Adaptive cohort design and LAT1 expression scale: study protocol for a Phase 2a trial of QBS72S in breast cancer brain metastases
Abstract Background Breast cancer is the most common cause of cancer death among women and frequently metastasizes to the brain. Up to 30% of patients with breast-to-brain metastases will develop leptomeningeal disease (LMD), with poor survival, rapid neurologic decline, and no durable treatment opt...
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BMC
2025-08-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-025-14282-x |
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| author | Rukayat Taiwo Paul M. Harary Thy T. H. Trinh Monica Granucci Sophie Bertrand Brandon Carlson-Clarke Sophia B. Chernikova Kate Therkelsen Mili Arora Michelle E. Melisko Michael Iv Hannes Vogel Summer Han Christine Xie Susie Brain Vivian Lee Krishna L. Bharani Seema Nagpal Melanie Hayden Gephart |
| author_facet | Rukayat Taiwo Paul M. Harary Thy T. H. Trinh Monica Granucci Sophie Bertrand Brandon Carlson-Clarke Sophia B. Chernikova Kate Therkelsen Mili Arora Michelle E. Melisko Michael Iv Hannes Vogel Summer Han Christine Xie Susie Brain Vivian Lee Krishna L. Bharani Seema Nagpal Melanie Hayden Gephart |
| author_sort | Rukayat Taiwo |
| collection | DOAJ |
| description | Abstract Background Breast cancer is the most common cause of cancer death among women and frequently metastasizes to the brain. Up to 30% of patients with breast-to-brain metastases will develop leptomeningeal disease (LMD), with poor survival, rapid neurologic decline, and no durable treatment options. The novel agent QBS72S, also known as QBS10072S, is designed to leverage the high expression of L-type amino acid transporter 1 (LAT1) on breast cancer cells and the blood-brain barrier. By conjugating an amino acid analogue with a DNA alkylating moiety, QBS72S can exploit LAT1 for specific delivery into the brain and metastatic tumor cells. Methods We designed a single-arm, Phase 2a study to test the preliminary efficacy and safety of QBS72S for breast-to-brain metastasis in two distinct cohorts: intraparenchymal metastasis (Cohort 1; no LMD), and LMD (Cohort 2; with or without intraparenchymal metastasis). The primary endpoint is overall response rate across evaluable participants in Cohort 1. Secondary endpoints include progression-free survival, overall survival, duration of response, and treatment-related adverse events in Cohort 1. Exploratory endpoints include correlation of LAT1 expression in formalin-fixed paraffin-embedded samples with treatment response, CSF pharmacokinetics, perfusion MRI, and novel CSF-based biomarkers. Discussion Adaptive clinical trial design enables rapid enrollment and tailored endpoints for patient cohorts with baseline disparate outcomes. Our LAT1 staining protocol will allow ongoing trials in glioblastoma (NCT02977780) and future studies in brain metastases to correlate LAT1 expression to drug efficacy. Our exploratory endpoints may facilitate identification of more rapid and reliable biomarkers of LMD treatment response and resistance. Trial registration ClinicalTrials.gov NCT05305365. |
| format | Article |
| id | doaj-art-c86cde2c2f1a419e82a9e8a14f2e0f48 |
| institution | Kabale University |
| issn | 1471-2407 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj-art-c86cde2c2f1a419e82a9e8a14f2e0f482025-08-20T04:02:55ZengBMCBMC Cancer1471-24072025-08-0125111310.1186/s12885-025-14282-xAdaptive cohort design and LAT1 expression scale: study protocol for a Phase 2a trial of QBS72S in breast cancer brain metastasesRukayat Taiwo0Paul M. Harary1Thy T. H. Trinh2Monica Granucci3Sophie Bertrand4Brandon Carlson-Clarke5Sophia B. Chernikova6Kate Therkelsen7Mili Arora8Michelle E. Melisko9Michael Iv10Hannes Vogel11Summer Han12Christine Xie13Susie Brain14Vivian Lee15Krishna L. Bharani16Seema Nagpal17Melanie Hayden Gephart18Department of Neurosurgery, Stanford University School of Medicine, Stanford Cancer CenterDepartment of Neurosurgery, Stanford University School of Medicine, Stanford Cancer CenterDepartment of Neurosurgery, Stanford University School of Medicine, Stanford Cancer CenterDepartment of Neurosurgery, Stanford University School of Medicine, Stanford Cancer CenterDepartment of Neurosurgery, Stanford University School of Medicine, Stanford Cancer CenterDepartment of Neurosurgery, Stanford University School of Medicine, Stanford Cancer CenterDepartment of Neurosurgery, Stanford University School of Medicine, Stanford Cancer