Atezolizumab + Tivozanib for Sarcoma

Recruiting in Palo Alto (17 mi)

Overseen by Jonathan Chatzkel, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: University of Florida

Must not be taking: VEGFR inhibitors, Immunotherapy

Disqualifiers: Hypertension, Autoimmune diseases, Cardiovascular, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, it mentions that you cannot take certain medications like systemic immunosuppressive drugs or cancer-directed therapies close to the start of the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug combination Atezolizumab and Tivozanib for sarcoma?

While there is no direct evidence for the combination of Atezolizumab and Tivozanib in sarcoma, research suggests that combining immune checkpoint inhibitors like Atezolizumab with other treatments may offer potential benefits. Additionally, the success of similar drugs in other cancers and the exploration of targeted therapies in sarcomas indicate a promising area for further study. ^{1 2 3 4 5}

Is the combination of Atezolizumab and Tivozanib safe for humans?

Atezolizumab (also known as Tecentriq) has been studied for safety in various cancers, including alveolar soft part sarcoma, ovarian cancer, and breast cancer. It has shown a generally acceptable safety profile in these studies, but specific safety data for the combination with Tivozanib (Fotivda) in sarcoma is not available from the provided research. ^{3 6 7 8 9}

How is the drug combination of Atezolizumab and Tivozanib unique for treating sarcoma?

The combination of Atezolizumab and Tivozanib is unique because it combines an immune checkpoint inhibitor (Atezolizumab) with a tyrosine kinase inhibitor (Tivozanib) that targets VEGF receptors, potentially offering a novel approach to treating sarcomas by both enhancing the immune response and inhibiting tumor blood vessel growth. ^{1 3 10 11 12}

Research Team

Jonathan Chatzkel, MD

Principal Investigator

University of Florida

Eligibility Criteria

Adults over 18 with certain advanced 'cold' tumors not responsive to immunotherapy, including specific cancers of the bile duct, gallbladder, breast (HR-negative HER2-positive), neuroendocrine system (grade 2 or 3), ovary (high grade serious/endometrioid), pancreas, soft tissue sarcoma, prostate (castrate-resistant), and vulvar. Participants must have had prior treatment failure and be in good physical condition with a life expectancy of at least 12 weeks. They should not have multiple cancers or HIV/hepatitis B unless stable on therapy.

Inclusion Criteria

I have had at least one treatment for my advanced or metastatic cancer that cannot be surgically removed.

If I need a new biopsy, it will be from a tumor site that is not the only site being measured for disease.

I can swallow pills.

Exclusion Criteria

History of severe allergic anaphylactic reactions to specific agents

I have had a previous transplant of stem cells or an organ.

Known hypersensitivity to specific components

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of the immune checkpoint inhibitor atezolizumab and the VEGF-TKI tivozanib

30 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Atezolizumab (Checkpoint Inhibitor)
• Tivozanib (Tyrosine Kinase Inhibitor)

Trial Overview The trial is testing Atezolizumab combined with Tivozanib in patients whose tumors are considered immunologically 'cold' and typically don't respond well to checkpoint inhibitor therapy alone. The goal is to see if blocking VEGF can enhance the immune response against these types of cancer.

Participant Groups

Group I: Atezolizumab + Tivozanib Experimental Treatment 2 Interventions

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

Dr. Stephen J. Motew

University of Florida

Chief Executive Officer since 2024

MD cum laude from the University of Illinois at Chicago School of Medicine, Master's in Healthcare Administration from the University of North Carolina at Chapel Hill

Dr. Timothy E. Morey

University of Florida

Chief Medical Officer since 2023

MD and Bachelor's from the University of Florida

Aveo Oncology Pharmaceuticals

Collaborator

Trials

1

Recruited

30+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

Recent research has identified novel therapies for sarcomas, particularly for cases resistant to traditional chemotherapy, including the use of tyrosine kinase inhibitors like imatinib, which has shown success in gastrointestinal stromal tumors.

Targeting specific pathways such as mTOR and the IGF-1 receptor has emerged as a promising strategy, highlighting the need for tailored treatment protocols that consider the unique characteristics of different sarcoma subtypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel targeted therapies in the treatment of soft-tissue sarcomas. Chao, J., Chow, WA., Somlo, G.[2010]

Currently, no PD-1 inhibitors have FDA approval specifically for sarcoma, but they are recommended as standard-of-care for certain subtypes according to NCCN guidelines.

Early phase trials indicate that combining PD-1 inhibitors with chemotherapy may offer potential benefits for sarcoma treatment, highlighting the need for further clinical trials to evaluate these combinations more thoroughly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combinations of Chemotherapy and PD-1/PD-L1 Inhibitors in Sarcoma. Lynch, MM., Alexiev, BA., Schroeder, BA., et al.[2023]

In a phase 2 study involving 86 patients with advanced soft-tissue or bone sarcoma, pembrolizumab demonstrated some efficacy, particularly in undifferentiated pleomorphic sarcoma (40% response rate) and dedifferentiated liposarcoma (20% response rate), although the overall response rate did not meet the primary endpoint.

The treatment was associated with some serious adverse events, including immune-related conditions like adrenal insufficiency and pneumonitis, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Tawbi, HA., Burgess, M., Bolejack, V., et al.[2022]

Initial clinical trials of immune checkpoint inhibitors (ICP) in sarcoma patients did not show lasting benefits, prompting research into combination therapies to enhance efficacy.

