Atezolizumab Plus Tivozanib in Immunologically Cold Tumor Types

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Brief Title

Atezolizumab Plus Tivozanib in Immunologically Cold Tumor Types

Official Title

Atezolizumab Plus Tivozanib in Immunologically Cold Tumor Types

Brief Summary

      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.

Study Phase

Phase 1/Phase 2

Study Type


Primary Outcome

Objective response rate (ORR)

Secondary Outcome

 Progression free survival (PFS)


Bile Duct Cancer



Study Arms / Comparison Groups

 Atezolizumab + Tivozanib


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

November 3, 2021

Completion Date

June 2024

Primary Completion Date

June 2023

Eligibility Criteria

        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 moderately-
             differentiated (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:
             1) 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
             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 study drug to minimize
             the risk of pregnancy.

          -  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.

          -  Measurable disease by RECIST criteria

          -  A life expectancy of ≥ 12 weeks

          -  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

          -  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

          -  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.

          -  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:

               1. subjects with a history of autoimmune-related hypothyroidism who are on
                  thyroid-replacement hormone are eligible for the study.

               2. subjects with controlled Type 1 diabetes mellitus who are on an insulin regimen
                  are eligible for the study.

               3. 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

                    -  Rash must cover <10% of body surface area

                    -  Disease is well controlled at baseline and requires only lowpotency topical

                    -  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

          -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
             active pneumonitis on screening chest computed tomography (CT) scan. History of
             radiation pneumonitis in the radiation field (fibrosis) is permitted.

          -  Active tuberculosis

          -  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

          -  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

          -  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

          -  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 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

          -  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

          -  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:

               1. 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.

               2. 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.

          -  History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
             or fusion proteins

          -  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 with Tumor Mutation Burden (TMB) ≥10

          -  Treatment with any cancer directed therapy (i.e. chemotherapy, radiation therapy, Y90,
             microwave ablation, immunotherapy, etc.) within 28 days of study start

          -  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.

          -  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




18 Years - 99 Years

Accepts Healthy Volunteers



Jonathan Chatzkel, MD, (352)-273-6772, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

University of Florida


 Genentech, Inc.

Study Sponsor

Jonathan Chatzkel, MD, Principal Investigator, University of Florida

Verification Date

August 2022