CenterDepartment of Neurology and Neurological Sciences, Stanford Cancer InstituteDivision of Hematology and Oncology, University of California, Davis Comprehensive Cancer Center, University of California, Davis School of MedicineDivision of Hematology/Oncology, Department of Medicine, University of California, San FranciscoDepartment of Radiology, Stanford University School of MedicineDepartment of Pathology, Stanford University School of MedicineQuantitative Sciences Unit, Stanford University School of MedicineDepartment of Neurosurgery, Stanford University School of Medicine, Stanford Cancer CenterPatient Advocate, Komen Advocates in SciencePatient Advocate, Komen Advocates in ScienceDepartment of Pathology, Stanford University School of MedicineDepartment of Neurology and Neurological Sciences, Stanford Cancer InstituteDepartment of Neurosurgery, Stanford University School of Medicine, Stanford Cancer CenterAbstract Background Breast cancer is the most common cause of cancer death among women and frequently metastasizes to the brain. Up to 30% of patients with breast-to-brain metastases will develop leptomeningeal disease (LMD), with poor survival, rapid neurologic decline, and no durable treatment options. The novel agent QBS72S, also known as QBS10072S, is designed to leverage the high expression of L-type amino acid transporter 1 (LAT1) on breast cancer cells and the blood-brain barrier. By conjugating an amino acid analogue with a DNA alkylating moiety, QBS72S can exploit LAT1 for specific delivery into the brain and metastatic tumor cells. Methods We designed a single-arm, Phase 2a study to test the preliminary efficacy and safety of QBS72S for breast-to-brain metastasis in two distinct cohorts: intraparenchymal metastasis (Cohort 1; no LMD), and LMD (Cohort 2; with or without intraparenchymal metastasis). The primary endpoint is overall response rate across evaluable participants in Cohort 1. Secondary endpoints include progression-free survival, overall survival, duration of response, and treatment-related adverse events in Cohort 1. Exploratory endpoints include correlation of LAT1 expression in formalin-fixed paraffin-embedded samples with treatment response, CSF pharmacokinetics, perfusion MRI, and novel CSF-based biomarkers. Discussion Adaptive clinical trial design enables rapid enrollment and tailored endpoints for patient cohorts with baseline disparate outcomes. Our LAT1 staining protocol will allow ongoing trials in glioblastoma (NCT02977780) and future studies in brain metastases to correlate LAT1 expression to drug efficacy. Our exploratory endpoints may facilitate identification of more rapid and reliable biomarkers of LMD treatment response and resistance. Trial registration ClinicalTrials.gov NCT05305365.https://doi.org/10.1186/s12885-025-14282-xBreast cancerLeptomeningeal diseaseChemotherapyExpression profilingLiquid biopsy |
| spellingShingle | Rukayat Taiwo Paul M. Harary Thy T. H. Trinh Monica Granucci Sophie Bertrand Brandon Carlson-Clarke Sophia B. Chernikova Kate Therkelsen Mili Arora Michelle E. Melisko Michael Iv Hannes Vogel Summer Han Christine Xie Susie Brain Vivian Lee Krishna L. Bharani Seema Nagpal Melanie Hayden Gephart Adaptive cohort design and LAT1 expression scale: study protocol for a Phase 2a trial of QBS72S in breast cancer brain metastases BMC Cancer Breast cancer Leptomeningeal disease Chemotherapy Expression profiling Liquid biopsy |
| title | Adaptive cohort design and LAT1 expression scale: study protocol for a Phase 2a trial of QBS72S in breast cancer brain metastases |
| title_full | Adaptive cohort design and LAT1 expression scale: study protocol for a Phase 2a trial of QBS72S in breast cancer brain metastases |
| title_fullStr | Adaptive cohort design and LAT1 expression scale: study protocol for a Phase 2a trial of QBS72S in breast cancer brain metastases |
| title_full_unstemmed | Adaptive cohort design and LAT1 expression scale: study protocol for a Phase 2a trial of QBS72S in breast cancer brain metastases |
| title_short | Adaptive cohort design and LAT1 expression scale: study protocol for a Phase 2a trial of QBS72S in breast cancer brain metastases |
| title_sort | adaptive cohort design and lat1 expression scale study protocol for a phase 2a trial of qbs72s in breast cancer brain metastases |
| topic | Breast cancer Leptomeningeal disease Chemotherapy Expression profiling Liquid biopsy |
| url | https://doi.org/10.1186/s12885-025-14282-x |
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