A Study of BEBT-908 in Combination With Chemotherapy in Patients With Previously Untreated Peripheral T-Cell Lymphoma (PTCL)

An Open-Label, Multicenter, Phase II Clinical Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of BEBT-908 Plus CHOP (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) in Patients With Previously Untreated Peripheral T-Cell Lymphoma (PTCL), and to Explore the Relationship Between Tumor Biomarkers and the Efficacy and Safety of BEBT-908 Plus CHOP.

The goal of this clinical study is to find the best way to combine the study drug BEBT-908 (ifupinostat hydrochloride for injection) with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for treating previously untreated peripheral T-cell lymphoma, and to find out whether this best combination is better than standard CHOP treatment alone.

The main questions this study will try to answer are:

What percentage of participants will respond well to treatment with BEBT-908 plus CHOP? Is BEBT-908 plus CHOP better than standard CHOP treatment? What medical problems will participants have while receiving this combination treatment?

This study includes an Exploration Phase and an Expansion Phase. The Exploration Phase has 3 cohorts. All participants receive both BEBT-908 and CHOP, but the dosing arrangements differ across cohorts: the dose of BEBT-908 differs, the sequencing of administration differs, and whether participants continue with CHOP or transition to BEBT-908 depends on their tolerability to CHOP. Eligible participants will receive the combination treatment for their assigned cohort. After that, based on the results from all 3 cohorts in the Exploration Phase, one optimal cohort will be selected to proceed into the Expansion Phase. In the Expansion Phase, eligible participants will be randomly assigned (like flipping a coin) in a 1:1 ratio to either the treatment group, receiving the optimal combination regimen identified in the Exploration Phase, or the control group, receiving 6 cycles of CHOP. This study design will help investigators find the best way to combine BEBT-908 and CHOP for treating previously untreated peripheral T-cell lymphoma, and check whether this optimal combination regimen is better than standard CHOP treatment.

This study is an open-label, multicenter Phase II clinical study designed to evaluate the efficacy, safety, and pharmacokinetic profile of BEBT-908 in combination with CHOP in patients with previously untreated peripheral T-cell lymphoma (PTCL), and to explore the relationship between tumor biomarkers and the efficacy and safety of BEBT-908 plus CHOP. The study consists of an Exploration Phase and an Expansion Phase.

Exploration Phase: Eligible participants are stratified by pathological subtype and enrolled into 3 study cohorts. Each treatment cycle is 21 days. The cohorts are as follows:

Cohort 1: BEBT-908 (8.2 mg/m²)in combination with CHOP for 6 cycles. This cohort follows a "3+3" design. The first 3 participants are enrolled, and based on the safety and tolerability findings from Cycle 1 of these participants, the investigator will determine whether to proceed with subsequent cycles and whether to continue enrolling additional participants.

Cohort 2: CHOP for 2 cycles, followed by BEBT-908 (18.5 mg/m²) for 4 cycles, followed by CHOP for 4 cycles. All enrolled participants in this cohort receive CHOP during cycles 1-2. Regardless of response, all participants switch to BEBT-908 (18.5 mg/m²) starting from Cycle 3 for consecutive 4 cycles. After these 4 cycles, participants without progressive disease (PD) will then receive CHOP for 4 more cycles.

Cohort 3: BEBT-908 (18.5 mg/m²) for 4 cycles, followed by CHOP for 2-6 cycles or BEBT-908 (18.5 mg/m²) for 4 more cycles. All enrolled participants in this cohort receive BEBT-908 (18.5 mg/m²) during cycles 1-4. After 4 cycles, participants without progressive disease (PD) will subsequently receive either CHOP or BEBT-908 depending on their clinical situation. Participants who are intolerant to CHOP chemotherapy will continue to receive BEBT-908 (18.5 mg/m²) for 4 more cycles. Participants who are tolerant to CHOP will receive CHOP treatment, with the number of cycles determined as follows: participants achieving complete response (CR) after 4 cycles of BEBT-908 will receive 2 to 4 cycles of CHOP (as determined by the investigator based on individual assessment); participants achieving partial response (PR) or stable disease (SD) after 4 cycles of BEBT-908 will receive 6 cycles of CHOP.

Upon completion of treatment in each cohort, participants without PD may continue receiving BEBT-908 (18.5 mg/m²) and enter a maintenance treatment phase for up to 24 months. Participants who are in CR will continue BEBT-908 treatment (the preferred approach is to maintain the original BEBT-908 dosing schedule; however, based on participant preference and investigator assessment, the dosing frequency may be reduced). Participants who are in SD or PR will also continue BEBT-908 treatment.

