Phase I dose-escalation study of oral administration of S55746 in patients with B-Cell Non-Hodgkin Lymphoma

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

Status

Active, not recruiting

Phases

Phase 1

Study type

Interventional

Source

ISRCTN

Registry ID

ISRCTN04804337

Enrollment

120

Registered

2014-03-21

Start date

2014-03-26

Completion date

Unknown

Last updated

2019-12-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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) Cancer 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, Multiple myeloma

Interventions

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

Eligibility

Sex/Gender

All

Inclusion criteria

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

Exclusion criteria

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

Design outcomes

Primary

Measure	Time frame
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	—

Measure

Time frame

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

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Secondary

Measure	Time frame
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	—

Measure

Time frame

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

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Countries

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

Outcome results

None listed

Source: ISRCTN (via WHO ICTRP) · Data processed: Feb 4, 2026