Reverse Triple Negative Immune Resistant Breast Cancer

Study Overview
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Brief Summary
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This is a Phase II, open-label, three-arm parallel study evaluating the efficacy and safety of combined treatment (sodium cromoglicate, choline, or efavirenz) with immune checkpoint inhibitor in mTNBC (triple negative breast cancer) patients who progressed during previous immune checkpoint inhibitors.

Detailed Description
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This is a Phase II, open-label, three-arm parallel study evaluating the efficacy and safety of combined treatment (sodium cromoglicate, choline, or efavirenz) with immune checkpoint inhibitors in metastatic TNBC (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 TMAO, choline, and efavirenz play a potentially important role in regulating the tumor immune microenvironment. Oral choline can improve TMAO content in mouse serum, play the role of activating anti-tumor immunity, and improve immunotherapy efficacy. Preclinical studies of our center also show that sodium cromoglicate can enhance the anti-tumor immune response by inhibiting the activation of mast cells, increase the infiltration and function of cytotoxic CD8+ T cells, inhibit the growth of tumors in mice, and enhance the efficacy of PD-1 inhibitors in mice. Furthermore, another preclinical study of our center shows that efavirenz can enhance the anti-tumor immune response by inhibiting the retrotransposon of LINE-1 and decreasing intratumor heterogeneity. The combination of efavirenz and PD-1 inhibitors effectively inhibits tumor growth 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 sodium cromoglicate, choline, or efavirenz combined with immunotherapy at a clinical level, providing new strategies of combined treatment for TNBC patients.

Official Title
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Reverse Triple Negative Immune Resistant Breast Cancer

Conditions
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Triple-negative Breast Cancer

Intervention / Treatment
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* Drug: Choline
* Drug: anti-PD-1 antibody and chemotherapy
* Drug: Sodium Cromoglicate
* Drug: Efavirenz


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Choline<br>Choline with anti-PD-1 immunotherapy | Drug: Choline<br>* Choline 300mg tid or 500mg bid, p.o<br>Drug: anti-PD-1 antibody and chemotherapy<br>* PD-1 antibody SHR1210 200mg q2w chemotherapy (whether and which should be given depends on the treatment regimen before enrollment)<br>|
| Experimental: Sodium cromoglicate<br>Sodium cromoglicate with anti-PD-1 immunotherapy | Drug: anti-PD-1 antibody and chemotherapy<br>* PD-1 antibody SHR1210 200mg q2w chemotherapy (whether and which should be given depends on the treatment regimen before enrollment)<br>Drug: Sodium Cromoglicate<br>* Sodium Cromoglicate will be administered intranasally (nasal spray) (5 spray each nostril 4 times a day, 1 mg/spray)<br>|
| Experimental: Efavirenz<br>Efavirenz with anti-PD-1 immunotherapy | Drug: anti-PD-1 antibody and chemotherapy<br>* PD-1 antibody SHR1210 200mg q2w chemotherapy (whether and which should be given depends on the treatment regimen before enrollment)<br>Drug: Efavirenz<br>* Efavirenz 600mg qd, p.o<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) |  | Baseline through end of study, assessed up to 6 months | 
| Progression Free Survival (PFS) |  | Randomization to death from any cause, through the end of study,assessed up to 6 months | 
| Safety and treatment-related AEs |  | Randomization to death from any cause, through the end of study,assessed up to 12 months | 
| Biomarker analysis1 | Mast cell function will be measured in pretreatment tissues to predict therapy response. | Baseline until disease progression or loss of clinical benefit, assessed up to 6 months | 
| Biomarker analysis2 | The expression of ZNF689 will be measured in pretreatment tissues to predict therapy response. | Baseline until disease progression or loss of clinical benefit, assessed up to 6 months | 
| Biomarker analysis3 | Before and after treatment, DNA and RNA were extracted from the tissues to detect the copy number and mRNA expression of long interspersed element-1 (LINE-1). | Baseline until disease progression or loss of clinical benefit, assessed up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TNBC, molecular subtype, precision Treatment, immunotherapy, choline, sodium cromoglicate, efavirenz