Certain histological subtypes of sarcoma, such as alveolar soft part sarcoma and chordoma, may respond better to ICP blockade, and ongoing trials are exploring combinations with chemotherapy and radiotherapy to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy in sarcoma: combinations or single agents? In whom? Dufresne, A., Brahmi, M.[2023]

Patients with metastatic sarcomas have a poor prognosis, with a median overall survival of less than 18 months despite standard chemotherapy regimens, highlighting the need for improved treatment strategies.

The ongoing SUCCEED trial is investigating the efficacy of the mTOR inhibitor ridaforolimus as a potential maintenance therapy to enhance progression-free and overall survival in patients with advanced bone and soft-tissue sarcomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A role for maintenance therapy in managing sarcoma. Ray-Coquard, I., Le Cesne, A.[2021]

Atezolizumab (Tecentriq) is an FDA-approved treatment for unresectable or metastatic alveolar soft part sarcoma (ASPS), showing a 24% overall response rate in a clinical trial with 49 patients, and a durable response rate of 67% at 6 months and 42% at 12 months.

The treatment has a manageable safety profile, with common severe side effects including musculoskeletal pain (8%) and hypertension (6%), making it a viable option for patients with limited treatment alternatives for this high-risk disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab as the First Systemic Therapy Approved for Alveolar Soft Part Sarcoma. Bergsma, EJ., Elgawly, M., Mancuso, D., et al.[2023]

In a phase Ib study involving 20 patients with platinum-resistant ovarian cancer, the combination of atezolizumab and bevacizumab demonstrated a safety profile consistent with the individual drugs, with 95% experiencing treatment-related adverse events, but no grade 5 events reported.

The treatment resulted in a 15% overall response rate, with some patients achieving durable responses lasting up to 18.9 months, and a disease control rate of 55%, indicating potential efficacy in managing this challenging cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Clinical Activity of Atezolizumab Plus Bevacizumab in Patients with Ovarian Cancer: A Phase Ib Study. Moroney, JW., Powderly, J., Lieu, CH., et al.[2021]

Atezolizumab, the first anti-PD-L1 monoclonal antibody approved by the FDA, has shown promising efficacy in treating metastatic triple-negative breast cancer, supported by data from the Phase III IMpassion130 trial.

The review highlights the pharmacodynamic and pharmacokinetic properties of atezolizumab, emphasizing its safety and effectiveness in various cancers, including small-cell lung cancer and renal cell cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab for use in PD-L1-positive unresectable, locally advanced or metastatic triple-negative breast cancer. Mavratzas, A., Seitz, J., Smetanay, K., et al.[2020]

In the phase III IMagyn050 trial involving patients with newly diagnosed ovarian cancer, the addition of atezolizumab to standard chemotherapy did not improve progression-free survival (PFS) in patients with BRCA1/2 mutations or homologous recombination deficiency (HRD).

Despite the presence of BRCA1/2 mutations or HRD, most ovarian tumors exhibited low tumor mutation burden (TMB), indicating that genomic instability does not predict enhanced sensitivity to immune checkpoint inhibitors like atezolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial. Landen, CN., Molinero, L., Hamidi, H., et al.[2023]

In a phase 2 study involving 98 patients with rare and ultra-rare sarcomas, pembrolizumab showed an objective response rate of 6.2% at week 12, indicating some activity in these difficult-to-treat cancers.

The treatment was associated with manageable toxicity, with the most common severe adverse events being anemia and liver enzyme increases, and no deaths were linked to the drug itself, suggesting it may be a safe option for selected sarcoma histotypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial. Blay, JY., Chevret, S., Le Cesne, A., et al.[2023]

A phase I trial involving 41 pediatric patients with recurrent or refractory solid tumors showed that the combination of talazoparib and irinotecan, with or without temozolomide, is feasible and has demonstrated activity, particularly in Ewing sarcoma, with objective response rates of 10.3% for arm A and 25% for arm B.

The most common severe side effects included neutropenia and thrombocytopenia, indicating that while the treatment is active, it also carries significant hematologic risks that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of talazoparib and irinotecan with and without temozolomide in children and young adults with recurrent or refractory solid malignancies. Federico, SM., Pappo, AS., Sahr, N., et al.[2021]

In a phase II trial involving 58 patients with metastatic soft tissue sarcomas, tivozanib demonstrated a 16-week progression-free survival (PFS) rate of 36.4% and a median PFS of 3.5 months, indicating its potential effectiveness in this heavily pretreated population.

Tivozanib was generally well tolerated, with the most common side effects being fatigue, hypertension, nausea, and diarrhea, suggesting a manageable safety profile for further clinical evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas. Agulnik, M., Costa, RLB., Milhem, M., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Novel targeted therapies in the treatment of soft-tissue sarcomas. [2010]

2. United States pubmed.ncbi.nlm.nih.gov

Combinations of Chemotherapy and PD-1/PD-L1 Inhibitors in Sarcoma. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Immunotherapy in sarcoma: combinations or single agents? In whom? [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

A role for maintenance therapy in managing sarcoma. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Atezolizumab as the First Systemic Therapy Approved for Alveolar Soft Part Sarcoma. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Safety and Clinical Activity of Atezolizumab Plus Bevacizumab in Patients with Ovarian Cancer: A Phase Ib Study. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Atezolizumab for use in PD-L1-positive unresectable, locally advanced or metastatic triple-negative breast cancer. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial. [2023]

11. England pubmed.ncbi.nlm.nih.gov

A phase I trial of talazoparib and irinotecan with and without temozolomide in children and young adults with recurrent or refractory solid malignancies. [2021]

12. England pubmed.ncbi.nlm.nih.gov

A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas. [2020]