Atezolizumab + Cabozantinib for Osteosarcoma

Overseen By John A Livingston, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anticoagulants, Kinase inhibitors

Disqualifiers: Brain metastases, Autoimmune disease, Cardiovascular disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 4

Duration: 21 days per cycle, repeated

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the combination of atezolizumab and cabozantinib for treating osteosarcoma that has returned or spread. Atezolizumab, an immunotherapy drug, helps the immune system attack cancer cells, while cabozantinib blocks enzymes that promote tumor growth. The trial aims to determine if this combination can better control the disease. It may suit individuals with osteosarcoma unresponsive to traditional treatments and measurable tumors. As a Phase 2 trial, researchers focus on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, certain medications like small molecule kinase inhibitors and some anticancer therapies must not be taken close to the start of the trial. It's best to discuss your specific medications with the trial team.

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

Research has shown that using atezolizumab and cabozantinib together can help treat various types of cancer. Atezolizumab boosts the immune system to fight cancer, while cabozantinib inhibits certain proteins that promote cancer cell growth.

Studies have found that this combination can extend the time patients live without their cancer worsening. However, some side effects require consideration. In one study, 49% of patients reduced their cabozantinib dose due to side effects like tiredness or diarrhea. Additionally, 73% paused their atezolizumab treatment, and 55% experienced treatment delays.

These findings suggest that while the treatment can be effective, it may also cause side effects. Participants should discuss the potential risks and benefits with their healthcare providers before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of atezolizumab and cabozantinib for osteosarcoma because it targets the cancer in a unique way. Unlike traditional treatments like chemotherapy, which attack cancer cells broadly, atezolizumab is an immunotherapy that helps the immune system recognize and fight cancer cells more effectively. Cabozantinib, on the other hand, inhibits certain proteins that promote tumor growth and blood vessel formation. This combination has the potential to provide a more targeted approach, potentially leading to better outcomes for patients with osteosarcoma.

What evidence suggests that atezolizumab and cabozantinib might be effective for osteosarcoma?

Research has shown that the combination of atezolizumab and cabozantinib, which participants in this trial will receive, may effectively treat recurring or spreading osteosarcoma. In earlier studies, atezolizumab shrank tumors in 15% of patients whose cancer worsened after chemotherapy. Although data on cabozantinib specifically for osteosarcoma is limited, it is known to block certain enzymes that aid cancer cell growth, potentially slowing the disease. Together, these drugs could help manage osteosarcoma by strengthening the immune system and preventing tumor growth. ^{1 2 5 6 7}

Who Is on the Research Team?

John A Livingston, MD MS

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adolescents and young adults aged 12 or older with recurrent or metastatic osteosarcoma, who have tried conventional therapies without success. Participants must have measurable disease, be able to provide a tumor specimen for research, and meet specific health criteria including organ function tests. They should not be HIV positive and must agree to use effective contraception.

Inclusion Criteria

I am mostly active and can care for myself despite my illness.

Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol), or 24-hour (h) urine protein =< 1 g (obtained within 14 days prior to initiation of study treatment)

Ability to comply with the study protocol, in the investigator's judgment

Exclusion Criteria

My calcium levels are normal and not causing symptoms.

I have a history of specific lung conditions or signs of lung inflammation on a CT scan.

I have not had significant bleeding or coughed up more than half a teaspoon of blood in the last 3 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive atezolizumab intravenously on day 1 and cabozantinib orally once daily on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

21 days per cycle, repeated

1 visit (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups within 30 days, then every 3 months for 2 years.

2 years

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Cabozantinib

Trial Overview The trial is testing the combination of Atezolizumab (an immunotherapy drug) and Cabozantinib (a drug that blocks tumor growth enzymes) in patients with advanced osteosarcoma. The study aims to see if this drug combo can control cancer better than current treatments.

How Is the Trial Designed?

Group I: Treatment (atezolizumab, cabozantinib) Experimental Treatment 2 Interventions

Patients receive atezolizumab IV over 60 minutes on day 1 and cabozantinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

Cabozantinib and temozolomide both significantly reduced the growth and viability of uterine sarcoma cells, with the combination of the two drugs showing even greater effectiveness in promoting cell death and inhibiting tumor growth.

In mouse models, the combined treatment of cabozantinib and temozolomide led to a significant reduction in tumor size, indicating a synergistic effect that supports further clinical trials for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticancer Activity of the Combination of Cabozantinib and Temozolomide in Uterine Sarcoma. Noh, JJ., Cho, YJ., Ryu, JY., et al.[2022]

In a Phase 1 study involving 12 patients with relapsed osteosarcoma and Ewing sarcoma, the combination of cabozantinib, topotecan, and cyclophosphamide showed acceptable toxicity levels, with manageable dose-limiting toxicities observed.

The treatment resulted in one partial response and stable disease in seven patients, suggesting that this combination therapy may provide potential disease control in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of cabozantinib in combination with topotecan-cyclophosphamide for patients with relapsed Ewing sarcoma or osteosarcoma. Campbell, K., Posner, A., Chen, N., et al.[2023]

Atezolizumab and pembrolizumab received accelerated FDA approval in 2017 for treating advanced urothelial carcinoma in patients who cannot receive cisplatin, showing objective response rates of 23.5% and 28.6%, respectively, in single-arm trials with a total of 746 patients.

Due to preliminary concerns from ongoing trials, the FDA revised the indications for these drugs, now specifying they are for patients not eligible for any platinum-based chemotherapy or those with high PD-L1 expression, ensuring a more targeted treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Atezolizumab or Pembrolizumab for the Treatment of Patients with Advanced Urothelial Carcinoma Ineligible for Cisplatin-Containing Chemotherapy. Suzman, DL., Agrawal, S., Ning, YM., et al.[2020]

Atezolizumab is a monoclonal antibody that targets PD-L1, which is being developed for treating various blood cancers and solid tumors, showing promise in cancer immunotherapy.

