Reverse Triple Negative Immune Resistant Breast Cancer

Обзор

This is a Phase II, open-label, seven-arm parallel study evaluating the efficacy and safety of combined treatment (sodium cromoglicate, choline, efavirenz, SHR 1811, SHR 2102, mecapegfilgrastim, theophylline) with immune checkpoint inhibitor or immune checkpoint inhibitor rechallenge(AK131) in mTNBC (triple negative breast cancer) patients who progressed during previous immune checkpoint inhibitors.

Подробное описание

This is a Phase II, open-label, three-arm parallel study evaluating the efficacy and safety of combined treatment (sodium cromoglicate, choline, efavirenz, SHR 1811, SHR 2102, mecapegfilgrastim) with immune checkpoint inhibitor or immune checkpoint inhibitor rechallenge(AK131) in mTNBC (triple negative breast cancer) patients who progressed during or following previous immune checkpoint inhibitors. The investigators have achieved a breakthrough in the FUTURE study with an ORR (objective response rate) reaching 52.6% in IM (immunomodulatory) subtype TNBC patients. Despite this, there are still some IM subtype patients resistant to immunotherapy. How to reverse immunotherapy resistance or how to increase the sensitivity of immunotherapy efficacy, has become an urgent clinical problem to be solved. The preclinical results of our center show that sodium cromoglicate, choline, efavirenz, SHR 1811, SHR 2102, mecapegfilgrastim, AK131, theophylline play a potentially important role in regulating the tumor immune microenvironment and can inhibit the growth of tumors in mice, and enhance the efficacy of PD-1 inhibitors in mice. Based on preclinical studies, the investigators designed this study to enroll mTNBC patients who have progressed during or following immunotherapy, and to explore the efficacy of these drugs at a clinical level, providing new strategies of combined treatment for TNBC patients.

Вмешательства

• Препарат Choline
  Choline 300mg tid or 500mg bid, p.o
• Препарат anti-PD-1 antibody and chemotherapy
  PD-1 antibody SHR1210 200mg q2w chemotherapy (whether and which should be given depends on the treatment regimen before enrollment)
• Препарат Sodium Cromoglicate
  Sodium Cromoglicate will be administered intranasally (nasal spray) (5 spray each nostril 4 times a day, 1 mg/spray)
• Препарат Efavirenz
  Efavirenz 600mg qd, p.o
• Препарат SHR-A1811
  4.8mg/kg q3w
• Препарат SHR-A2102
  6mg/kg q3w
• Препарат SHR-1316
  1200mg q3w
• Препарат Mecapegfilgrastim
  Mecapegfilgrastim, 6mg, d3, q3w, s.c.
• Препарат AK131
  AK131, 40mg/kg i.v., q2w
• Препарат Theophylline
  Theophylline, 100mg bid, p.o.

Первичные конечные точки

• Objective Response Rate (ORR) [Срок оценки: Baseline until disease progression or loss of clinical benefit, assessed up to 6 months]
• Immune changes in peripheral blood [Срок оценки: Baseline until disease progression or loss of clinical benefit, assessed up to 6 months]

Вторичные конечные точки (6)

• Disease Control Rate (DCR) [Срок оценки: Baseline through end of study, assessed up to 6 months]
• Progression Free Survival (PFS) [Срок оценки: Randomization to death from any cause, through the end of study,assessed up to 6 months]
• Safety and treatment-related AEs [Срок оценки: Randomization to death from any cause, through the end of study,assessed up to 12 months]
• Biomarker analysis1 [Срок оценки: Baseline until disease progression or loss of clinical benefit, assessed up to 6 months]
• Biomarker analysis2 [Срок оценки: Baseline until disease progression or loss of clinical benefit, assessed up to 6 months]
• Biomarker analysis3 [Срок оценки: Baseline until disease progression or loss of clinical benefit, assessed up to 6 months]

Критерии участия

Критерии включения

• ECOG Performance Status of 0, 1, or 2
• Metastatic or locally advanced, histologically documented TNBC (absence of HER2, ER, and PR expression)
• Radiologic/objective evidence of recurrence or disease progression after immunotherapy(combined with targeted therapy or chemo ) for metastatic breast cancer(MBC)
• Adequate hematologic and end-organ function, laboratory test results, obtained within 14 days prior to initiation of study treatment.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures as outlined for each specific treatment arm
• Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1)
• have the cognitive ability to understand the protocol and be willing to participate and to be followed up.

Критерии исключения

• Symptomatic, untreated, or actively progressing CNS metastases
• Active or history of autoimmune disease or immune deficiency
• Significant cardiovascular disease
• History of malignancy other than breast cancer within 5 years prior to screening, with the exception of those with a negligible risk of metastasis or death
• Treatment with chemotherapy, radiotherapy,immunotherapy or surgery (outpatient clinic surgery excluded) within 3 weeks prior to initiation of study treatment.
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study
• History of allergies to the drug components of this trial
• History of eosinophilosis or mastocytosis
• Patients who have been using oral steroid hormones for a long time will need to stop for 4 weeks if they have used them occasionally in the past
• For the Mecapegfilgrastim group, patients had previously received PEG-rhG-CSF in combination with immunotherapy.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Fudan University Shanghai Cancer Center — Шанхай

Публикации

• Wu SY, Jin X, Liu Y, Wang ZY, Zuo WJ, Ma D, Xiao Y, Fu T, Xiao YL, Chen L, Liu XY, Fan L, Wang ZH, Shen M, Liu R, Chai WJ, Shao ZM, Jiang YZ. Mobilizing antigen-presenting mast cells in anti-PD-1-refractory triple-negative breast cancer: a phase 2 trial. Nat Med. 2025 Jul;31(7):2405-2415. doi: 10.1038/s41591-025-03776-7. Epub 2025 Jun 25. PMID 40563015

Идентификаторы

NCT: NCT05076682 · 2107239-9

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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