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)

Phase 2

Completed

Conditions: Drug and/or Toxin-induced Diarrhea

Interventions: Drug: Placebo
Drug: Elsiglutide

Registration Number: NCT02383810

Lead Sponsor: Helsinn Healthcare SA

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 498

Inclusion Criteria

Written informed consent
Male or female > 18 years of age;
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;
A performance status of ≤ 2 according to the Eastern Cooperative Oncology Group (ECOG) scale;
Non-childbearing female patient or female patient of childbearing potential using reliable contraceptive measures and having negative pregnancy test before treatment administration;
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

Any investigational drugs within 30 days before enrollment or foreseen use of investigational agents during the study;
Treatment with chemotherapy of any type within 12 months before enrollment;
Patient with any type of ostomy (temporary ostomy should be closed at least 6 months prior to enrollment);
Patient who underwent total colectomy;
Patient who had abdominal-perineal resection or surgery leaving the patient without a functioning rectum;
Any radiotherapy to the abdomen or pelvis in the 6 months prior to enrollment;
Scheduled to receive radiotherapy to abdomen or pelvis during the study;
a) Exclusion from the Target population Scheduled to receive any concomitant chemotherapeutic agent, other than FOLFOX or FOLFIRI agents; any type of monoclonal antibodies;
b) Exclusion from the Additional population Scheduled to receive any concomitant chemotherapeutic agent, other than FOLFOX or FOLFIRI agents;
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;
History of chronic (≥ 30 consecutive days) use of laxatives;
Active and ongoing systemic infection;
Lactating woman;
History of hypersensitivity or allergies to drugs or compounds potentially related to this investigational drug class;
Previous exposure to Glucagon-like peptide-2 (GLP-2) or other compounds in this investigational drug class;
Patient who participated in a previous study with elsiglutide;
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 ;
1. 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;
2. Any medical condition that precludes the administration of chemotherapy;
3. Use of laxatives within 7 days prior to study Day 1;
4. Use of antibiotics within 7 days prior to study Day 1;
5. Any diarrhea in the 48 hours preceding study drug administration on Day 1;
6. Major surgery within the previous 21 days before study Day 1;
7. 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo - target population	Placebo	Placebo once daily as s.c. injection for 4 consecutive days in patients receiving 5-FU based chemotherapy
Placebo - additional population	Placebo	Placebo once daily as s.c. injection for 4 consecutive days in patients receiving 5-FU based chemotherapy with monoclonal antibody.
Elsiglutide 10 mg - additional population	Elsiglutide	Elsiglutide 10 mg once daily as s.c. injection for 4 consecutive days in patients receiving 5-FU based chemotherapy with monoclonal antibody.
Elsiglutide 40 mg - target population	Elsiglutide	Elsiglutide 40 mg once daily as s.c. injection for 4 consecutive days in patients receiving 5-FU based chemotherapy
Elsiglutide 20 mg - target population	Elsiglutide	Elsiglutide 20 mg once daily as s.c. injection for 4 consecutive days in patients receiving F-FU based chemotherapy
Elsiglutide 10 mg - target population	Elsiglutide	Elsiglutide 10 mg once daily as s.c. injection for 4 consecutive days in patients receiving 5-FU based chemotherapy
Elsiglutide 20 mg - additional population	Elsiglutide	Elsiglutide 20 mg once daily as s.c. injection for 4 consecutive days in patients receiving 5-FU based chemotherapy with monoclonal antibody.
Elsiglutide 40 mg - additional population	Elsiglutide	Elsiglutide 40 mg once daily as s.c. injection for 4 consecutive days in patients receiving 5-FU based chemotherapy with monoclonal antibody.

