Atezolizumab Plus Tivozanib in Immunologically Cold Tumor Types

NCT05000294 | Suspended Phase 1 DMC FDA Drug

• 3 other identifiers: UF-STO-ETG-003OCR40357IRB202101773
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

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.

Conditions

Bile Duct Cancer; Gall Bladder Cancer; Breast Cancer; Neuroendocrine Tumors; Ovarian Cancer; Pancreatic Adenocarcinoma; Soft Tissue Sarcoma; Vulvar Cancer; Prostate Cancer

Keywords

immunologically cold tumors; breast cancer; bile duct cancer; gallbladder cancer; neuroendocrine cancer; ovarian cancer; pancreatic adenocarcinoma; soft tissue sarcoma; prostate cancer; vulvar cancer; TKI; checkpoint inhibitor

Outcome Measures

Primary Outcomes (1)

• Objective response rate (ORR)

  To determine the best overall response rate (ORR) of atezolizumab plus tivozanib in subjects with immunologically cold tumors

  30 months

Secondary Outcomes (3)

• Progression free survival (PFS)

  30 months

• Overall survival (OS)

  30 months

• Disease control rate (DCR)

  30 months

Study Arms (1)

Atezolizumab + Tivozanib

EXPERIMENTAL

Drug: Atezolizumab; Drug: Tivozanib

Interventions

Atezolizumab DRUG

Subjects 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.

Also known as: Tecentriq

Atezolizumab + Tivozanib

Tivozanib DRUG

Subjects 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.

Also known as: Fotivda

Atezolizumab + Tivozanib

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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 resistant, with no acceptable standard of care 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 years.

You may not qualify if:

• 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
• 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:
• 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.
• 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 met:
• Rash must cover \<10% of body surface area
• Disease is well controlled at baseline and requires only lowpotency topical corticosteroids

Sponsors & Collaborators

• University of Florida: lead
• Genentech, Inc.: collaborator
• Aveo Oncology Pharmaceuticals: collaborator

Study Sites (1)

University of Florida

Gainesville, Florida, 32608, United States

Location

Related Publications (1)

• Ramnaraign BH, Lee JH, Ali A, Rogers SC, Fabregas JC, Thomas RM, Allegra CJ, Sahin I, DeRemer DL, George TJ, Chatzkel JA. Atezolizumab plus tivozanib for immunologically cold tumor types: the IMMCO-1 trial. Future Oncol. 2022 Nov 18. doi: 10.2217/fon-2022-0392. Online ahead of print.

  PMID: 36399037 DERIVED

MeSH Terms

Conditions

Bile Duct Neoplasms; Gallbladder Neoplasms; Breast Neoplasms; Neuroendocrine Tumors; Ovarian Neoplasms; Sarcoma; Vulvar Neoplasms; Prostatic Neoplasms; Carcinoma, Neuroendocrine

Interventions

atezolizumab; tivozanib

Condition Hierarchy (Ancestors)

Biliary Tract Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Gallbladder Diseases; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Neoplasms, Connective and Soft Tissue; Vulvar Diseases; Genital Neoplasms, Male; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial

Study Officials

• Leighton Elliott, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 10, 2021
• First Posted: August 11, 2021
• Study Start: December 7, 2021
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): June 1, 2027
• Last Updated: February 18, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)