Checkpoint inhibitor therapy represents a significant advance in cancer care. The interaction between PD-1 and PD-L1 induces immune tolerance, and the inhibition of this interaction is an effective treatment strategy for numerous malignancies.
Despite its demonstrated potential, immunotherapy is not currently thought to be an effective intervention in the treatment of several immunologically "cold" tumors such as prostate cancer, biliary tract cancers, soft tissue sarcomas, well-differentiated neuroendocrine tumors, microsatellite stable colorectal cancer, pancreatic cancer, and non-triple negative breast cancer.
Vascular endothelial growth factor (VEGF) is thought to play a key role in modulating the anti-tumor immune response. Vascular endothelial growth factor (VEGF) is secreted by tumors and leads to endothelial cell proliferation, vascular permeability, and vasodilation. This in turn leads to the development of an abnormal vasculature with excessive permeability and poor blood flow, limiting immune surveillance. In addition, VEGF inhibits dendritic cell differentiation, limiting the presentation of tumor antigens to CD4 and CD8 T cells. Vascular endothelial growth factor (VEGF). VEGF tyrosine kinase inhibitors (TKIs) VEGF-TKIs are currently utilized in the treatment of a variety of malignancies and are widely utilized in combination with checkpoint blockade in the treatment of clear cell kidney cancer.
Through the inhibition of VEGF, it may be possible to potentiate the effect of immune checkpoint blockade even in tumors which have traditionally been thought to be unresponsive to immunotherapy. This study aims to evaluate the combination of the immune checkpoint inhibitor atezolizumab and the VEGF-TKI tivozanib in a variety of tumors which have a low response rate to checkpoint inhibitor therapy alone.
Subjects must have had at least one prior treatment with systemic therapy for advanced and unresectable, or metastatic disease OR is intolerant to, has refused or for whom there are no standard therapies that impart significant clinical benefit in the opinion of the treating investigator.
An Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 1 for phase 1B. An ECOG Performance Status less than or equal to 2 for phase 2.
Subjects must not have more than one malignancy at the time of enrollment
Adult subjects ≥ eighteen years of age
Subjects with known MSI-H or dMMR tumor status
Subjects with severe uncontrolled hypertension as defined as systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg
Subjects who have had prior treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors
Females or males of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 160 days after the last dose of study drug
Sequential
Atezolizumab
DrugSubjects on both the phase Ib and phase II portions of this study will receive 1680 mg intravenously of atezolizumab on Day 1 of each 28 day cycle.
Tivozanib
DrugSubjects in both the phase Ib and phase II portions of the study will take tivozanib orally once daily on Days 1-21 of each 28 day cycle. Subjects on the phase Ib will be assigned to receive either 1.34 mg/day (Dose level 0) or 0.89 mg/day (Dose level -1). Subjects in the phase II portion of the study will receive 0.89 mg/day.
Objective response rate (ORR)
To determine the best overall response rate (ORR) of atezolizumab plus tivozanib in subjects with immunologically cold tumors
Progression free survival (PFS)
To determine the progression free survival (PFS) of subjects with immunologically cold tumors receiving atezolizumab plus tivozanib
Overall survival (OS)
To determine the overall survival (OS) of subjects with immunologically cold tumors receiving atezolizumab plus tivozanib.
Disease control rate (DCR)
To determine the disease control rate (DCR) of subjects with immunologically cold tumors receiving atezolizumab plus tivozanib. DCR is defined as percentage of subjects who achieve complete response, partial response and stable disease during the course of study using RECIST v1.1 criteria.
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University of Florida
Lead sponsor
Genentech, Inc.
Collaborator
Aveo Oncology Pharmaceuticals
Collaborator