Expansion Phase: Based on the efficacy and safety results from the Exploration Phase, the investigator and sponsor will jointly select one optimal cohort to proceed into the Expansion Phase. This phase uses an open-label, multicenter, randomized controlled design, with stratification by pathological subtype: angioimmunoblastic T-cell lymphoma (AITL) vs. non-AITL. About 60 eligible participants will be randomized in a 1:1 ratio to either the experimental arm or the control arm. Participants in the experimental arm will receive the dosing regimen of the optimal cohort identified in the Exploration Phase; Participants in the control arm will receive 6 cycles of CHOP.

Participants enrolled in both the Exploration Phase and the Expansion Phase will go through three study periods: the screening period, the treatment period, and the follow-up period.

Participants will:

Receive study treatment according to their assigned cohort regimen for a maximum duration of 24 months; Undergo periodic tumor assessments and safety evaluations during the study.

Inclusion Criteria:

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Participants must meet all of the following inclusion criteria:

1. Participants must fully understand the study and voluntarily sign an informed consent form (ICF).
2. Age 18 to 75 years (inclusive), either sex.
3. Histologically confirmed peripheral T-cell lymphoma (PTCL), including not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL) deemed by the investigator to be ineligible for or unable to receive anti-CD30 monoclonal antibody therapy (e.g., brentuximab vedotin) due to economic burden or intolerable toxicity (if ALK-positive, International Prognostic Index [IPI] score must be ≥2), subcutaneous panniculitis-like T-cell lymphoma (SPTCL), enteropathy-associated T-cell lymphoma (EATL), hepatosplenic T-cell lymphoma (HSTL), and other T-cell lymphomas deemed appropriate for enrollment by the investigator.
4. No prior systemic anti-PTCL therapy.
5. Life expectancy >6 months.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
7. At least one measurable and evaluable tumor lesion (per Lugano 2014 criteria: nodal lesions must have a longest diameter >1.5 cm; extranodal lesions must have a longest diameter >1.0 cm).
8. At screening, laboratory parameters must meet the following standards, unless the investigator determines the abnormality is due to lymphoma (with no corrective or supportive treatment for the following parameters within 2 weeks prior to assessment):

Peripheral Blood: a) Absolute Neutrophil Count (ANC) ≥1.5×10⁹/L (≥1.0×10⁹/L for patients with bone marrow involvement); b) White Blood Cell count (WBC) ≥3.0×10⁹/L (≥2.0×10⁹/L for patients with bone marrow involvement); c) Hemoglobin (HGB) ≥80 g/L; d) Platelet count (PLT) ≥75×10⁹/L (≥50×10⁹/L for patients with bone marrow involvement).

Hepatic and Renal Function: a) Serum total bilirubin ≤1.5×Upper Limit of Normal (ULN) (≤3.0×ULN for patients with liver involvement); b) Serum creatinine <1.5×ULN; c) Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤2.5×ULN, or ≤5×ULN if the investigator determines the elevation is due to hepatic infiltration.

Exclusion Criteria:

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Participants who meet any of the following exclusion criteria are not eligible for enrollment:

1. History or current diagnosis of immune thrombocytopenia, autoimmune hemolytic anemia, aplastic anemia, or other primary or secondary hematologic disorders that may affect bone marrow function, other than the primary malignancy.

2. Receipt of transfusion, recombinant human thrombopoietin (rhTPO), erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), or similar treatments within 2 weeks prior to the first dose of study drug.

3. Active bleeding within 2 months prior to the first dose, or current use of anticoagulant medications (e.g., warfarin, phenprocoumon), or evidence of a clear bleeding tendency as determined by the investigator (e.g., esophageal varices at risk of bleeding, active localized ulcerative lesions, fecal occult blood >2+), except for bleeding attributed by the investigator to lymphoma itself (e.g., gastrointestinal bleeding caused by gastrointestinal lymphoma).

4. Participation in another interventional clinical trial within 3 months prior to the first dose.

5. PTCL with involvement of special sites such as testis, breast, or ovary; extranodal natural killer/T-cell lymphoma (ENKTL); cutaneous T-cell lymphoma (except subcutaneous panniculitis-like T-cell lymphoma [SPTCL]); or concurrent hemophagocytic lymphohistiocytosis (HLH).

6. Receipt of the following treatments within 7 days prior to study entry: drugs known to be strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers, or drugs known to significantly prolong the QT interval.

7. Major surgery requiring general anesthesia within 4 weeks prior to enrollment, or surgery requiring local/epidural anesthesia within 2 weeks prior to enrollment with incomplete recovery (excluding bone marrow biopsy or local lymphoid tissue biopsy).

8. Active infection requiring systemic treatment (oral or intravenous) within 2 weeks prior to the first dose, or imaging findings suggestive of interstitial lung disease (ILD), pulmonary fibrosis, or pneumonia (infectious or non-infectious) requiring treatment: participants receiving prophylactic antibiotic therapy (e.g., for interstitial pneumonia) are eligible for enrollment; participants with patchy changes from old or previously treated lesions, determined by the investigator to not affect lung function and not require treatment, are eligible for enrollment.

9. Corticosteroid use >30 mg/day prednisone or equivalent for purposes other than lymphoma symptom control; the following permitted scenarios must meet corresponding requirements:

   If currently receiving corticosteroid therapy at ≤30 mg/day prednisone or equivalent, documented evidence of stable dosing for at least 4 weeks prior to initiation of study drug is required.

   If urgent corticosteroid therapy is needed prior to the first dose to control lymphoma symptoms, prednisone up to 100 mg/day or equivalent may be used for a maximum of 7 days; however, all tumor assessments must be completed before initiation of corticosteroid therapy.

10. Mean corrected QT interval (QTc) >450 msec (male) or >470 msec (female) derived from 3 electrocardiogram (ECG) recordings at rest (repeat testing and averaging of 3 corrected values is required only when the first ECG indicates QTc >450 msec [male] or >470 msec [female]); history of long QT syndrome or confirmed family history of long QT syndrome; history of clinically significant ventricular arrhythmia, or current use of antiarrhythmic drugs or implanted defibrillator for treatment of ventricular arrhythmia.

11. Inability to discontinue during the study period medications that may cause QT prolongation (e.g., antiarrhythmic drugs).

12. Tumor invasion of surrounding vital organs or vessels (e.g., heart and pericardium, trachea, esophagus, aorta, superior vena cava) with risk of bleeding, or risk of esophagotracheal fistula or esophagopleural fistula.

13. Participants with clinically symptomatic pleural effusion, ascites, or pericardial effusion that remains poorly controlled despite repeated treatment.

14. Comorbid conditions: a) Cerebrovascular accident within 6 months prior to the first dose, or history of deep vein thrombosis (DVT), arterial thrombosis, or pulmonary embolism (PE). b) History of other malignancy within 3 years prior to enrollment that does not meet criteria for clinical cure. Exceptions: locally treatable and cured basal cell carcinoma or squamous cell carcinoma of the skin, superficial bladder cancer, cervical carcinoma in situ, ductal carcinoma in situ of the breast, and papillary thyroid carcinoma. c) Concurrent central nervous system (CNS) lymphoma or meningeal involvement, or history of or current CNS disorders including but not limited to: epilepsy, paralysis, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome. d) Poorly controlled diabetes mellitus (random blood glucose ≥11.1 mmol/L despite anti-diabetic treatment, or glycated hemoglobin [HbA1c] ≥8.5%). e) Uncontrolled hypertension [systolic blood pressure (SBP) ≥160 mmHg and/or diastolic blood pressure (DBP) ≥100 mmHg despite standard treatment, or history of hypertensive crisis or, hypertensive encephalopathy, or history of cerebrovascular accident]. f) Significant cardiac disease [including any of the following: 1) congestive heart failure above NYHA Class II (i.e., Class III or IV), unstable angina, symptomatic pericarditis, or myocardial infarction within 6 months prior to the first dose of study drug; 2) arrhythmia requiring treatment, or left ventricular ejection fraction (LVEF) <50% at screening; 3) primary cardiomyopathy (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, unclassified cardiomyopathy); 4) symptomatic coronary artery disease requiring medication at screening; 5) other cardiovascular diseases deemed by the investigator as inappropriate for enrollment]. g) Significant renal or hepatic dysfunction. h) Uncontrolled active hepatitis B or hepatitis C disease [clinically significant active infections including hepatitis B virus (HBV) and hepatitis C virus (HCV). Active hepatitis B is defined as: hepatitis B surface antigen (HBsAg) or hepatitis B e antigen (HBeAg) positive with HBV DNA ≥2000 IU/mL (equivalent to 10⁴ copies/mL); (if HBsAg or HBeAg positive with HBV DNA <2000 IU/mL, per infectious disease control requirements, the participant must continue entecavir until one year after study completion or as recommended by an infectious disease specialist). Active hepatitis C is defined as: HCV RNA above the lower limit of quantification]. i) Human immunodeficiency virus (HIV) positive or syphilis (anti-treponemal antibody [Anti-TP]) positive. j) History of immunodeficiency, including other acquired or congenital immunodeficiency disorders, or history of organ transplantation. k) History of psychiatric disorder, family history of psychiatric disorder, or mood disorder as determined by the investigator or psychologist [including medical records of depressive episodes, bipolar disorder (Type I or II), obsessive-compulsive disorder, schizophrenia, history of suicide attempt or suicidal ideation, or homicidal ideation (immediate risk of harm to others), or anxiety grade 3 or above, etc.].

15. Known severe hypersensitivity to BEBT-908 for injection or any component of CHOP regimen or any excipient in their formulations.

16. Female participants who are pregnant or breastfeeding, or participants who cannot guarantee use of contraceptive measures during the study and for at least 6 months after the last dose of study drug.

17. Any unstable condition or condition that may jeopardize participant safety or compliance with the study, as determined by the investigator.

18. Participants deemed by the investigator as unsuitable for treatment under this protocol.