Phase I dose-escalation study of oral administration of S55746 in patients with B-Cell Non-Hodgkin Lymphoma
| ISRCTN | ISRCTN04804337 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN04804337 |
| EudraCT/CTIS number | 2013-003779-36 |
| ClinicalTrials.gov number | NCT02920697 |
| Secondary identifying numbers | CL1-55746-001 |
- Submission date
- 31/01/2014
- Registration date
- 21/03/2014
- Last edited
- 22/11/2019
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English Summary
Not provided at time of registration and not expected to be available in the future
Contact information
Prof Steven Le Gouill
Scientific
Scientific
Université de Nantes, Hotel-Dieu
Service dhématologie clinique
Place Alexis Ricordeau
Nantes
44093
France
Study information
| Study design | Phase I dose-escalation study non-randomized trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| 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 |
| Study hypothesis | To determine the safety profile and tolerability and establish the recommended Phase II dose of S55746. |
| Ethics approval(s) | Ethics approval was obtained before recruitment of the first participants |
| 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 | Current interventions as of 13/01/2017: Film-coated tablets containing 50 mg or 100mg of S55746. This trial is a dose escalation trial. A panel of doses from 50 to 1500 mg could be tested. Patients, who clearly benefiting from the study treatment, and in the opinion of the investigator it is in the patient’s best interest to continue S 55746 may remain on study treatment until evidence of progressive disease, the occurrence of unacceptable toxicity, death or investigator’s/patient’s decision. Total number of cycles is at the discretion of the investigator. Interventions from 07/09/2016 to 13/01/2017: Film-coated tablets containing 50 mg or 100 mg 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. Original interventions: Film-coated tablets containing 50 mg or 100 mg 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 investigators opinion, they receive benefit according to tumour evaluation. Maximum number of cycles is at the discretion of the investigator. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | S55746 |
| Primary outcome measure | Current primary outcome measures as of 13/01/2017: 1. Dose Limiting Toxicities (DLTs) in cycle 1 2. Maximum Tolerated Dose, defined as the highest drug dosage that is unlikely (<25% posterior probability) to cause DLTs in more than 33% of the treated patients in the first cycle of S 055746 treatment 3. Safety profile at each visit, assessed by adverse events monitoring, laboratory tests, vital signs and performance status, clinical examination and ECG parameters Previous 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 | Current secondary outcome measures as of 13/03/2018: 1. Pharmacokinetic parameters on blood sample during cycles 1 and 2 2. Preliminary anti-leukaemic activity of S 055746 throughout the study (blood, BMA and biopsy if available) Previous secondary outcome measures from 13/01/2017 to 13/03/2018: 1. Pharmacokinetic parameters on blood sample during cycles 1 and 2 2. Pharmacodynamic parameters on blood, bone marrow aspiration (BMA) and biopsy if available from cycle 1 to cycle 3 and in any time in case of suspicion of disease progression 3. Optional pharmacogenomic analysis on Cycle 1, D1 pre-dose 4. Preliminary anti-leukaemic activity of S 055746 throughout the study (blood, BMA and biopsy if available) Secondary outcome measures from 07/09/2016 to 13/01/2017: 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 Original secondary outcome measures: 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 |
| Overall study start date | 03/10/2013 |
| Overall study end date | 22/10/2018 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 120 patients |
| Participant inclusion criteria | Current inclusion criteria: 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 0-2 6. Adequate bone marrow, renal and hepatic functions 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 Previous inclusion criteria as of 13/01/2017: 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 0-2 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 Inclusion criteria from 07/09/2016 to 13/01/2017: 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. Original inclusion criteria: 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 exclusion criteria | Current inclusion criteria: 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 within 7 days prior to first S 55746 intake 7. Positive direct antiglobulin test (Coombs test) and haptoglobin below normal value 8. Prior allogenic stem cell transplant 9. Autologous stem cell transplant within 3 months before the first intake of S55746. 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. Solitary extramedullary plasmacytoma 17. Strong or moderate CYP3A4 inhibitors/inducers (treatment, food or drink products) 18. Treatment highly metabolized by the CYP3A4 or CYP2D6 and/or substrates with a narrow therapeutic index, multienzyme and/or OATP substrates and/or P-gp, or herbal products. 19. Known hypersensitivity to rasburicase 20. G6PD deficiency and other cellular metabolic disorders known to cause haemolytic anaemia 21. Laboratory Signs of Tumor Lysis Syndrome 22. Patients receiving proton pump inhibitor Previous exclusion criteria as of 13/01/2017: 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. Autologous stem cell transplant within 3 months before the first intake of S55746. 