Primary Outcome Measures

Name	Time	Method
Proportion of Patients Experiencing a Maximum Grade ≥ 2 Diarrhea During the First Cycle of Chemotherapy in the Target Population	15 days	The endpoint of primary interest for efficacy was the proportion of patients within the Target population experiencing a maximum Grade ≥ 2 diarrhea in Cycle 1 (as assessed by the Investigator). For patient 8031362 who withdrew consent after 11 day in Cycle 1, Investigator assessments for the individual diarrhea events were missing. The data were imputed as Grade 0 for the primary endpoint, in line with the patient's eDiary data. Additional population is not included in primary endpoint evaluation.

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (54): Wojewódzki Szpital Zespolony im. Rydygiera
🇵🇱
Toruń, Poland
Healthcare Institution Minsk City Clinical Oncologic Dispensary
🇧🇾
Minsk, Belarus
State Budgetary Institution of Arkhangelsk Region "Arkhangelsk Clinical Oncology Dispensary"
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Arkhangelsk, Russian Federation
State Healthcare Institution "City Hospital #9" (Saint Petersburg Theoretical & Practical Centre of Coloproctology)
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Saint Petersburg, Russian Federation
State Budgetary Healthcare Institution "Orenburg Regional Clinical Oncology Dispensary"
🇷🇺
Orenburg, Russian Federation
Research Institute of Pulmonology of State Budgetary Educational Institution of Higher Professional Education "First Saint Petersburg State Medical University named after Academician I.P. Pavlov" of the Ministry of Healthcare of the Russian Federation
🇷🇺
Saint Petersburg, Russian Federation
Regional Сommunal Institution Kryvyi Rig Oncology Dispensary
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Kryvyi Rih, Ukraine
State Budgetary Healthcare Institution of Nizhny Novgorod region "Clinical Diagnostic centre"
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Nizhniy Novgorod, Russian Federation
Budgetary Healthcare Institution of Omsk Region "Clinical Oncology Dispensary"
🇷🇺
Omsk, Russian Federation
State Budgetary Healthcare Institution of Perm Territory "Perm Territorial Oncology Dispensary"
🇷🇺
Perm, Russian Federation
State Budgetary Healthcare Institution of Stavropol Territory "Pyatigorsk Oncology Dispensary"
🇷🇺
Pyatigorsk, Russian Federation
State Budgetary Educational Institution of Higher Professional Education "First Saint Petersburg State Medical University named after Academician I.P. Pavlov"
🇷🇺
Saint Petersburg, Russian Federation
Communal Institution "Chernivtsi Regional clinical oncology dispensary"
🇺🇦
Chernivtsi, Ukraine
Communal Institution Kharkiv Regional Clinical Oncology Center
🇺🇦
Kharkiv, Ukraine
Kyiv City Clinical Oncological Center
🇺🇦
Kyiv, Ukraine
Lviv State Oncological Regional Treatment and Preventive Center
🇺🇦
Lviv, Ukraine
Institution Gomel Regional Clinical Oncology Dispensary
🇧🇾
Gomel, Belarus
Healthcare Institution Brest Regional Oncologic Dispensary
🇧🇾
Brest, Belarus
Multifunctional Hospital for Active Treatment for Women's Health Nadezhda Ltd.
🇧🇬
Sofia, Bulgaria
Complex Oncology Centre - Plovdiv Ltd
🇧🇬
Plovdiv, Bulgaria
"Specialized Hospital for Active Treatment of Oncology Diseases - Sofia city" EOOD
🇧🇬
Sofia, Bulgaria
Pardubicka krajska nemocnice a.s
🇨🇿
Pardubice, Czechia
Klinikum Neuperlach
🇩🇪
München, Germany
Országos Onkológiai Intézet "C" Belgyógyászati-Onkológiai és Klinikai Farmakológiai Osztály
🇭🇺
Budapest, Hungary
