SYST-06. PHASE II TRIAL OF PAXALISIB (GDC-0084) IN COMBINATION WITH TRASTUZUMAB FOR PATIENTS WITH HER2-POSITIVE BREAST CANCER BRAIN METASTASES (BCBM)

Abstract BACKGROUND The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. Paxalisib is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. METHODS This is a single-center, phase II study to evaluate the efficacy of the combination of paxalisib with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive paxalisib (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to paxalisib/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha <10%. Cohort B will enroll 10 patients. The trial opened in February, 2019 and 8 patients have been enrolled. NCT03765983.

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TRLS-03. PHASE II TRIAL OF GDC-0084 IN COMBINATION WITH TRASTUZUMAB FOR PATIENTS WITH HER2-POSITIVE BREAST CANCER BRAIN METASTASES (BCBM)

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.036 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i9-i9

Author(s):

Jose Pablo Leone ◽

Lorenzo Trippa ◽

Lindsey Milisits ◽

Chelsea Andrews ◽

Jennifer Ligibel ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Phase Ii ◽

Primary Endpoint ◽

Cns Metastases ◽

Her2 Positive ◽

Two Stage ◽

Her2 Positive Breast Cancer ◽

Cns Metastasis ◽

Positive Breast Cancer

Abstract BACKGROUND: The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. GDC-0084 is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. METHODS: This is a single-center, phase II study to evaluate the efficacy of the combination of GDC-0084 with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive GDC-0084 (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to GDC-0084/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha < 10%. Cohort B will enroll 10 patients. The trial opened in February, 2019. NCT03765983.

Download Full-text