previous 21 days before study Day 1;

  23. Use of anti-diarrheal agents and probiotics within the 48 hours prior to study drug administration on study Day 1.

Exclusion criteria 1 to 18 will be checked during the screening visit. Exclusion criteria 19 to 23 should be checked on Day 1 of Cycle 1. Exclusion criteria 7, 8, 9, 11 and 17 to 23 will be re-checked on Day 1 of Cycle 2.