Proof-of-Concept Study in Cancer Patients to Assess Efficacy of Elsiglutide in Preventing Chemotherapy-Induced Diarrhea

• Safety and tolerability of the administered repeated doses of elsiglutide (ZP1846) will be evaluated [ Time Frame: Day 1 to Day 32 ] [ Designated as safety issue: Yes ]

  Safety will be evaluated by monitoring:

  • Physical examination
  • Vital signs
  • Clinical laboratory parameters (hematology, blood chemistry, urinalysis)
  • 12-lead ECG
  • AEs
  • Immunogenicity testing in a subset of patients
• PK of elsiglutide will be evaluated [ Time Frame: Day 1 to Day 5 ] [ Designated as safety issue: No ]

  The followin standard PK parameters will be evaluated:

  Tmax, Cmax, AUC0-t, AUC0-24, AUC0-∞, t1/2Z, λZ, CL/F, VZ/F, the effect of multiple dosing will be evaluated (accumulation ratio). Blood sampling for PK will be performed at: pre-dose, 2h, 4, 6, 12, 24 h post-dose

The main objective of this study will be to obtain data on the efficacy of elsiglutide in preventing Chemotherapy Induced Diarrhea (CID) in patients with colorectal cancer receiving 5-FU based chemotherapy (FOLFOX4 or FOLFIRI regimen) in comparison to placebo.

• Drug: Elsiglutide
  24 mg administered s.c. once daily for 4 consecutive days from Day 1 chemotherapy
• Drug: Placebo
  24 mg administered s.c. once daily for 4 consecutive days from Day 1 chemotherapy

• Experimental: Elsiglutide
  Intervention: Drug: Elsiglutide
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

1. Written informed consent;
2. Male or female patient ≥ 18 years of age;
3. Confirmed diagnosis of colorectal cancer;
4. Chemotherapy naïve patient;

5. Patient scheduled to receive a FOLFOX4 or FOLFIRI chemotherapy regimen according to the following scheme and dosage (1st cycle):

   AGENT DOSE ROUTE/DURATION DAYS Oxaliplatin or Irinotecan 85/180 mg m2 i.v. infusion/2h 1 FolinicAcid (leucovorin) 200 mg m2 i.v. infusion/2h 1+2 5-Fluorouracil (5FU) 400 mg m2 i.v. bolus 1+2 5-Fluorouracil (5FU) 600 mg m2 i.v. infusion/22h 1+2

6. A performance status of ≤ 2 according to the Eastern Cooperative Oncology Group(ECOG);
7. Non-fertile patient or fertile patient (male or female) using reliable contraceptive measures
8. Female patient of childbearing potential; need to have a negative pregnancy test at screening.

Inclusion criteria 1-8 will be verified at screening.

Inclusion criteria 8 will be re-confirmed on Day 1.

Exclusion Criteria:

1. Inability to understand study procedures and/or cooperate with the study Investigator;
2. Any investigational drugs within 30 days before enrollment in the study or foreseen use of investigational agents during the study;
3. Patient with any type of ostomy;
4. Any previous radiotherapy to the abdomen or pelvis;
5. Scheduled to receive radiotherapy to abdomen or pelvis during the study (Day 1 to Day 14);
6. Scheduled to receive any concomitant chemotherapeutic agent other than FOLFOX4 or FOLFIRI agents (Oxaliplatin, Irinotecan, Folinic acid, 5-FU) from Day 1 to Day 14;
7. Previous use or scheduled to receive monoclonal antibodies (e.g. bevacizumab, cetuximab, etc) during the study (From Day 1 to Day 14);
8. Major surgery within the previous 3 weeks;
9. Any type of condition leading to chronic diarrhea, including but not limited to inflammatory bowel diseases (e.g. ulcerative colitis and Crohn's disease), chronic diarrhea of presumed or confirmed infectious origin and irritable bowel syndrome;
10. Any diarrhea in the 48 hours preceding study drug administration;
11. Use of anti-diarrheal agents within the 48 hours prior to study drug administration;
12. Use of laxatives within 7 days prior to study drug administration;
13. Use of antibiotics within 7 days prior to study drug administration;
14. History of chronic (≥ 30 consecutive days) use of laxatives;
15. Active and ongoing systemic infection;
16. Lactating woman;
17. History of hypersensitivity or allergies to drugs or compounds potentially related to this investigational drug class;
18. Previous exposure to GLP-2 or other compounds in this investigational drug class;

19. Abnormal laboratory values, including

    • Aspartate aminotransferase (AST) ≥ 5 x upper limit of normal
    • Alanine aminotransferase (ALT) ≥ 5 x upper limit of normal
    • Bilirubin > 2 mg/dL (34 μmol/L)
    • Creatinine > 2 mg/dL (177 μmol/L)
    • Albumine < 2 g/dL (20 g/L)
    • Neutrophils< 1.5 x109/L
    • Platelet count < 100 x109/L;
20. Concomitant bleeding disorders;
21. Other serious concomitant illness, which could interfere with the study;
22. Patient who participated in a previous study with elsiglutide (ZP1846).

Exclusion criteria 1-9 and 12-22 will be verified at screening. Exclusion criteria 10 and 11 will be checked on Day 1 only. Exclusion criteria 12, 13 and 15 will be re-checked on Day 1.