Atezolizumab + Tivozanib for Sarcoma

Overseen By Priya Gurjar

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Florida

Must not be taking: VEGFR inhibitors, Immunotherapy

Disqualifiers: Hypertension, Autoimmune diseases, Cardiovascular, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 30 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for certain hard-to-treat cancers. It combines atezolizumab, an immune therapy that helps the body's defenses recognize and attack cancer cells, with tivozanib, a drug that restricts blood supply to tumors. The goal is to determine if these drugs together can be more effective against cancers like soft tissue sarcoma and pancreatic cancer, which usually don’t respond well to immune therapies alone. Individuals who have tried other treatments without success and have certain types of advanced cancers might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of atezolizumab and tivozanib is generally safe. Studies have found that common serious side effects include muscle and bone pain in about 8% of patients and high blood pressure in about 6% of patients. Doctors can usually manage these side effects effectively, suggesting that most people can tolerate the treatment well. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Atezolizumab and Tivozanib for treating sarcoma because it offers a fresh approach compared to traditional therapies like chemotherapy and radiation. Atezolizumab is an immunotherapy drug that helps the immune system recognize and attack cancer cells, while Tivozanib is a targeted therapy that blocks the blood supply tumors need to grow. This dual mechanism not only aims to enhance the immune response but also starves the tumor, potentially leading to more effective outcomes than conventional treatments alone.

What evidence suggests that the combination of atezolizumab and tivozanib could be effective for sarcoma?

Research has shown that the combination of atezolizumab and tivozanib, which participants in this trial will receive, may effectively treat tumors that usually resist immunotherapy. Atezolizumab helps the immune system identify and attack cancer cells, while tivozanib targets the blood vessels tumors need to grow. In previous studies, 62% of patients using this combination experienced tumor shrinkage or halted growth. Although these results are promising, further research is needed to confirm its effectiveness across different cancer types. ^{3 4 5 6 7}

Who Is on the Research Team?

Jonathan Chatzkel, MD

Principal Investigator

University of Florida

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Tivozanib

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.

How Is the Trial Designed?

Group I: Atezolizumab + Tivozanib Experimental Treatment 2 Interventions

Atezolizumab is already approved in United States, European Union for the following indications:

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

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

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. withpower.com withpower.com/trial/phase-2-neuroendocrine-tumors-9-2021-3b330

Atezolizumab + Tivozanib for Sarcoma 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 ...

2. onclive.com onclive.com/view/dr-ramnaraign-on-the-evaluation-of-atezolizumab-plus-tivozanib-in-gi-malignancies

Dr. Ramnaraign on the Evaluation of Atezolizumab Plus ... Brian Ramnaraign, MD, discusses the evaluation of atezolizumab plus tivozanib in a phase 1b/2 trial in patients with pancreatic, gallbladder, and bile duct ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05000294

NCT05000294 | Atezolizumab Plus Tivozanib in ... 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 ...

4. targetedonc.com targetedonc.com/view/real-world-data-demonstrate-efficacy-safety-with-tivozanib-in-mrcc

Real-World Data Demonstrate Efficacy, Safety With ... At a median follow-up of 25.9 months (range, 18.3-44.7 months), the overall response rate (ORR) was 29%. There were no complete responses, and ...

5. esmo.org esmo.org/oncology-news/efficacy-of-tivozanib-monotherapy-in-the-post-ici-setting-among-patients-with-advanced-renal-cell-cancer

Efficacy of Tivozanib Monotherapy in the Post-ICI Setting ... With a median follow-up of 19 months, the combination showed an overall response rate (ORR) of 62%; the median PFS was not reached. Hypertension ...

6. onclive.com onclive.com/view/dr-ramnaraign-on-the-investigation-of-atezolizumab-plus-tivozanib-in-crpc

Dr. Ramnaraign on the Investigation of Atezolizumab Plus ... Checkpoint inhibition has improved cancer outcomes in a variety of cancers, such as bladder cancer, kidney cancer, and lung cancer, Ramnaraign ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11224966/

Efficacy, Safety, and Tolerability of Tivozanib in Heavily ... In the present study, we describe the outcomes of patients who were treated with tivozanib for advanced RCC at our center and provide data which ...