Nivolumab +/- Azacitidine for Osteosarcoma

Not currently recruiting at 25 trial locations

Overseen By Jessica R Crimella, BSN, RN

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Pregnancy, Autoimmune disorders, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of two treatments, nivolumab (an immunotherapy drug) and azacitidine (a chemotherapy drug), for individuals with osteosarcoma (a type of bone cancer) that has recurred and can be surgically removed. Participants will receive either nivolumab alone or in combination with azacitidine before and after surgery to determine which approach is most effective. The trial seeks individuals with a prior osteosarcoma diagnosis and a recurrence in the lungs that can be surgically removed. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial requires that you stop taking corticosteroids or other immunosuppressive medications. If you are on these medications, you would need to discontinue them to participate in the study.

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

Research has shown that nivolumab and azacitidine have been studied for safety in various contexts. Nivolumab is usually well-tolerated, though serious side effects like severe infections (sepsis) occurred in about 3.6% of patients when combined with chemotherapy. The FDA has approved it for many cancer types, indicating a strong safety record.

Azacitidine is also FDA-approved for certain blood disorders. It is generally well-tolerated, with common side effects including blood issues, stomach problems, and injection site reactions.

The combination of nivolumab and azacitidine is under study for safety in treating osteosarcoma, a type of bone cancer. Early research in other areas shows promise, but the safety of this combination specifically for osteosarcoma remains under investigation. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Nivolumab and Azacitidine for osteosarcoma because these treatments work differently from traditional chemotherapy, which is the current standard. Nivolumab is an immunotherapy drug that enhances the body's immune system to attack cancer cells, while Azacitidine may modify the tumor environment to make the cancer more vulnerable to immune attack. This approach could potentially lead to better outcomes by not only targeting the cancer cells directly but also by helping the immune system fight the disease more effectively. Unlike standard treatments that primarily attack cancer cells directly, this combination aims to boost the body's own defenses, offering a promising new avenue for treating osteosarcoma.

What evidence suggests that nivolumab and azacitidine could be effective for osteosarcoma?

Research has shown that nivolumab, one of the treatments in this trial, may help treat advanced bone cancer. Studies found that 42% of patients did not experience cancer progression for at least 6 months when nivolumab was combined with another drug, such as sunitinib. In this trial, participants may receive nivolumab alone or with azacitidine.

Azacitidine, another treatment option in this trial, has proven effective in treating other cancers, such as myeloid sarcoma, where patients lived longer than with standard treatments. It has also improved response rates and quality of life for individuals with certain blood disorders. These early results suggest that these treatments could be promising for osteosarcoma. ^{6 7 8 9 10}

Who Is on the Research Team?

Patrick Thompson, M.D.

Principal Investigator

University of North Carolina, Chapel Hill

Mihaela Druta, MD

Principal Investigator

H. Lee Moffitt Cancer Center and Research Institute, Coordinating Center

Are You a Good Fit for This Trial?

This trial is for people with osteosarcoma that has come back and can be surgically removed. They should have recovered from previous treatments, not have metastasis beyond the lungs, and must agree to surgery for all tumors. Participants need normal organ function, no severe autoimmune disorders or uncontrolled illnesses, no history of certain allergies or reactions to similar drugs, and cannot be on immunosuppressants or other cancer treatments.

Inclusion Criteria

My organs and bone marrow are functioning normally.

You cannot participate in the clinical trial if you have had an organ transplant in the past.

My osteosarcoma has come back in my lungs only.

Exclusion Criteria

Intercurrent Illnesses: Patients with uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection, Symptomatic congestive heart failure, Unstable angina pectoris, Cardiac arrhythmia, Psychiatric illness/social situations that would limit compliance with study requirements, Autoimmune disorders: Patients with a history of any Grade autoimmune disorder are not eligible. Asymptomatic laboratory abnormalities (e.g., ANA, rheumatoid factor, altered thyroid function studies) will not render a patient ineligible in the absence of a diagnosis of an autoimmune disorder. Patients with ≥ Grade 2 hypothyroidism due to history of autoimmunity are not eligible. Note: Hypothyroidism due to previous irradiation or thyroidectomy will not impact eligibility, Allergies: Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Nivolumab (e.g., another humanized antibody) or Azacitidine are not eligible, Safety and Monitoring: Patients who are considered unable to comply with the safety monitoring requirements of the study are not eligible, Patients with known HIV or hepatitis B or C are excluded, Patients who have received prior solid organ transplantation are not eligible, Patients who have received prior anti-PD-1 directed therapy (mAb or small molecule) are not eligible

I am not taking steroids, immunosuppressants, or any cancer treatments.

I am using two forms of birth control, one highly effective and another as required.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive 1 cycle of neoadjuvant Nivolumab or Nivolumab + Azacitidine

4 weeks

Surgery

Surgery to render participants in surgical remission

Adjuvant Treatment

Participants continue to receive Nivolumab or Nivolumab + Azacitidine for up to 12 additional cycles or until recurrence

48 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Nivolumab
• Post Treatment Surgery

Trial Overview The study tests the safety and effectiveness of Nivolumab alone or combined with Azacitidine in patients whose osteosarcoma has returned but can still be operated on. The goal is to see how well these treatments work before they go through surgery to remove their tumors.

How Is the Trial Designed?