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. Solitary extramedullary plasmacytoma 17. Strong or moderate CYP3A4 inhibitors/inducers (treatment, food or drink products) 18. Treatment highly metabolized by the CYP3A4 or CYP2D6 and/or substrates with a narrow therapeutic index, multienzyme and/or OATP substrates or herbal products. 19. Known hypersensitivity to rasburicase 20. G6PD deficiency and other cellular metabolic disorders known to cause haemolytic anaemia 21. Laboratory Signs of Tumor Lysis Syndrome 22. Patients receiving proton pump inhibitor Exclusion criteria from 07/09/2016 to 13/01/2017: 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 Original exclusion criteria: 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 | 26/12/2017 |
Locations
Countries of recruitment
- Australia
- England
- France
- Germany
- Hungary
- Korea, South
- Poland
- Singapore
- United Kingdom
Study participating centres
University Hospital of Nantes (Université de Nantes)
Hôtel-Dieu
Nantes
44093
France
Nantes
44093
France
Claude Huriez Hospital (Hospital Claude Huriez)
Rue Michel Polonowski
Lille
59000
France
Lille
59000
France
Gustave Roussy Institute of Oncology
114 Rue Edouard Vaillant
Villejuif
94800
France
Villejuif
94800
France
Lyon-Sud Hospital (Centre Hospitalier Lyon-Sud)
165 Chemin du Grand Revoyet
Pierre-Bénite
69310
France
Pierre-Bénite
69310
France
Schwabing Hospital
Kölner Platz 1
München
80804
Germany
München
80804
Germany
University Hospital of Ulm
Ulm
-
Germany
-
Germany
University Hospital Carl Gustav Carus
Dresden
-
Germany
-
Germany
National Cancer Center (NCC)
11 Hospital Drive
169610
Singapore
169610
Singapore
National University Cancer Institute
119074
Singapore
Singapore
National Institute of Oncology
1122 Budapest Ráth György u. 7-9.
-
Hungary
-
Hungary
CRU Hungary Kft
Miskolc
-
Hungary
-
Hungary
Warsaw Institute of Oncology
ul. Roentgena 5
Warsaw
-
Poland
Warsaw
-
Poland
Medical University of Warsaw
Żwirki i Wigury 61
Warszawa
Warsaw
-
Poland
Warszawa
Warsaw
-
Poland
St. Mary's Hospital
Seoul
06591
Korea, South
06591
Korea, South
Severance Hospital
50-1 Yonsei-ro, Seodaemun-gu
Seoul
-
Korea, South
Seoul
-
Korea, South
University College London Hospitals
London
-
United Kingdom
-
United Kingdom
Freeman Hospital
Freeman Rd
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
The Alfred Hospital Malignant Haematology & Stem Cell Transplantation Services
Level 1, South Block
55 Commercial Road
Melbourne
VIC 3004
Australia
55 Commercial Road
Melbourne
VIC 3004
Australia
Sponsor information
Institut de Recherches Internationales Servier (France)
Industry
Industry
50, rue Carnot
Suresnes
92284
France
| Website | http://www.servier.com/ |
|---|---|
"ROR" |
https://ror.org/034e7c066 |
Funders
Funder type
Industry
ADIR
No information available
Results and Publications
| Intention to publish date | 08/10/2020 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Other |
| Publication and dissemination plan | Current publication and dissemination plan as of 22/11/2019: The trialists will comply with regulatory requirements. Summary results and a lay summary will be published on https://clinicaltrials.servier.com within 12 months after the end of the study. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from https://clinicaltrials.servier.com after Marketing Authorisation has been granted. A plain English summary of results has been uploaded as an additional file (ISRCTN04804337_ResultsPlainEnglish_16Sep2019) Previous publication and dissemination plan: Summary results and a lay summary will be published on www.clinicaltrials.servier.com within 12 months after the end of the study. IPD sharing plan: The datasets generated during and/or analysed during the current study will be available upon request from www.clinicaltrials.servier.com after the Marketing Authorisation has been granted. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Basic results | 16/09/2019 | 22/11/2019 | No | No | |
| Results article | 16/09/2019 | 22/11/2019 | Yes | No |
Additional files
- ISRCTN04804337_BasicResults_16Sep2019.pdf
- uploaded 22/11/2019
- ISRCTN04804337_ResultsPlainEnglish_16Sep2019.pdf
- uploaded 22/11/2019
Editorial Notes
22/11/2019: The following changes were made to the trial record:
1. The publication and dissemination plan was changed.
2. The basic results of this trial have been uploaded as an additional file.
3. The plain English results summary has been uploaded as an additional file.
19/06/2019: Internal review.
14/11/2018: The overall trial end date was changed from 30/09/2018 to 22/10/2018.
22/03/2018: The following changes have been made:
1. The recruitment end date has been changed from 06/10/2018 to 26/12/2017.
2. The overall trial end date has been changed from 08/10/2019 to 30/09/2018.
3. The secondary outcome measures have been changed.
4. The participant inclusion criteria have been changed.
5. The participant exclusion criteria have been changed.
6. The publication and dissemination plan has been changed.
16/01/2017: The overall trial end date was changed from 05/02/2018 to 08/10/2019.
13/01/2017: The recruitment end date was changed from 05/08/2017 to 06/10/2018.
07/09/2016: Amended interventions, outcomes, inclusion/exclusion criteria. Added EudraCT 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.
