Clinical trial NCT02383810: 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)
Official title: Randomized, Double-blind, Parallel Group, Placebo-controlled, Dose Finding Study in Colorectal Cancer Patients Receiving 5-FU-based Chemotherapy to Assess the Efficacy of Different Doses of s.c. Elsiglutide in the Prevention of Chemotherapy Induced Diarrhea (CID)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Drug and/or Toxin-induced Diarrhea
Keywords: Chemotherapy Induced Diarrhea (CID)
Lead sponsor: Helsinn Healthcare SA
Sponsor class: INDUSTRY
Collaborators: name: Chiltern International Inc.
First posted: 2015-03-09
Enrollment: 498
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Primary outcomes:
measure: Proportion of Patients Experiencing a Maximum Grade ≥ 2 Diarrhea During the First Cycle of Chemotherapy in the Target Population
timeFrame: 15 days
Secondary outcomes:
Other outcomes:
Locations:
city: Lesnoy
country: Belarus
facility: State Institution "Republic Scientific and Practical Center of oncology and medical radiology n.a.N.N.Alexandrov"
state: Minsk Region
city: Brest
country: Belarus
facility: Healthcare Institution Brest Regional Oncologic Dispensary
city: Gomel
country: Belarus
facility: Institution Gomel Regional Clinical Oncology Dispensary
city: Minsk
country: Belarus
facility: Healthcare Institution Minsk City Clinical Oncologic Dispensary
city: Mogilev
country: Belarus
facility: Healthcare Institution Mogilev Regional Oncologic Dispensary
city: Haskovo
country: Bulgaria
facility: Specialized Hospital for active treatment in oncology - Haskovo Ltd
city: Plovdiv
country: Bulgaria
facility: ''Multifunctional Hospital for Active Treatment Central Onco Hospital" Ltd
city: Plovdiv
country: Bulgaria
facility: Complex Oncology Centre - Plovdiv Ltd
city: Sofia
country: Bulgaria
facility: Multifunctional Hospital for Active Treatment for Women's Health Nadezhda Ltd.
city: Sofia
country: Bulgaria
facility: "Specialized Hospital for Active Treatment of Oncology Diseases - Sofia city" EOOD
city: Sofia
country: Bulgaria
facility: "Specialized Hospital for Active Treatment ofOncologal Diseases - Sofia District"
city: Pardubice
country: Czechia
facility: Pardubicka krajska nemocnice a.s
city: München
country: Germany
facility: Klinikum Neuperlach
city: Budapest
country: Hungary
facility: Semmelweis Egyetem, ÁOK I. Sz. Belgyógyászati Klinika, Onkológiai Részleg
city: Budapest
country: Hungary
facility: Országos Onkológiai Intézet "C" Belgyógyászati-Onkológiai és Klinikai Farmakológiai Osztály
city: Budapest
country: Hungary
facility: Uzsoki Utcai Kórház Onkoradiológia, Sugárterápia, ővárosi Onkoradiológiai Központ
city: Debrecen
country: Hungary
facility: Debreceni Egyetem, OEC Onkológiai Tanszék
city: Kaposvár
country: Hungary
facility: Somogy Megyei Kaposi Mór Oktató Kórház Klinikai Onkológiai Osztály
city: Nyíregyháza
country: Hungary
facility: Jósa András Oktatókórház Onkoradiológiai Osztály
city: Szeged
country: Hungary
facility: Szegedi Tudományegyetem, ÁOK, Szent-Györgyi Albert Klinikai Központ Onkoterápiás Klinika
city: Szolnok
country: Hungary
facility: Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház Onkológiai Osztály
city: Rzeszów
country: Poland
facility: Centrum Medyczne MrukMed
city: Toruń
country: Poland
facility: Wojewódzki Szpital Zespolony im. Rydygiera
city: Śrem
country: Poland
facility: Centrum Medyczne Malgorzata
city: Saransk
country: Russian Federation
facility: State Budgetary Healthcare Institution of Republic of Mordovia "Republican Oncology Dispensary"
state: Republic Of Mordovia
city: Volzhskiy
country: Russian Federation
facility: State Budgetary Healthcare Institution "Volgograd Regional Oncology Dispensary"
state: Volgograd Region
city: Arkhangelsk
country: Russian Federation
facility: State Budgetary Institution of Arkhangelsk Region "Arkhangelsk Clinical Oncology Dispensary"