Group I: Dose Escalation, Resection, Dose Expansion Experimental Treatment 3 Interventions

Participants will receive 1 cycle of neoadjuvant Nivolumab or Nivolumab + Azacitidine, followed by surgery to render them in surgical remission. Subsequently they will continue to receive Nivolumab or Nivolumab + Azacitidine for 12 additional cycles or until recurrence, whichever occurs first. Once the recommended Phase II dose (RP2D) is identified during Phase I, the Dose Expansion Phase II will be opened at this dose level. The Phase II portion of the study will consist of a maximum 33 evaluable patients (27-30 in addition to the 3-6 enrolled at RP2D on the Phase I portion).

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

In a phase 2 trial involving 117 patients with advanced, refractory squamous non-small-cell lung cancer, nivolumab demonstrated a 14.5% objective response rate, indicating its potential effectiveness as a treatment option.

The safety profile of nivolumab was manageable, with 17% of patients experiencing severe treatment-related adverse events, suggesting that while there are risks, the benefits may outweigh them for patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Rizvi, NA., Mazières, J., Planchard, D., et al.[2022]

The anti-PD-L1 antibody ZKAB001 demonstrated a manageable safety profile in a Phase I/II study involving 21 patients with localized high-grade osteosarcoma, with the most common side effects being thyroiditis (76.2%) and dermatitis (42.9%).

Preliminary efficacy results indicated a promising 24-month event-free survival rate of 71.4% and a 100% overall survival rate, particularly benefiting patients with PD-L1 positive or MSI-H subtypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Maintenance Therapy for Localized High-Grade Osteosarcoma: An Open-Label Phase I/II Trial of the Anti-PD-L1 Antibody ZKAB001. Zhou, Y., Yang, Q., Dong, Y., et al.[2023]

Nivolumab, an immune checkpoint inhibitor, significantly improved overall survival and progression-free survival compared to docetaxel in patients with advanced squamous non-small cell lung cancer (NSCLC) in the CheckMate 017 trial.

Nivolumab was better tolerated than docetaxel, with manageable adverse effects, making it a promising treatment option for patients who have already undergone chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review in advanced squamous non-small cell lung cancer. Keating, GM.[2022]

Nivolumab, an immune checkpoint inhibitor, significantly improves overall survival and progression-free survival in patients with advanced stage squamous cell non-small cell lung cancer (NSCLC) compared to docetaxel, as shown in the CHECKMATE 017 study.

The safety and tolerability of nivolumab are favorable, and interestingly, the expression of the PD-L1 ligand does not predict treatment outcomes, suggesting that other factors may influence the effectiveness of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab in the treatment of metastatic squamous non-small cell lung cancer: a review of the evidence. Lim, JS., Soo, RA.[2018]

Nivolumab (Opdivo) significantly improves overall survival and response rates in previously-treated patients with advanced nonsquamous non-small cell lung cancer (NSCLC) compared to docetaxel, as shown in the CheckMate 057 trial.

Nivolumab has a manageable adverse event profile and is better tolerated than docetaxel, making it a valuable treatment option for patients who have progressed after chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: A Review in Advanced Nonsquamous Non-Small Cell Lung Cancer. Keating, GM.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6392782/

Successful 5-azacytidine treatment of myeloid sarcoma ... In these patients, overall survival is 24.5 months in the 5-Aza group, compared with 15.0 months in the conventional care group (best supportive care, low dose ...

2. ashpublications.org ashpublications.org/blood/article/145/11/1126/534406/Efficacy-and-safety-of-venetoclax-plus-azacitidine

Efficacy and safety of venetoclax plus azacitidine for patients ... Overall, venetoclax plus azacitidine at the RP2D was well tolerated and had favorable outcomes. A phase 3 study (NCT04401748) is ongoing to ...

3. curetoday.com curetoday.com/view/vidaza-with-novel-drug-shows-improvement-for-myelodysplastic-syndromes-with-genetic-mutations-and-acute-myeloid-leukemia

Vidaza With Novel Drug Shows Improvement for ... Patients with myelodysplastic syndromes had an overall response rate of 62%. This included 47% of patients achieving complete remission. In ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3921030/

Optimizing outcomes with azacitidine: recommendations ... Study patients receiving azacitidine experienced improved response rates and quality of life, a reduction in transfusion requirements, and a significant delay ...

5. cancernetwork.com cancernetwork.com/view/safety-profile-of-oral-azacitadine-remains-consistent-in-lower-risk-mds

Safety Profile of Oral Azacitadine Remains Consistent in ... The safety profile of oral azacitadine was shown to be similar across the 200-mg and 300-mg arms in patients with lower- to intermediate-risk MDS.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/050974s034lbl.pdf

VIDAZA (azacitidine - accessdata.fda.gov Safety and effectiveness of VIDAZA in pediatric patients with MDS have not been established. Reference ID: 4987350. This label may not be the latest approved by ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5167077/

Safety and efficacy of azacitidine in elderly patients with ... The treatment is generally well tolerated with the most common side effects being myelosuppression, gastrointestinal disturbances, and injection site reactions.

8. mayoclinic.org mayoclinic.org/drugs-supplements/azacitidine-injection-route/description/drg-20062061

Azacitidine (injection route) - Side effects & uses Safety and efficacy have not been established. Geriatric. Appropriate studies performed to date have not demonstrated geriatric-specific ...

9. ema.europa.eu ema.europa.eu/en/documents/product-information/vidaza-epar-product-information_en.pdf

Vidaza, INN-azacitidine - EMA 5.3 Preclinical safety data. Azacitidine induces both gene mutations and chromosomal aberrations in bacterial and mammalian cell systems in vitro. The ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2948932/

Safety and efficacy of azacitidine in myelodysplastic ... Azacitidine is the first drug FDA-approved for the treatment of myelodysplastic syndromes that has demonstrated improvements in overall survival.