Clinical Study of XNW5004 Tablets in the Treatment of Relapsed and Refractory Follicular Lymphoma

Summary

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.

Eligibility

Inclusion Criteria:

1. Age ≥ 18 years; no gender restriction.
2. Histologically confirmed follicular lymphoma (FL) grade 1-3a (classic FL per WHO 2022 classification) with wild-type EZH2, as assessed at the study site.
3. 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.
4. Prior radiotherapy is permitted; radiotherapy alone is not considered a systemic therapy.
5. Availability of sufficient biological samples for EZH2 mutation testing.
6. 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.
7. Life expectancy ≥12 weeks.
8. ECOG performance status 0 or 1.

   Adequate organ function:

   Hematologic function:
9. 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.
10. 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.
11. Signed and dated written informed consent prior to any study-specific procedures, and ability to comply with study visits and protocol-required assessments.

Exclusion Criteria:

1. Follicular lymphoma grade 3b, mixed histology, potential for transformation, or documented histologic transformation.
2. Prior treatment with an EZH2 inhibitor or EZH1/2 inhibitor (including but not limited to tazemetostat).
3. Known hypersensitivity to the investigational product, its active ingredients, or excipients.
4. Received chemotherapy, immunotherapy, radiotherapy, targeted therapy, antitumor traditional Chinese medicine, or other antitumor therapy within 4 weeks or 5 half-lives (whichever is shorter) prior to the first dose; received CAR-T therapy within 12 weeks prior to the first dose; underwent autologous hematopoietic stem cell transplantation (auto-HSCT) within 3 months prior to the first dose.
5. Received investigational antitemporal agents not approved in China within 28 days prior to initiation of study treatment.
6. Underwent major surgery within 4 weeks prior to initiation of study treatment, or planning major surgery during the study period (excluding procedures such as puncture or lymph node biopsy).
7. Prior allogeneic hematopoietic stem cell transplantation or solid organ transplantation.
8. Disease requiring systemic therapy with corticosteroids (\> 10 mg prednisone daily or equivalent) or other immunosuppressive agents within 14 days prior to study drug administration. Inhaled or topical steroids and adrenal replacement therapy with ≤ 10 mg prednisone daily or equivalent are permitted in the absence of active autoimmune disease.
9. Received moderate or strong CYP3A4 inhibitors/inducers within 14 days prior to the first dose (see Appendix 4 for details).
10. Received live or live-attenuated viral vaccines within 28 days prior to dosing. Inactivated vaccines are permitted.
11. History of psychoactive substance abuse or drug addiction (except for insomnia with stable, long-term therapy as assessed by the investigator).
12. Toxicities from prior antitumor therapy not recovered to ≤ Grade 1 per NCI-CTCAE version 5.0, except for toxicities deemed by the investigator not to affect patient safety evaluation (e.g., alopecia).
13. History of another malignancy within 3 years prior to enrollment that does not meet criteria for clinical cure, except for adequately treated and cured basal cell carcinoma or squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast, and papillary thyroid carcinoma.
14. Previous or current central nervous system involvement by lymphoma.
15. Previous or current testicular or breast involvement by lymphoma.
16. Previous or current hemophagocytic lymphohistiocytosis.
17. Previous or current primary or secondary hematologic disorders other than the primary malignant neoplasm that may affect bone marrow function, including immune thrombocytopenia, autoimmune hemolytic anemia, and aplastic anemia.
18. Previous or current acute myeloid leukemia (AML).
19. Previous or current T-lymphoblastic lymphoma (T-LBL) or T-lymphoblastic leukemia (T-ALL).
20. History of any myeloid malignancy, including myelodysplastic syndrome (MDS), or abnormal laboratory findings associated with MDS or myeloproliferative neoplasms (MPN).
21. Previous or current central nervous system disorders including, but not limited to: epilepsy, paralysis, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis, etc. (excluding stroke with adequate treatment and stable disease for ≥12 months before first dose, or asymptomatic lacunar infarction not requiring treatment).
22. Impaired cardiac function or clinically significant cardiac disease, including any of the following:

    Acute myocardial infarction within 12 months prior to first dose; Unstable angina; Congestive heart failure (NYHA Class III or IV, see Appendix 5); Uncontrolled serious arrhythmia, hypertension ≥ 150/100 mmHg; Prolonged QTcF interval (\> 450 ms in males, \> 470 ms in females) calculated by Fredericia's formula (see Appendix 6); History of other major cardiovascular disease (e.g., valve replacement, coronary artery bypass grafting, etc.).
23. Tumor invasion of adjacent vital organs, gastrointestinal tract, or blood vessels (e.g., heart and pericardium, trachea, esophagus, aorta, superior vena cava) with risk of hemorrhage, or risk of esophagotracheal fistula, esophagopleural fistula, gastrointestinal perforation, etc.
24. Clinically symptomatic pleural effusion, ascites, or pericardial effusion poorly controlled despite repeated treatment.
25. Unexplained fever with body temperature \> 38.0 °C (including tumor fever); body temperature must be within normal range for 2 weeks prior to first dose.
26. Systemic active severe infection: at least 2 weeks washout after completion of antifungal therapy (intravenous or oral), at least 1 week washout after completion of other intravenous antimicrobial therapy, and oral antimicrobial therapy must be discontinued prior to first dose.
27. History of tuberculosis infection within 1 year prior to enrollment, or history of active tuberculosis infection more than 1 year prior without adequate anti-tuberculosis treatment.
28. Positive HIV test or positive syphilis (Anti-TP) test (patients with negative non-treponemal test and syphilis deemed cured by the investigator are not excluded).
29. Positive HBsAg with HBV-DNA above the lower limit of detection, or anti-HBc positive with HBV-DNA above the lower limit of detection; positive HCV antibody with HCV-RNA above the lower limit of detection.
30. Inability to swallow, or active gastrointestinal inflammation, chronic diarrhea, known diverticular disease, or history of gastrectomy, gastric banding, or other conditions affecting drug absorption. Proton pump inhibitor-treated gastroesophageal reflux is permitted if no potential drug-drug interaction exists.
31. Known bleeding disorders such as von Willebrand disease or hemophilia.
32. Female patients who are pregnant or breastfeeding.
33. Patients who may be unable to complete the study for any other reason, or whom the investigator deems ineligible for enrollment.

Conditions5

Interventions1

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