Uzsoki Utcai Kórház Onkoradiológia, Sugárterápia, ővárosi Onkoradiológiai Központ
🇭🇺
Budapest, Hungary
Debreceni Egyetem, OEC Onkológiai Tanszék
🇭🇺
Debrecen, Hungary
Somogy Megyei Kaposi Mór Oktató Kórház Klinikai Onkológiai Osztály
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Kaposvár, Hungary
Szegedi Tudományegyetem, ÁOK, Szent-Györgyi Albert Klinikai Központ Onkoterápiás Klinika
🇭🇺
Szeged, Hungary
Centrum Medyczne MrukMed
🇵🇱
Rzeszów, Poland
State Budgetary Healthcare Institution of Republic of Mordovia "Republican Oncology Dispensary"
🇷🇺
Saransk, Republic Of Mordovia, Russian Federation
Centrum Medyczne Malgorzata
🇵🇱
Śrem, Poland
State Budgetary Healthcare Institution "Volgograd Regional Oncology Dispensary"
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Volzhskiy, Volgograd Region, Russian Federation
Non-State Healthcare Institution "Railway Clinical Hospital at Chelyabinsk Station of Joint Stock Company "Russian Railways"
🇷🇺
Chelyabinsk, Russian Federation
State Healthcare Institution "Kursk Regional Clinical Oncology Dispensary"
🇷🇺
Kursk, Russian Federation
Federal State Budgetary Institution "Russian Oncology Scientific Centre named after N.N. Blokhin" of the Russian Academy of Medical Science
🇷🇺
Moscow, Russian Federation
State Budgetary Healthcare Institution "City Clinical Hospital #40" of the Healthcare Department of Moscow
🇷🇺
Moscow, Russian Federation
State Budgetary Healthcare Institution of Nizhniy Novgorod Region "Nizhniy Novgorod Regional Oncology Dispensary"
🇷🇺
Nizhniy Novgorod, Russian Federation
Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház Onkológiai Osztály
🇭🇺
Szolnok, Hungary
Budgetary Healthcare Institution of Orel Region "Orel Oncology Dispensary"
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Orel, Russian Federation
Municipal institution "Kirovograd Regional Oncology Center"
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Kirovogrado, Ukraine
''Multifunctional Hospital for Active Treatment Central Onco Hospital" Ltd
🇧🇬
Plovdiv, Bulgaria
State Institution "Republic Scientific and Practical Center of oncology and medical radiology n.a.N.N.Alexandrov"
🇧🇾
Lesnoy, Minsk Region, Belarus
State Budgetary Healthcare Institution "Saint Petersburg Clinical Theoretical & Practical Centre of Special Types of Medical Care (Oncology)"
🇷🇺
Saint Petersburg, Russian Federation
State Budgetary Healthcare Institution "Samara Regional Clinical Oncology Dispensary" (Chemotherapy Unit #1)
🇷🇺
Samara, Russian Federation
State Budgetary Healthcare Institution "Republican Clinical Oncology Dispensary"
🇷🇺
Ufa, Russian Federation
Chernigiv medical and prophylactic establishment "Chernigiv regional oncological center"
🇺🇦
Chernihiv, Ukraine
Communal Institution Dnipropetrovsk City Multifunctional Clinical Hospital #4
🇺🇦
Dnipropetrovsk, Ukraine
Ivano-Frankivsk Regional Oncological Center
🇺🇦
Ivano-Frankivsk, Ukraine
Semmelweis Egyetem, ÁOK I. Sz. Belgyógyászati Klinika, Onkológiai Részleg
🇭🇺
Budapest, Hungary
State Budgetary Healthcare Institution of Moscow "Moscow City Oncology Hospital #62" of Healthcare Department of Moscow
🇷🇺
Moscow, Russian Federation
Healthcare Institution Mogilev Regional Oncologic Dispensary
🇧🇾
Mogilev, Belarus
"Specialized Hospital for Active Treatment ofOncologal Diseases - Sofia District"
🇧🇬
Sofia, Bulgaria
Specialized Hospital for active treatment in oncology - Haskovo Ltd
🇧🇬
Haskovo, Bulgaria
Jósa András Oktatókórház Onkoradiológiai Osztály
🇭🇺
Nyíregyháza, Hungary