Natalizumab for Metastatic Osteosarcoma

Overseen By Kristen VanHeyst, DO

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Case Comprehensive Cancer Center

Must not be taking: Immunosuppressants, Antiretrovirals

Disqualifiers: Osteosarcoma outside lungs, Uncontrolled illness, others

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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of Natalizumab (also known as Tysabri) for young people with metastatic osteosarcoma, a type of bone cancer that has spread to the lungs. The study aims to determine how well this treatment controls the disease and improves survival. Suitable participants are those with this specific lung cancer that hasn't responded well to other treatments and who experience noticeable symptoms affecting daily life. As a Phase 1 and Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop your current medications. However, you cannot be on immunosuppressive therapy or other investigational agents while participating.

Is there any evidence suggesting that Natalizumab is likely to be safe for humans?

Research shows that Natalizumab, a treatment under study for advanced bone cancer (metastatic osteosarcoma), has a known safety record from its use in other diseases. It is already approved for treating multiple sclerosis, providing some understanding of its safety. Over 10 years of data suggest that while some serious side effects can occur, they are not very common.

Specifically, about 13.5% of patients experienced serious side effects, with infections being the most common at 4.1%. Less than 1% of patients had more severe reactions. This indicates that while risks exist, they are infrequent. It is important to note that this safety information comes from its use in treating multiple sclerosis, not bone cancer, so experiences in this trial might differ.

Prospective trial participants should discuss potential risks with the study team or a healthcare provider to understand how this information applies to them. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for metastatic osteosarcoma, which often include chemotherapy and surgery, Natalizumab is unique because it targets a specific protein called integrin alpha-4. This protein plays a role in the movement of cancer cells, and by blocking it, Natalizumab may help prevent the spread of the disease. Researchers are excited about this treatment because it offers a novel approach that could complement existing therapies, potentially leading to better outcomes for patients with this aggressive form of bone cancer.

What evidence suggests that Natalizumab might be an effective treatment for metastatic osteosarcoma?

Research has shown that Natalizumab effectively treats conditions like multiple sclerosis (MS), leading to its re-approval after demonstrating long-term safety. This trial investigates Natalizumab's potential for treating metastatic osteosarcoma. The drug targets specific proteins on immune cells to reduce inflammation and possibly slow tumor growth. Early studies in this trial focus on safety and tolerability, with hope for its effectiveness in challenging cases like lung-related metastatic osteosarcoma. In other cancer types, similar treatments have extended patient survival, offering early hope for Natalizumab's potential in this new area. ^{1 2 3 6 7}

Who Is on the Research Team?

Kristen VanHeyst, DO

Principal Investigator

University Hospitals Cleveland Medical Center

Are You a Good Fit for This Trial?

This trial is for children and young adults with a type of bone cancer that has spread to the lungs (pulmonary metastatic osteosarcoma) and hasn't improved with standard treatments. Participants need normal heart, liver, and marrow function, no severe ongoing illnesses or infections, not be on immunosuppressive therapy or other investigational drugs, and agree to use contraception if applicable.

Inclusion Criteria

My liver is working well.

Peripheral absolute neutrophil count (ANC) ≥ 750/mcL

My organ and bone marrow functions are normal.

Exclusion Criteria

I have side effects from previous treatments, but they are mild except for hair loss, lack of appetite, bone, and tumor pain.

I do not have any severe illnesses that would stop me from following the study's requirements.

Women of childbearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Traditional 3+3 design escalation of Natalizumab at a weight-based dosing 2mg/kg not to exceed a maximum dose of 300mg

6 cycles

Phase II Treatment

Treatment continues if the participant has Complete Response (CR), Partial Response (PR) or Stable Disease (SD) of pOS after every 3 cycles after the first 6 cycles but not beyond 24 cycles

Up to 24 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days

What Are the Treatments Tested in This Trial?

Interventions

• Natalizumab

Trial Overview The study tests Natalizumab's safety and how well it works in patients with pulmonary metastatic osteosarcoma. It aims to see if this drug can improve survival rates in those who have not responded well to conventional therapies.

How Is the Trial Designed?

Group I: Phase I: Natalizumab Experimental Treatment 1 Intervention

Traditional 3+3 design escalation of Natalizumab at a weight-based dosing 2mg/kg not to exceed a maximum dose of 300mg Phase II treatment to continue if the participant has Complete Response (CR), Partial Response (PR) or Stable Disease (SD) of pOS as defined by RECIST 1.1 criteria after every 3 cycles after the first 6 cycles but not beyond 24 cycles. If the participant has progressive disease after 6 cycles, they will be removed from the study.

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

Approved in European Union as Tysabri for:

• Multiple sclerosis
• Crohn's disease

Approved in United States as Tysabri for:

• Multiple sclerosis
• Crohn's disease

Approved in Canada as Tysabri for:

• Multiple sclerosis
• Crohn's disease

Approved in Japan as Tysabri for:

• Multiple sclerosis

Approved in Switzerland as Tysabri for:

• Multiple sclerosis
• Crohn's disease

Who Is Running the Clinical Trial?

