Atezolizumab Plus Tivozanib in Immunologically Cold Tumor Types

  • End date
    Jun 16, 2024
  • participants needed
  • sponsor
    University of Florida
Updated on 7 October 2022
systemic therapy
measurable disease
breast cancer
growth factor
cancer chemotherapy
soft tissue sarcoma
peritoneal cancer
cancer of the ovary


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.

Condition Bile Duct Cancer, Gall Bladder Cancer, Breast Cancer, Neuroendocrine Tumors, Ovarian Cancer, Pancreatic Adenocarcinoma, Soft Tissue Sarcoma, Vulvar Cancer, Prostate Cancer
Treatment Atezolizumab, Tivozanib
Clinical Study IdentifierNCT05000294
SponsorUniversity of Florida
Last Modified on7 October 2022


Yes No Not Sure

Inclusion Criteria

Subjects must have had at least one prior treatment with systemic therapy for advanced and unresectable, or metastatic disease
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
A clinical diagnosis consistent with stage IV "immunogenically cold" or otherwise incurable cancer of one of the following histologies: i) bile duct or gallbladder cancer ii) Metastatic breast cancer, HR-negative HER2-positive, who have received at least 3 lines of therapy for disease progression that includes: trastuzumab, pertuzumab/trastuzumab, and ado-trastuzumab emtansine iii) neuroendocrine cancer with the following pathological characteristics: grade 2 or 3; well- or moderatelydifferentiated (Grades 1, 4, and poorly differentiated neuroendocrine pathologies are not eligible) iv) FIGO stage IV or metastatic (using 2021 FIGO classification) high grade serious or high grade endometrioid (based on local histopathological findings) ovarian cancer, primary peritoneal cancer and / or fallopian-tube cancer that is platinum-refractory v) pancreatic adenocarcinoma vi) soft tissue sarcoma vii) prostate cancer subjects who are castrate-resistant (testosterone ≤ 50 ng/dL) and have progressed on, declined, or are intolerant to other standard of care therapies. Subjects with prostate cancer must have failed at least one line of treatment with an androgen inhibitor (AI) (i.e. enzalutamide, abiraterone, etc.) or cytotoxic chemotherapy in the advanced or metastatic setting viii) vulvar cancer
Adequate hematologic and end-organ function
Subjects receiving therapeutic anticoagulation must be on a stable anticoagulant regimen for ≥ 2 weeks at start of protocol treatment
Negative hepatitis B surface antigen (HBsAg) test at screening
Negative HIV test at screening with the following exceptions: subjects with a positive HIV test at screening are eligible only if they meet the following three conditions
Are stable on anti-retroviral therapy 2) Have a CD4 count ≥ 200/uL AND 3) Have an undetectable viral load
Women of childbearing potential (WOCBP) must be using an adequate method of
Males with female partners of child-bearing potential must agree to use physician-approved contraceptive methods throughout the study and should avoid conceiving children for 160 days following the last dose of study drug
contraception (with a failure rate of <1% per year) to avoid pregnancy
throughout the study and for at least 160 days after the last dose of either
Measurable disease by RECIST criteria
study drug to minimize the risk of pregnancy
Written informed consent obtained from the subject and the subject agrees to comply with all the study-related procedures
Must have formalin-fixed paraffin embedded (FFPE) tissue or 12 unstained slides available for research purposes. Tissue must have been obtained within the last 3 years
A life expectancy of ≥ 12 weeks
If a new biopsy is needed for diagnostic reasons, the biopsy must be performed from a tumor site that is not the only site of measurable disease
Subject must be able to swallow capsules

Exclusion Criteria

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 use of checkpoint inhibitor immunotherapy or TKI
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
Females who are pregnant or breastfeeding
History of leptomeningeal disease
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
Uncontrolled tumor-related pain
subjects with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study
subjects with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently, except in the case of ovarian cancer with ascites, which may require more frequent drainage). Subjects with indwelling catheters are allowed
subjects with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., subjects with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are
Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions
Rash must cover <10% of body surface area
Disease is well controlled at baseline and requires only lowpotency topical corticosteroids
Active tuberculosis
There has been no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence
History of malignancy other than the malignancies listed in the inclusion criteria of enrollment within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer
of active pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Note: Subjects receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
Prior allogeneic stem cell or solid organ transplantation
Current treatment with anti-viral therapy for hepatitis B virus (HBV)
Treatment with investigational therapy within 28 days prior to initiation of study treatment
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
Severe infection within 4 weeks prior to initiation of study treatment including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could impact patient safety
Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions
Subjects who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study
Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
History of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician
Administration of a vaccine containing live virus within 30 days prior to the first dose of trial treatment, during treatment with atezolizumab, and for 160 days after the last dose of atezolizumab. Note: Most flu vaccines are killed viruses, with the exception of the intra-nasal vainer (Flu-Mist) which is an attenuated live virus and therefore prohibited for 30 days prior to first dose. Subjects may receive non-live COVID-19 vaccine
Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness
Subjects who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study
Treatment with any cancer directed therapy (i.e. chemotherapy, radiation therapy, Y90, microwave ablation, immunotherapy, etc.) within 28 days of study start
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
Subjects with treated brain metastases that have remained stable for at least 90 days without steroids are allowed. Subjects with signs of symptoms or history of brain metastasis must have a CT or MRI of the brain within 30 days prior to the start of protocol therapy
Subjects with autoimmune diseases requiring current treatment and subjects with history of severe autoimmune diseases, subjects with hypothyroidism, adrenal insufficiency, or pituitary insufficiency who are stable on therapy are allowed
or fusion proteins
Inability to discontinue use of medications contraindicated by the study treatment
Proteinuria > 2.5 g/24 hours or 3+ with urine dipstick
QTc interval > 470 at screening or known cardiovascular disease defined as (a) a clinically significant abnormal ECG at screening, or (b) myocardial infarction within 12 weeks prior to start of protocol therapy
Subjects with Tumor Mutation Burden (TMB) ≥10
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