It has already been approved in the US as a second-line treatment for urothelial carcinoma and is pending approval for non-small cell lung cancer, highlighting its potential efficacy in these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab: First Global Approval. Markham, A.[2019]

In a retrospective analysis of 16 adult patients with advanced osteosarcoma and Ewing sarcoma, cabozantinib showed antitumor activity, with 9 out of 16 patients achieving stable disease and a median progression-free survival of 5 months.

While cabozantinib was associated with common side effects like fatigue and weight loss, it also resulted in one serious adverse event (cerebral hemorrhage), highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Data on Cabozantinib in Advanced Osteosarcoma and Ewing Sarcoma Patients: A Study from the Hellenic Group of Sarcoma and Rare Cancers. Kokkali, S., Kyriazoglou, A., Mangou, E., et al.[2023]

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 a study of 115 patients with metastatic urothelial carcinoma treated with atezolizumab (ATZ) after failing first-line chemotherapy, the objective response rate was 28.7%, indicating that ATZ is effective in this patient population.

The treatment was well tolerated, with 98% of patients experiencing adverse events, but only 21.2% had severe (grade 3-4) treatment-related adverse events, suggesting a manageable safety profile similar to previous clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab in Patients with Metastatic Urothelial Carcinoma Who Have Progressed After First-line Chemotherapy: Results of Real-life Experiences. Tural, D., Ölmez, ÖF., Sümbül, AT., et al.[2022]

In a study involving 132 patients with metastatic castration-resistant prostate cancer, the combination of cabozantinib and atezolizumab demonstrated an objective response rate of 23%, indicating promising antitumor activity after prior hormonal therapies.

While the treatment showed efficacy, 55% of patients experienced grade 3-4 treatment-related adverse events, with pulmonary embolism and diarrhea being the most common, suggesting that while the combination is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021). Agarwal, N., McGregor, B., Maughan, BL., et al.[2022]

Atezolizumab is an FDA-approved treatment for advanced bladder cancer that works by blocking the PD-L1/PD-1 immune checkpoint, enhancing T-cell immunity against tumors.

In clinical trials, atezolizumab showed a 15% objective response rate in patients whose cancer progressed after chemotherapy, and a 24% response rate in chemotherapy-naïve patients, with a favorable safety profile compared to other second-line treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab: A PD-L1-Blocking Antibody for Bladder Cancer. Inman, BA., Longo, TA., Ramalingam, S., et al.[2022]

In the COSMIC-312 trial involving 837 patients with advanced hepatocellular carcinoma, the combination of cabozantinib and atezolizumab showed a median progression-free survival of 6.8 months, significantly longer than the 4.2 months observed with sorafenib, indicating improved efficacy for the combination treatment.

While the overall survival rates were similar between the combination treatment and sorafenib (15.4 months vs. 15.5 months), the combination was associated with a higher incidence of serious treatment-related adverse events, suggesting a need for careful patient selection and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Kelley, RK., Rimassa, L., Cheng, AL., et al.[2022]

Atezolizumab significantly improves overall survival in patients with metastatic non-small cell lung cancer (mNSCLC), with median survival times of 13.8 months in the atezolizumab group compared to 9.6 months in the docetaxel group in the OAK trial.

The treatment has an acceptable safety profile, with common side effects including fatigue and decreased appetite, and serious immune-related adverse events occurring in a small percentage of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. Food and Drug Administration Approval Summary: Atezolizumab for Metastatic Non-Small Cell Lung Cancer. Weinstock, C., Khozin, S., Suzman, D., et al.[2022]

Citations

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NCT05019703 | Atezolizumab and Cabozantinib for the ... This phase II trial studies the effect of atezolizumab and cabozantinib in treating adolescents and young adults with osteosarcoma that has come back ...

2. withpower.com withpower.com/trial/phase-3-osteosarcoma-10-2021-36350

Atezolizumab + Cabozantinib for Osteosarcoma In clinical trials, atezolizumab showed a 15% objective response rate in patients whose cancer progressed after chemotherapy, and a 24% response rate in ...

3. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2021-0409.html

A Phase 2 Trial of Atezolizumab and Cabozantinib in ... This phase II trial studies the effect of atezolizumab and cabozantinib in treating adolescents and young adults with osteosarcoma that has come back (recurrent) ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11541244/

Neoadjuvant Chemotherapy for Adults with Osteogenic Sarcoma In a 2018 study, 37 participants with advanced osteosarcoma received apatinib, and the objective response rate (ORR) was 43.24%, while the PFS ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39965176/

COSMIC-021 Phase Ib Study of Cabozantinib Plus ... The median progression-free survival (95% CI) was 5.5 (1.6 to 11.6), 5.6 (3.1 to 11.1), 5.4 (1.6 to 7.6), and 3.0 (1.8 to 5.5) months, ...

6. cancernetwork.com cancernetwork.com/view/cabozantinib-atezolizumab-significantly-improves-pfs-in-metastatic-crpc

Cabozantinib/Atezolizumab Significantly Improves PFS in ... Cabozantinib (Cabometyx) in combination with atezolizumab (Tecentriq) elicited a statistically significant improvement in progression-free survival (PFS)

7. onclive.com onclive.com/view/cabozantinib-plus-atezolizumab-fails-to-improve-os-over-subsequent-novel-hormonal-therapy-in-mcrpc

Cabozantinib Plus Atezolizumab Fails to Improve OS Over ... AEs leading to dose reduction of cabozantinib, dose hold, or dose delay of atezolizumab were reported in 49%, 73% and 55% of patients, ...