Tocilizumab for the Treatment of Refractory Granulomatous Lobular Mastitis

Efficacy and Safety of Tocilizumab in the Treatment of Refractory Granulomatous Lobular Mastitis: A Two-Center, Single-Arm Clinical Trial

Non-Lactational Granulomatous Lobular Mastitis (NL-GLM) is an inflammatory disease of unknown etiology, characterized clinically by local breast masses, accompanied by redness and swelling of the overlying skin, sinus tract formation, and other symptoms. Currently, there is no universally accepted standard treatment for this condition; previous expert consensus or practice guidelines have mostly recommended systemic glucocorticoid therapy as the primary treatment approach. Our team's preliminary research has confirmed that local glucocorticoid injection achieves efficacy equivalent to systemic administration but with better safety, making it a first-line treatment option for NL-GLM. However, in our preliminary studies and literature reports, we found that some patients still exhibit glucocorticoid dependence or resistance (i.e., refractory NL-GLM) after receiving either local or systemic glucocorticoid therapy. The lack of high-quality evidence to support subsequent-line treatments has become a major bottleneck in clinical management. Additionally, some patients cannot tolerate glucocorticoid therapy due to its adverse effects. Research has shown that the IL-6 inflammatory pathway is significantly activated in the lesion tissues and peripheral blood of NL-GLM patients, and the IL-6 inhibitor tocilizumab has demonstrated efficacy in various autoimmune diseases. Based on this, this study intends to conduct a dual-center, single-arm clinical trial to systematically evaluate the efficacy and safety of tocilizumab in the treatment of refractory NL-GLM. The aim is to fill the treatment gap, provide high-level evidence for clinical practice, and ultimately improve patient outcomes.

Inclusion Criteria:

1. Females aged 20 to 50 years;
2. Clinically diagnosed (combined with pathology) with non-lactational granulomatous mastitis (cessation of lactation for more than 6 months);
3. M-Activity-Score ≥ 2;
4. Steroid-refractory NL-GLM or intolerant to steroid therapy.
5. Female subjects of childbearing potential agree to use highly effective contraception starting at least 7 days before the first dose until 16 weeks after dosing. Pregnancy tests for female subjects of childbearing potential must be negative within 7 days before the first dose.

Exclusion Criteria:

1. Bilateral mastitis occurring simultaneously or sequentially within six months.

2. Clinical diagnosis (combined with pathological findings) of periductal mastitis.

3. History of lymphoproliferative disorder; or presence of signs or symptoms suggestive of a possible lymphoproliferative disorder (including lymphadenopathy or splenomegaly); or active primary or recurrent malignancy; or clinically significant malignancy with a remission duration of less than 5 years.

   1. Patients with carcinoma in situ of the cervix may participate if successfully treated with no evidence of recurrence or metastasis for at least 3 years.
   2. Patients with basal cell or squamous cell carcinoma of the skin may participate if successfully treated with no evidence of recurrence for at least 3 years.

4. Patients who are pregnant.

5. Current or recent severe viral, bacterial, fungal, or parasitic infection, including but not limited to:

   1. Symptomatic herpes zoster infection within 12 weeks prior to screening.
   2. History of disseminated/complicated herpes zoster (e.g., multidermatomal involvement, herpes zoster ophthalmicus, CNS involvement, or postherpetic neuralgia).
   3. Symptomatic herpes simplex at the time of enrollment.
   4. Active or chronic infection with hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV).
   5. Household contact with an individual with active tuberculosis (TB) and not having received appropriate and documented TB prophylaxis.
   6. Evidence of active TB, or history of active TB without appropriate and documented treatment.
   7. Clinically significant infection within 4 weeks prior to enrollment, or having received intravenous antibiotic therapy for an infection.
   8. Any other active or recent infection within 4 weeks prior to enrollment that, in the investigator's judgment, would pose an unacceptable risk to the patient.

   Note: Recent viral upper respiratory tract infections or uncomplicated urinary tract infections should not be considered clinically significant.

6. Patients with hepatic or renal insufficiency, gastrointestinal ulcer, active hepatitis, active rheumatic autoimmune disease, active tuberculosis, or poorly controlled psychiatric disorders.

7. Cardiac, pulmonary, hepatic, renal, or coagulation dysfunction that, in the investigator's judgment, makes the patient unsuitable for enrollment.

8. History of hypersensitivity to tocilizumab.

9. Previous treatment with tocilizumab (a single prior dose may be exempted upon investigator's assessment).

10. Any major surgery within 8 weeks prior to screening, or requirement for major surgery during the study period, which, in the investigator's judgment, would pose an unacceptable risk to the patient.

11. Presence of the following laboratory abnormalities, or any other laboratory value outside the reference range deemed by the investigator to pose an unacceptable risk for participation:

    1. AST or ALT ≥ 2 × upper limit of normal (ULN)
    2. Alkaline phosphatase (ALP) ≥ 2 × ULN
    3. Total bilirubin (TBL) ≥ 1.5 × ULN
    4. Hemoglobin < 9.0 g/dL
    5. Total white blood cell count < 2.5 × 10⁹ cells/L
    6. Neutropenia (absolute neutrophil count [ANC] < 1.2 × 10⁹ cells/L)
    7. Lymphopenia (lymphocyte count < 0.75 × 10⁹ cells/L)
    8. Thrombocytopenia (platelets < 100 × 10⁹/L)
    9. Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m² (based on the CKD-EPI equation) Note: The above abnormalities may be retested during the screening period, with eligibility determined based on the retest results.

12. Administration of a live or attenuated vaccine within 6 weeks prior to the first dose, or planned administration during the treatment period or within 6 weeks after the last dose.

13. Body weight ≥ 100 kg.