Condition category
Cancer
Date applied
31/01/2014
Date assigned
21/03/2014
Last edited
08/09/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Not provided at time of registration and not expected to be available in the future

Trial website

Contact information

Type

Scientific

Primary contact

Prof Steven Le Gouill

ORCID ID

Contact details

Université de Nantes
Hotel-Dieu
Service d’hématologie clinique
Place Alexis Ricordeau
Nantes
44093
United Kingdom

Additional identifiers

EudraCT number

2013-003779-36

ClinicalTrials.gov number

Protocol/serial number

CL1-55746-001

Study information

Scientific title

Phase I dose-escalation study of oral administration of the selective Bcl2 inhibitor S55746 in patients with refractory or relapsed Chronic Lymphocytic Leukaemia and B-Cell Non-Hodgkin Lymphoma

Acronym

Study hypothesis

To determine the safety profile and tolerability and establish the recommended Phase II dose of S55746.

Ethics approval

Ethics approval was obtained before recruitment of the first participants

Study design

Phase I dose-escalation study non-randomized trial

Primary study design

Interventional

Secondary study design

Non randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Chronic Lymphocytic Leukaemia (CLL) and B-Cell Non-Hodgkin Lymphoma (NHL) including Follicular Lymphoma (FL) , Mantle Cell Lymphoma (MCL), Diffuse Large B-Cell Lymphoma, Small Lymphocytic Lymphoma, Marginal Zone Lymphoma and and Multiple myeloma (MM)

Intervention

As of 07/09/2016:
Film-coated tablets containing 50 mg or 100mg of S55746.

This trial is a dose escalation trial. A modified version of the Continual Reassessment Method (mCRM) will be used for dose allocation process and performed in each arm independently. A panel of doses from 50 to 1500 mg could be tested according to the dose allocation process of the mCRM. Intermediate doses could be tested if needed. Patients will receive at least 2 cycles of treatment. Patients will receive the treatment(s) as long as, in the investigators opinion, they receive benefit according to tumour evaluation. Maximum number of cycles is at the discretion of the investigator.

Initial:
Film-coated tablets containing 50 mg or 100mg of S55746.

This trial is a dose escalation trial. A modified version of the Continual Reassessment Method (mCRM) will be used for dose allocation process and performed in each arm independently. A panel of doses from 50 to 1000 mg could be tested according to the dose allocation process of the mCRM. Doses over 1000 mg and intermediate doses could be tested if needed. Patients will receive at least 2 cycles of treatment. Patients will receive the treatment(s) as long as, in the investigator’s opinion, they receive benefit according to tumour evaluation. Maximum number of cycles is at the discretion of the investigator.

Intervention type

Drug

Phase

Phase I

Drug names

S55746

Primary outcome measures

1. Maximum Tolerated Dose will be evaluated following Dose Limiting Toxicities at the end of cycle 1 for a given dose measured by adverse events monitoring.
2. Safety profile at each visit measured by adverse events monitoring, ECG, cardiac function parameters, physical examination, performance status, vital signs and laboratory tests.

Secondary outcome measures

As of 07/09/2016:
1. Pharmacokinetic parameters on blood and urine samples during cycles 1 and 2
2. Assess the influence of food intake on PK profile of S55746
3. Pharmacodynamic parameters from blood samples during cycle 1 or from archival and optional biopsy in case of pharmacodynamic after objective response (complete or partial response)
4. Pharmacogenomic analysis on a blood sample during cycle 1
5. Tumour response based on clinical and radiological evaluation, throughout the study

Initial:
1. Pharmacokinetics parameters on blood and urine samples during cycles 1 and 2
2. Pharmacodynamics parameters on blood samples and optional biopsy during cycle 1
3. Pharmacogenomics analysis on a blood sample during cycle 1
4. Tumour response based on clinical and radiological evaluation, throughout the study

Measured throughout the study.

Overall trial start date

03/10/2013

Overall trial end date

05/02/2018

Reason abandoned

Eligibility

Participant inclusion criteria

As of 07/09/2016:
1. Women or men aged >/=18 years
2. Patients with a measurable histologically confirmed FL, MCL, DLBCL, SLL
and MZL (Arm A) or patients with an evaluable immunophenotypically confirmed CLL (Arm B), or patients with a measurable MM t(11;14) (arm A expansion part)according to IMWG criteria
3. Previously treated relapsed after or refractory disease to standard treatments, and require treatment in the opinion of the investigator
4. Estimated life expectancy > 12 weeks
5. WHO performance status 0¬1
6. Adequate bone marrow, renal and hepatic functions, normal coagulation profile
7. No evidence or treatment for another malignancy within 2 years prior to study entry. Curatively treated non¬melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia is allowed

Additional eligibility criteria for food interaction cohort:
8. Patients with B-cell NHL and defined as low risk of TLS according to published criteria (Cairo et al., 2010).
9. Patients not having taken any treatment likely to have an impact on S55746 absorption (antacids, antisecretory including H2-receptor antagonists and proton pump inhibitors) within 7 days prior to first S55746 intake.

Initial:
1. Women or men aged >/=18 years
2. Patients with a measurable histologically confirmed and previously treated FL, MCL, DLBCL, SLL and MZL or patients with an evaluable immunophenotypically confirmed and previously treated CLL
3. Relapsed after or refractory disease to standard treatments, and required treatment in the opinion of the investigator
4. Estimated life expectancy > 12 weeks
5. WHO performance status 0-1
6. Adequate bone marrow, renal and hepatic functions, normal coagulation profile
7. Kaliemia and calcemia within the local normal range
8. No evidence or treatment for another malignancy within 2 years prior to study entry. Curatively treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia is allowed

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

120 patients

Participant exclusion criteria

As of 07/09/2016:
1. Previous treatment with a BH3 mimetic
2. Previous chemotherapy within 3 weeks before first intake
3. Radioimmunotherapy, radiotherapy within 8 weeks before first intake
4. Major surgery within 3 weeks before first day of study drug dosing
5. Corticosteroids > 20 mg prednisone equivalent per day within 7 days before first intake
6. Anticoagulant oral drugs, aspirin > 325 mg/day
7. Positive direct antiglobulin test (Coombs test) and haptoglobin below normal value
8. Prior allogenic stem cell transplant
9. NHL patients diagnosed with Post¬Transplant Lymphoproliferative Disease, Burkitt's lymphoma, Burkitt¬like lymphoma, or lymphoblastic lymphoma/leukaemia
10. Human immunodeficiency virus (HIV)
11. Known acute or chronic hepatitis B or hepatitis C
12. Impaired cardiac function
13. Medications known to prolong QTc interval
14. History or/ clinically suspicious for cancer¬related CNS disease
15.Solitary extramedullary plasmacytoma
16. Strong or moderate CYP3A4 inhibitors/inducers (treatment, food or drink products)
17. Treatment highly metabolized by the CYP3A4 or CYP2D6 and/or substrates with a narrow therapeutic index, multienzyme and/or OATP substrates or herbal products.
18. Known hypersensitivity to rasburicase
19. G6PD deficiency and other cellular metabolic disorders known to cause haemolytic anaemia
20. Laboratory Signs of Tumor Lysis Syndrome

Initial:
1. Previous treatment with a BH3 mimetic
2. Previous chemotherapy within 3 weeks before first intake
3. Radioimmunotherapy, radiotherapy within 8 weeks before first intake
4. Major surgery within 3 weeks before first day of study drug dosing
5. Corticosteroids > 20 mg prednisone equivalent per day within 7 days before first intake
6. Anticoagulant oral drugs, aspirin > 325 mg/day
7. Positive direct antiglobulin test (Coombs test) and haptoglobin below normal value
8. CLL and NHL prior allogenic stem cell transplant
9. Autologous stem cell transplant within 3 months before first intake
10. NHL patients diagnosed with Post-Transplant Lymphoproliferative Disease, Burkitt's lymphoma, Burkitt-like lymphoma, or lymphoblastic lymphoma/leukaemia
11. Human immunodeficiency virus (HIV)
12. Known acute or chronic hepatitis B or hepatitis C
13. Impaired cardiac function
14. Medications known to prolong QTc interval
15. History or/ clinically suspicious for cancer-related CNS disease
16. Treatment, food or drink products known to inhibit or induce CYP3A4
17. Treatment highly metabolized by the CYP3A4 and with a narrow therapeutic index
18. Known hypersensitivity to rasburicase
19. G6PD deficiency and other cellular metabolic disorders known to cause haemolytic anaemia

Recruitment start date

26/03/2014

Recruitment end date

05/08/2017

Locations

Countries of recruitment

France, Germany, Hungary, Korea, South, Poland, Singapore, United Kingdom

Trial participating centre

University Hospital of Nantes (Université de Nantes)
Hôtel-Dieu
Nantes
44093
France

Trial participating centre

Claude Huriez Hospital (Hospital Claude Huriez)
Rue Michel Polonowski
Lille
59000
France

Trial participating centre

Gustave Roussy Institute of Oncology
114 Rue Edouard Vaillant
Villejuif
94800
France

Trial participating centre

Lyon-Sud Hospital (Centre Hospitalier Lyon-Sud)
165 Chemin du Grand Revoyet
Pierre-Bénite
69310
France

Trial participating centre

Schwabing Hospital
Kölner Platz 1
München
80804
Germany

Trial participating centre

University Hospital of Ulm
Ulm
-
Germany

Trial participating centre

University Hospital Carl Gustav Carus
Dresden
-
Germany

Trial participating centre

National Cancer Center (NCC)
11 Hospital Drive
169610
Singapore

Trial participating centre

National University Cancer Institute
119074
Singapore

Trial participating centre

National Institute of Oncology
1122 Budapest Ráth György u. 7-9.
-
Hungary

Trial participating centre

CRU Hungary Kft
Miskolc
-
Hungary

Trial participating centre

Warsaw Institute of Oncology
ul. Roentgena 5
Warsaw
-
Poland

Trial participating centre

Medical University of Warsaw
Żwirki i Wigury 61 Warszawa
Warsaw
-
Poland

Trial participating centre

St. Mary's Hospital
Seoul
06591
Korea, South

Trial participating centre

Severance Hospital
50-1 Yonsei-ro, Seodaemun-gu
Seoul
-
Korea, South

Trial participating centre

University College London Hospitals
London
-
United Kingdom

Trial participating centre

Freeman Hospital
Freeman Rd High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom

Sponsor information

Organisation

Institut de Recherches Internationales Servier (France)

Sponsor details

50
rue Carnot
Suresnes
92284
United Kingdom

Sponsor type

Industry

Website

http://www.servier.com/

Funders

Funder type

Industry

Funder name

ADIR

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Researchers will comply with regulatory requirements

Intention to publish date

05/02/2019

Participant level data

Other

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

08/09/2016: Internal review 07/09/2016: Amended interventions, outcomes, inclusion/exclusion criteria. Added EndraCT number. Overall start date changed from 01/01/2014 to 03/10/2013 . Overall end date changed from 01/01/2016 to 05/02/2016. Recruitment start date changed from 01/01/2014 to 26/03/2014. Recruitment end date changed from 01/01/2016 to 05/08/2017.