Reverse Triple Negative Immune Resistant Breast Cancer

Overview

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.

Detailed description

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.

Interventions

• Drug Choline
  Choline 300mg tid or 500mg bid, p.o
• Drug 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)
• Drug Sodium Cromoglicate
  Sodium Cromoglicate will be administered intranasally (nasal spray) (5 spray each nostril 4 times a day, 1 mg/spray)
• Drug Efavirenz
  Efavirenz 600mg qd, p.o
• Drug SHR-A1811
  4.8mg/kg q3w
• Drug SHR-A2102
  6mg/kg q3w
• Drug SHR-1316
  1200mg q3w
• Drug Mecapegfilgrastim
  Mecapegfilgrastim, 6mg, d3, q3w, s.c.
• Drug AK131
  AK131, 40mg/kg i.v., q2w
• Drug Theophylline
  Theophylline, 100mg bid, p.o.

Primary outcome measures

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

Secondary outcome measures (6)

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

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Fudan University Shanghai Cancer Center — Shanghai

Publications

• 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

Identifiers

NCT: NCT05076682 · 2107239-9

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