Clinical trial NCT05076682: Reverse Triple Negative Immune Resistant Breast Cancer
Official title: Reverse Triple Negative Immune Resistant Breast Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Triple-negative Breast Cancer
Keywords: TNBC
molecular subtype
precision Treatment
immunotherapy
choline
sodium cromoglicate
efavirenz
Lead sponsor: Fudan University
Sponsor class: OTHER
First posted: 2021-10-13
Enrollment: 30
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

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

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
measure: Immune changes in peripheral blood
timeFrame: Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
Secondary outcomes:
measure: Disease Control Rate (DCR)
timeFrame: Baseline through end of study, assessed up to 6 months
measure: Progression Free Survival (PFS)
timeFrame: Randomization to death from any cause, through the end of study,assessed up to 6 months
measure: Safety and treatment-related AEs
timeFrame: Randomization to death from any cause, through the end of study,assessed up to 12 months
measure: Biomarker analysis1
timeFrame: Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
measure: Biomarker analysis2
timeFrame: Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
measure: Biomarker analysis3
timeFrame: Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
Study officials:
affiliation: Fudan U
name: Zhimin Shao, Professor
role: PRINCIPAL_INVESTIGATOR
References: