Diffuse Large B Cell Lymphoma (DLBCL) MedDRA version: 20.0 Level: PT Classification code 10012818 Term: Diffuse large B-cell lymphoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Entospletinib
Product Code: GS-9973
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ENTOSPLETINIB
Current Spo
Sponsors
LYSARC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients with histologically confirmed de novo DLBCL (CD20 positive) 2. Age between 60 and 80 years included, on the day of the informed consent document signature 3. Age adjusted International Prognosis Index (aaIPI) score = 1 4. No prior treatment for DLBCL. However prephase treatment with 1mg/kg/day prednisone or equivalent, for a maximum of 14 days, is permitted prior to begin the treatment 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (0 or 1 only for phase 1b) 6. Life expectancy of = 90 days (3 months) before starting Entospletinib 7. Signed informed consent 8. At least one bi-dimensionally measurable lesion defined as at least one node or tumor lesion on CT scan = 1.5 cm 9. FDG PET/CT performed at baseline with a FDG positive result 10. Adequate hematologic functions defined as follows (unless secondary to bone marrow involvement by lymphoma): - Absolute neutrophil count (ANC) > 1.5 X 10^9 G/l and - Platelets count = 75 X 10^9/l without platelet transfusion dependency during the last 7 days and - Haemoglobin level > 9 g/dl (may receive transfusion) 11. Adequate liver function defined as follows: - Total bilirubin 40 ml/min by local institutional formula 13. Patients with prior Hepatitis B must be given antiviral prophylaxis and HBV DNA monitored; Patients with prior Hepatitis C are eligible if, HCV RNA is undetectable. 14. Left ventricular ejection fraction (LVEF) = 50% of echocardiography or multiple gated acquisition (MUGA) scan 15. Adequate tissue for central retrospective testing for cell of origin (10-15 slides of tumor biopsy must be available at baseline) 16. Heterosexually active females of childbearing potential (as defined in the protocol) must: - have a negative serum pregnancy test at baseline and prior to the first study drug administration (C1D-4) - have practiced at least 1 reliable method of contraception for at least 2 months prior to the first study drug administration (C1D-4) - agree to utilize highly effective methods of contraception (as defined in the protocol) from Cycle 1Day -4 until 12 months following the last treatment administration 17. Heterosexually active males with partners of childbearing potential must agree to use reliable forms of contraception during treatment and up to 12 months after last treatment administration 18. Male subjects must agree to avoid sperm donation from Cycle 1 Day -4 until 12 months following the last treatment administration Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 34 F.1.3 Elderly (>=65 years) yes
Exclusion criteria
Exclusion criteria: 1. Central nervous system or meningeal involvement with DLBCL 2. Contraindication to any drug contained in the chemotherapy regimen 3. Prior treatment with Entospletinib or other SYK inhibitor 4. Patients with a prior history of other malignancy, exceptions include: - a subject who has been disease-free after curative local treatment (surgical resection) for at least 3 years, - a subject with a history of a completely resected non-melanoma skin cancer or in situ carcinoma with surgical complete excision. 5. Patients taking current therapy with proton pump inhibitors and current therapy with medicines that are strong CYP3A or CYP2C9 inducers, or moderate CYP2C9 inducers. 6. Ongoing active pneumonitis 7. Peripheral sensory or motor neuropathy grade > 1. 8. Major surgery within 4 weeks before first dose of study drug (minor procedures including transcutaneous biopsy, central line placement are permitted at any time) 9. Inability to take oral medication or malabsorption syndrome or any other uncontrolled gastrointestinal condition that would impair ability to take entospletinib 10. Significant cardiovascular impairment: congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of first dose of entospletinib or ventricular arrhythmia 11. Active infection as judged by the investigator 12. Known hypersensitivity to ENTO 13. Congenital immunodeficiency or known HIV (human immunodeficiency virus infection) or active viral hepatitis B or C 14. Any other major illness that in the investigator’s judgement, will substantially increase the risk associated with the subject’s participation in the study 15. Subjects who have undergone a solid organ transplant and stem cell transplant 16. Previous treatment for B cell lymphoma or Richter’s transformation 17. Primary Mediastinal B Cell Lymphoma
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Phase I RP2D = after 1 cycle of treatment (from Cycle 1/Day -4 to Cycle 2/Day-4) Phase II CMR rate = end of treatment (8 cycles) ; Main Objective: Phase I : to determine the recommended phase 2 dose (RP2D) for ENTO in patients treated with R-CHOP 21 Phase II : to determine the CMR rate by the Lugano classification 2014 (Deauville scale 1-3) at the end of treatment ; Primary end point(s): Phase I RP2D Phase II CMR rate by the Lugano classification 2014 ; Secondary Objective: Phase I - to evaluate the safety of ENTO in patients treated with 8 cycles of R-CHOP 21 - to evaluate the preliminary anti-tumor activity of ENTO in patients treated with R-CHOP 21 as assessed by rate of complete metabolic response at the intermediate evaluation and at the end of treatment Phase II - to evaluate time to response, duration of response, the progression free survival (PFS) and overall survival (OS) - to evaluate the complete metabolic response rate at the intermediate evaluation, the overall metabolic response rate (OMRR) at the intermediate evaluation and at the end of treatment, - to assess the safety of 8 cycles of ENTO in patients treated with R-CHOP 21 Exploratory Objectives - to assess the pharmacokinetics of ENTO in the presence of R-CHOP chemotherapy - analysis of circulating tumor DNA before therapy, at the end of cycle 2, at the end of cycle 4, end of treatment, 6 months after the end of treatment and in case of relapse or progression | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase I - safety - CMR rate Phase II - time to response (TTR), duration of response (DOR), progression free survival (PFS) and overall survival (OS) - complete metabolic response rate (CMR rate) - overall metabolic response rate (OMR rate) - safety Exploratory Objectives (all phases) - pharmacokinetics - circulating tumor DNA ; Timepoint(s) of evaluation of this end point: Phase I - safety : up to 30 days after the last treatment administration - CMR : after Cycle 4 and after Cycle 8 (or premature discontinuation) Phase II - TTR, DOR, PFS and OS = end of follow-up (30 months) - CMR rate = after Cycle 4 - OMR rate = after Cycle 4 and after Cycle 8 (or premature discontinuation) - safety = up to 30 days after the last treatment administration Exploratory Objectives - PK= on C2D1: T0 (within 30 minutes before ENTO dose, 12 hours after the last ENTO dose on Day -1), and then T1H, 1.5H, 2H, 4H, 6H, 8H and 10H after the dose of ENTO. - circulating tumor DNA = before therapy, at the end of cycle 2, at the end of cycle 4, end of treatment (cycle 8), 6 months after the end of treatment and in case of relapse or progression | — |
Countries
Belgium
Contacts
Public ContactProject Management
LYSARC
Outcome results
None listed