Triple-negative Breast Cancer
Conditions
Keywords
TNBC, molecular subtype, precision Treatment, immunotherapy, choline, sodium cromoglicate, efavirenz
Brief summary
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
DRUGCholine
Choline 300mg tid or 500mg bid, p.o
PD-1 antibody SHR1210 200mg q2w chemotherapy (whether and which should be given depends on the treatment regimen before enrollment)
DRUGSodium Cromoglicate
Sodium Cromoglicate will be administered intranasally (nasal spray) (5 spray each nostril 4 times a day, 1 mg/spray)
DRUGEfavirenz
Efavirenz 600mg qd, p.o
DRUGSHR-A1811
4.8mg/kg q3w
DRUGSHR-A2102
6mg/kg q3w
DRUGSHR-1316
1200mg q3w
Mecapegfilgrastim, 6mg, d3, q3w, s.c.
DRUGAK131
AK131, 40mg/kg i.v., q2w
DRUGTheophylline
Theophylline, 100mg bid, p.o.
Sponsors
Fudan University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Objective Response Rate (ORR) | Baseline until disease progression or loss of clinical benefit, assessed up to 6 months |
| Immune changes in peripheral blood | Baseline until disease progression or loss of clinical benefit, assessed up to 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and treatment-related AEs | Randomization to death from any cause, through the end of study,assessed up to 12 months | — |
| Biomarker analysis1 | Baseline until disease progression or loss of clinical benefit, assessed up to 6 months | Mast cell function will be measured in pretreatment tissues to predict therapy response. |
| Disease Control Rate (DCR) | Baseline through end of study, assessed up to 6 months | — |
| Biomarker analysis3 | Baseline until disease progression or loss of clinical benefit, assessed up to 6 months | The quantity and function of innate lympoid cells will be measured in tissues and/or peripheral blood before and after treatment |
| Biomarker analysis2 | Baseline until disease progression or loss of clinical benefit, assessed up to 6 months | Immunohistochemical staining of pre- and post-treatment tissue sections was carried out to evaluate PD-L1 expression, mast cell function, innate lymphoid cell porprotion and activity, and overall inflammatory status |
| Progression Free Survival (PFS) | Randomization to death from any cause, through the end of study,assessed up to 6 months | — |
Countries
China
Contacts
Primary ContactZhimin Shao, Professor
Backup ContactZhonghua Wang, Professor
Outcome results
None listed