city: Chelyabinsk
country: Russian Federation
facility: Non-State Healthcare Institution "Railway Clinical Hospital at Chelyabinsk Station of Joint Stock Company "Russian Railways"
city: Kursk
country: Russian Federation
facility: State Healthcare Institution "Kursk Regional Clinical Oncology Dispensary"
city: Moscow
country: Russian Federation
facility: Federal State Budgetary Institution "Russian Oncology Scientific Centre named after N.N. Blokhin" of the Russian Academy of Medical Science
city: Moscow
country: Russian Federation
facility: State Budgetary Healthcare Institution "City Clinical Hospital #40" of the Healthcare Department of Moscow
city: Moscow
country: Russian Federation
facility: State Budgetary Healthcare Institution of Moscow "Moscow City Oncology Hospital #62" of Healthcare Department of Moscow
city: Nizhniy Novgorod
country: Russian Federation
facility: State Budgetary Healthcare Institution of Nizhny Novgorod region "Clinical Diagnostic centre"
city: Nizhniy Novgorod
country: Russian Federation
facility: State Budgetary Healthcare Institution of Nizhniy Novgorod Region "Nizhniy Novgorod Regional Oncology Dispensary"
city: Omsk
country: Russian Federation
facility: Budgetary Healthcare Institution of Omsk Region "Clinical Oncology Dispensary"
city: Orel
country: Russian Federation
facility: Budgetary Healthcare Institution of Orel Region "Orel Oncology Dispensary"
city: Orenburg
country: Russian Federation
facility: State Budgetary Healthcare Institution "Orenburg Regional Clinical Oncology Dispensary"
city: Perm
country: Russian Federation
facility: State Budgetary Healthcare Institution of Perm Territory "Perm Territorial Oncology Dispensary"
city: Pyatigorsk
country: Russian Federation
facility: State Budgetary Healthcare Institution of Stavropol Territory "Pyatigorsk Oncology Dispensary"
city: Saint Petersburg
country: Russian Federation
facility: State Budgetary Educational Institution of Higher Professional Education "First Saint Petersburg State Medical University named after Academician I.P. Pavlov"
city: Saint Petersburg
country: Russian Federation
facility: State Healthcare Institution "City Hospital #9" (Saint Petersburg Theoretical & Practical Centre of Coloproctology)
city: Saint Petersburg
country: Russian Federation
facility: 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
city: Saint Petersburg
country: Russian Federation
facility: State Budgetary Healthcare Institution "Saint Petersburg Clinical Theoretical & Practical Centre of Special Types of Medical Care (Oncology)"
city: Samara
country: Russian Federation
facility: State Budgetary Healthcare Institution "Samara Regional Clinical Oncology Dispensary" (Chemotherapy Unit #1)
city: Ufa
country: Russian Federation
facility: State Budgetary Healthcare Institution "Republican Clinical Oncology Dispensary"
city: Chernihiv
country: Ukraine
facility: Chernigiv medical and prophylactic establishment "Chernigiv regional oncological center"
city: Chernivtsi
country: Ukraine
facility: Communal Institution "Chernivtsi Regional clinical oncology dispensary"
city: Dnipropetrovsk
country: Ukraine
facility: Communal Institution Dnipropetrovsk City Multifunctional Clinical Hospital #4
city: Ivano-Frankivsk
country: Ukraine
facility: Ivano-Frankivsk Regional Oncological Center
city: Kharkiv
country: Ukraine
facility: Communal Institution Kharkiv Regional Clinical Oncology Center
city: Kirovogrado
country: Ukraine
facility: Municipal institution "Kirovograd Regional Oncology Center"
city: Kryvyi Rih
country: Ukraine
facility: Regional Сommunal Institution Kryvyi Rig Oncology Dispensary
city: Kyiv
country: Ukraine
facility: Kyiv City Clinical Oncological Center
city: Lviv
country: Ukraine
facility: Lviv State Oncological Regional Treatment and Preventive Center
Study officials:
References: