Clinical trial NCT06164327: Study of BEBT-908 Combined With Drugs in the Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Official title: A Multicenter, Open Phase Ib Study of the Safety and Efficacy of BEBT-908 Combined With Drugs in the Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Keywords: BEBT-908
Drug combination
Safety
Efficacy
Lead sponsor: BeBetter Med Inc
Sponsor class: INDUSTRY
First posted: 2023-12-11
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study sets up three cohorts of BEBT-908 combined with different drugs.The researchers decide whether to terminate the cohort study according to the safety and tolerability results of each cohort during the first cycle of medication. If the participants in the above three cohorts are unable to receive the treatment during the first cycle of medication, two alternative cohort studies will be conducted.
Primary purpose: TREATMENT

Brief summary: This is a multicenter, open Phase Ib clinical study to evaluate the safety,efficacy and pharmacokinetics of BEBT-908 combined with Rituximab (R) or combined with Rituximab-Gemcitabine-Oxaliplatin (R-GemOx) or combined with Rituximab-Ifosfamide-Carboplatin-Etoposide (R-ICE) in the treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL).

Detailed description: This study sets up three cohorts, including BEBT-908 combined with R, BEBT-908 combined with R-ICE, and BEBT-908 combined with R-GemOx. The researchers decide whether to terminate the cohort study according to the safety and tolerability results of each cohort during the first cycle of medication. If the participants in the above three cohorts are unable to receive the treatment during the first cycle of medication, two alternative cohort studies will be conducted. Namely, BEBT-908 monotherapy (alternative cohort 1), adjustment of BEBT-908 combined with GemOx administration regimen (alternative cohort 2).

The study process for each participant includes a screening period, a treatment period, and a post-treatment follow-up period. During treatment, participants are evaluated for tumors every 6 weeks, follow up after termination of treatment with efficacy follow-up every 6 weeks for those without disease progression and survival follow-up every 3 months until disease progression (PD), death, emergence of intolerable toxicity, or withdrawal of informed consent (whichever occurred first).

Eligibility criteria: Inclusion Criteria:

1. The subject is willing to sign the informed consent form (ICF) after comprehensive understanding;
2. Age ≥18 years and ≤75 years, both male and female;
3. The pathology was confirmed as diffuse large B-cell lymphoma according to the 2016 World Health Organization classification definition;
4. Evaluation by Positron Emission Computed Tomography (PET-CT) or Computed Tomography (CT) or Magnetic resonance imaging (MRI) using Lugano 2014 standard, with measurable lesion injection;
5. Must have recurrent or refractory diffuse large B-cell lymphoma after at least 1 systemic therapy, and at least 1 systemic therapy included CD20 antibody;
6. Eastern Cooperative Oncology Group (ECOG) scores 0-2 points;
7. Life expectancy \>12 weeks;
8. The level of organ function must meet the following requirements:

Peripheral blood:

1. Absolute neutrophil count (ANC) ≥1000/μL;
2. Hemoglobin (HGB) ≥8g/dL;
3. Platelet count (PLT) ≥100,000/μL;

Liver function:

1. Serum total bilirubin ≤1.5×ULN (for patients with Gilbert syndrome, total bilirubin \<3.0×ULN and Direct bilirubin within normal range);
2. Serum creatinine \<1.5×ULN;
3. ALT, AST or ALP≤2.5×ULN (≤5×ULN when liver involvement occurs).

Exclusion Criteria:

1. Known severe allergy to the investigational drug or any of its excipients;
2. Due to the possibility of genotoxicity, mutagenicity and teratogenicity of the investigational drug, the following subjects should be excluded:

   1. Men and women who have not had sperm or egg preservation in vitro before the trial and plan to have another child within 5 years unless subsequent studies confirm reproductive safety;
   2. Pregnant or lactating women;
3. Primary central nervous system lymphoma or lymphoma invading the central nervous system;
4. Previous chronic lymphoma transformation (such as Richter syndrome, prelymphocytic leukemia, etc.);
5. There are other active malignant tumors requiring treatment that may interfere with the study;
6. Pre-trial treatment:

   1. Received any persistent or intermittent PI3K inhibitor and HDAC inhibitor prior to enrollment or received other small-molecule targeted drug therapy within 2 weeks;
   2. Received BEBT-908 (not allowed to be in all cohorts) or R-ICE (not allowed to be in cohorts with BEBT-908+R-ICE) or R-GemOx (not allowed to be in cohorts with BEBT-908+R-GemOx) prior to enrollment;
   3. Autologous hematopoietic stem cell transplantation within 3 months before enrollment;
   4. Received radiotherapy that affected the evaluation of the efficacy of the study or local supportive radiotherapy that affected the bone marrow function of the subjects within 3 months before enrollment;
   5. Received myelosuppressive chemotherapy or biotherapy within 3 weeks prior to enrollment;
   6. Used Chinese medicines and proprietary Chinese medicines with anti-tumor effects within 2 weeks before enrollment;
   7. Undergone major surgery other than tumor biopsy within 4 weeks prior to enrollment, or the side effects of surgery had not stabilized;
   8. Any hematopoietic colony-stimulating factor (e.g., granulocyte colony-stimulating factor G-CSF, granulocyte macrophage colony-stimulating factor GM-CSF) or thrombopoietin TPO were treated within 2 weeks prior to enrollment；
   9. Received prednisone \>10mg daily (or another equivalent dose of glucocorticoid) within 7 days prior to enrollment;
   10. Received chimeric antigen receptor T cell immunotherapy (CAR-T therapy) within 3 months before enrollment;
7. Persistent grade 2 or higher \[Common Terminology Criteria for Adverse Events V5.0 standard (CTCAE V5.0 standard)\] toxicity after previous treatment (chemotherapy or biotherapy), not stable at enrollment (except alopecia);
8. Active clinical severe infection of grade 2 or above (CTCAE V5.0 standard);
9. Complicated diseases:

   1. diabetes mellitus with poor glycemic control (random glycemic value ≥11.1mmol/L after hypoglycemic treatment, or glycosylated hemoglobin（HbA1c）≥ 8.5%);
   2. severe lung disease (CTCAE V5.0 grade III-IV);
   3. Serious heart disease;
   4. have significant kidney or liver dysfunction;
   5. Poorly controlled active diseases such as hepatitis B or C;
   6. Known human immunodeficiency virus (HIV) positive;
   7. A history of mental illness, family history of mental illness, or mood disorder, as judged by the investigator or psychologist, and the researcher judged that they were not suitable for inclusion;
   8. Combination of anticoagulation and antiplatelet therapy is required during the study period;
   9. uncontrolled hypertension (systolic blood pressure ≥180mmHg and/or diastolic blood pressure ≥110mmHg);
   10. Serious physical disease combined with the risk of major bleeding or a history of major bleeding;
10. Combined with use of drugs that cause QT interval prolongation or torsional ventricular tachycardia;
11. Receiving cytochrome P450 (CYP) 3A4 isozyme suppressant or strongly induced drug therapy during the first 4 weeks of enrollment；
12. Participated in other clinical trials and used investigational drugs within 4 weeks before enrollment;
13. Any condition that the investigator determines to be unstable or likely to compromise the subject's safety and compliance with the study;
14. Subjects deemed unsuitable for treatment with this protocol by the investigator.

Primary outcomes:
measure: ORR
timeFrame: Every 6 weeks，assessed up to 24 months.
measure: AE
timeFrame: From the first administration of the study drug to 28 days after the last administration of the study drug
Secondary outcomes:
measure: ORR-EoT
timeFrame: Every 6 weeks，assessed up to 6 treatment cycles (each cycle is 21 days).
measure: PFS
timeFrame: From date of administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
measure: OS
timeFrame: From date of administration until date of death from any cause, assessed up to 24 months.
measure: CBR
timeFrame: Every 6 weeks，assessed up to 24 months.
measure: DOR
timeFrame: Every 6 weeks，assessed up to 24 months.
measure: DCR
timeFrame: Every 6 weeks，assessed up to 24 months.
measure: TTR
timeFrame: Every 6 weeks，assessed up to 24 months.
measure: Tmax
timeFrame: From 1 hour before dosing on day 1 and day 12 of the first cycle to 48 hours after dosing, and from 1 hour before dosing on day 8 and day 10 of the first cycle (each cycle is 21 days).
measure: Cmax
timeFrame: From 1 hour before dosing on day 1 and day 12 of the first cycle to 48 hours after dosing, and from 1 hour before dosing on day 8 and day 10 of the first cycle (each cycle is 21 days).
measure: t1/2
timeFrame: From 1 hour before dosing on day 1 and day 12 of the first cycle to 48 hours after dosing, and from 1 hour before dosing on day 8 and day 10 of the first cycle (each cycle is 21 days).
measure: AUC0-t
timeFrame: From 1 hour before dosing on day 1 and day 12 of the first cycle to 48 hours after dosing, and from 1 hour before dosing on day 8 and day 10 of the first cycle (each cycle is 21 days).
measure: CL
timeFrame: From 1 hour before dosing on day 1 and day 12 of the first cycle to 48 hours after dosing, and from 1 hour before dosing on day 8 and day 10 of the first cycle (each cycle is 21 days).
Other outcomes:
Locations:
city: Beijing
country: China
facility: Cancer Hospital Chinese Academy of Medical Sciences
state: Beijing
Study officials:
affiliation: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
name: Yuankai Shi, Phd
role: PRINCIPAL_INVESTIGATOR
References: