Phase II Study of XNW5004 in the Treatment of Patients With Relapsed or Refractory Follicular Lymphoma (EZH2 Wild-type)
This is a single-arm, open-label, multicenter Phase II clinical study designed to enroll 65 subjects with relapsed or refractory follicular lymphoma (EZH2 wild-type). The study procedures include a pre-screening phase, screening phase, treatment phase, and follow-up phase.Eligible subjects will enter the treatment phase and receive 1200 mg of XNW5004 tablets twice daily, with a 10-14-hour interval between doses. Each treatment cycle consists of 28 consecutive days of dosing, and pharmacokinetic (PK) blood samples will be collected at the designated time points.Safety assessments and quality-of-life (QoL) assessments will be performed in accordance with the study follow-up schedule.Tumor assessments will be conducted every 8 weeks (every 2 cycles) for the first 48 weeks after the first dose (Cycles 1 to 12), and every 12 weeks (every 3 cycles) thereafter (from Cycle 13 onward).Subjects who discontinue treatment must complete an end-of-treatment visit and safety follow-up. For long-term follow-up:Subjects who terminate treatment for reasons other than disease progression and do not initiate new antineoplastic therapy will continue tumor assessments per the original schedule until disease progression, initiation of new antineoplastic therapy, withdrawal of informed consent, loss to follow-up, or death, whichever occurs first.For all patients (excluding those who withdraw informed consent, are lost to follow-up, or die), survival follow-up will be performed every 12 weeks (±7 days) starting from the date of the last tumor assessment, until withdrawal of informed consent, loss to follow-up, or death, whichever occurs first.
• Age ≥ 18 years; no gender restriction.
• Histologically confirmed follicular lymphoma (FL) grade 1-3a (classic FL per WHO 2022 classification) with wild-type EZH2, as assessed at the study site.
• Relapsed or refractory disease following at least 3 prior lines of systemic therapy, including at least one line with adequate treatment using a commercially available anti-CD20 monoclonal antibody and at least one line with adequate treatment using a novel agent (including but not limited to PI3K inhibitors, CD3×CD20 bispecific antibodies, BTK inhibitors, etc.):
• Adequate anti-CD20 mAb treatment: at least 4 cycles of continuous therapy or disease progression during treatment; subjects not meeting this criterion may be included only with a valid justification (e.g., intolerance).
• Adequate novel agent treatment: failure to achieve response, disease progression during treatment, or treatment discontinuation due to intolerance (intolerance defined as meeting treatment discontinuation criteria per the package insert).
• Relapsed disease: relapse ≥6 months after achieving response to any line of therapy.
• Refractory disease, defined by any of the following:
• Response duration \<6 months and ineligible for or unwilling to undergo autologous hematopoietic stem cell transplantation (auto-HSCT); Failure to achieve response after at least 4 cycles of treatment; Best response or treatment discontinuation due to progressive disease, regardless of number of cycles; Relapse after auto-HSCT.
• Prior radiotherapy is permitted; radiotherapy alone is not considered a systemic therapy.
• Availability of sufficient biological samples for EZH2 mutation testing.
• At least one measurable lesion: nodal lesion with longest diameter \>1.5 cm; extranodal lesion with longest diameter \>1.0 cm and FDG-PET positive.
• Life expectancy ≥12 weeks.
• ECOG performance status 0 or 1.
• Adequate organ function:
• Hematologic function:
• Absolute neutrophil count (ANC) ≥1.5×10⁹/L (≥1.0×10⁹/L if bone marrow involvement); no G-CSF within 1 week or long-acting G-CSF within 2 weeks before screening CBC.
• Platelets ≥90×10⁹/L (≥75×10⁹/L if bone marrow involvement); no platelet transfusion or TPO receptor agonist within 1 week before screening CBC.
• Hemoglobin ≥90 g/L (≥80 g/L if bone marrow involvement); no red blood cell transfusion or EPO within 1 week before screening CBC.
• Hepatic function:
• Total bilirubin ≤1.5×ULN (≤3×ULN for Gilbert's syndrome); ALT and AST ≤2.5×ULN; ≤5×ULN with liver involvement; ALP ≤5×ULN with liver and/or bone involvement.
• Renal function:
• Serum creatinine ≤1.5×ULN or estimated creatinine clearance ≥60 mL/min by Cockcroft-Gault equation.
• Left ventricular ejection fraction (LVEF) ≥50%. INR ≤1.5×ULN, or PT and APTT ≤1.5×ULN.
⁃ Women of childbearing potential must have a negative serum pregnancy test at study entry and agree to use highly effective contraception from study start until at least 6 months after last dose of study drug.
⁃ Non-childbearing potential is defined as:
⁃ Amenorrhea ≥12 months with confirmation of menopausal status by hormonal testing and specialist assessment; OR Bilateral oophorectomy, hysterectomy, or tubal ligation ≥6 weeks before screening.
⁃ Male subjects must agree to use effective contraception and refrain from sperm donation from study start until at least 6 months after last dose of study drug.
⁃ Signed and dated written informed consent prior to any study-specific procedures, and ability to comply with study visits and protocol-required assessments.