Case Comprehensive Cancer Center

Lead Sponsor

Trials

472

Recruited

33,400+

Published Research Related to This Trial

Natalizumab is an effective treatment for moderate-to-severe Crohn's disease, showing better results than placebo in inducing response and maintaining remission.

Despite its efficacy, natalizumab carries a risk of serious side effects, including progressive multifocal leukoencephalopathy, leading to its restricted distribution under the TOUCH program in the USA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Natalizumab for the treatment of Crohn's disease. Bickston, SJ., Muniyappa, K.[2015]

Natalizumab is an effective treatment for relapsing-remitting multiple sclerosis (RR-MS) as it reduces the movement of immune cells into the brain, which helps manage the disease's symptoms.

However, there is a significant safety concern, as its use has been linked to an increased risk of progressive multifocal leukoencephalopathy (PML), a serious brain infection, highlighting the need for careful monitoring in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological properties, toxicology and scientific rationale for the use of natalizumab (Tysabri) in inflammatory diseases. Stüve, O., Bennett, JL.[2020]

This study identified five key targets (CD4, RUNX2, OMD, COL9A3, and JUN) that are crucial for the progression of Osteosarcoma, highlighting their potential as therapeutic targets.

Molecular docking analysis suggests that the drugs vincristine, dexamethasone, and vinblastine could effectively bind to the identified targets RUNX2, OMD, and CD4, indicating a promising approach for Osteosarcoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of therapeutic targets for osteosarcoma by integrating single-cell RNA sequencing and network pharmacology. Wang, Y., Qin, D., Gao, Y., et al.[2023]

In a study involving 1,094 patients over 240 weeks, natalizumab demonstrated long-term efficacy by stabilizing Expanded Disability Status Scale (EDSS) scores and significantly reducing annualized relapse rates in patients with relapsing-remitting multiple sclerosis.

The safety profile of natalizumab remained consistent with known risks, including a risk of progressive multifocal leukoencephalopathy, and higher incidences of anti-natalizumab antibodies and hypersensitivity reactions were observed in patients with shorter exposure before redosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety and effectiveness of natalizumab redosing and treatment in the STRATA MS Study. O'Connor, P., Goodman, A., Kappos, L., et al.[2022]

In a study of 451 multiple sclerosis patients receiving their third infusion of natalizumab, 97% reported improvements or stability in their overall quality of life after treatment, indicating high patient satisfaction.

Significant improvements were observed in disease level and functional status scores after just three infusions, suggesting that natalizumab may provide early benefits in managing MS symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of natalizumab on patient-reported outcomes in a clinical practice setting: a cross-sectional survey. Kamat, SA., Rajagopalan, K., Stephenson, JJ., et al.[2021]

Osteosarcoma, the most common bone tumor in children and young adults, has seen no significant improvements in treatment outcomes for decades due to its biological complexity and lack of targeted therapies.

The New Agents for Osteosarcoma Task Force identified multitargeted tyrosine kinase inhibitors as the most promising agents for frontline evaluation, and these have been included in an upcoming phase III clinical trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Charting a path for prioritization of novel agents for clinical trials in osteosarcoma: A report from the Children's Oncology Group New Agents for Osteosarcoma Task Force. Whittle, SB., Offer, K., Roberts, RD., et al.[2022]

In a study of 45 patients with relapsing-remitting multiple sclerosis (RRMS) who switched to natalizumab after inadequate response to other treatments, 62% showed no signs of disease activity after 44 weeks, indicating its effectiveness in controlling the disease.

Approximately 29% of patients experienced significant improvements in disability status, as measured by the Expanded Disability Status Scale (EDSS), and about 30% showed enhanced walking speed, suggesting that natalizumab can rapidly improve both disability and ambulation in patients with high disease activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Natalizumab induces a rapid improvement of disability status and ambulation after failure of previous therapy in relapsing-remitting multiple sclerosis. Belachew, S., Phan-Ba, R., Bartholomé, E., et al.[2021]

The methotrexate-bisphosphonate conjugate significantly inhibits the growth of human osteosarcoma MG-63 cells, with a notable decrease in cell survival observed at concentrations of 2000 mg/ml or higher over 24 to 96 hours.

This conjugate effectively induces apoptosis in MG-63 cells, as evidenced by various assays including TUNEL and flow cytometry, making it a promising candidate for targeted therapy in osteosarcoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted antiosteosarcoma methotrexate-bisphosphonate conjugate induces apoptosis of osteosarcoma cells in vitro. Yang, XN., Zeng, JC., Song, YC., et al.[2014]

In a study involving C3H mice with osteosarcoma, honokiol treatment significantly reduced lung micrometastases by 41% and macrometastases in the liver by 80%, indicating its strong antimetastatic potential.

Honokiol caused rapid cell death in osteosarcoma cell lines through a unique mechanism that did not involve necrosis, apoptosis, or autophagy, suggesting it could be a novel therapeutic option for treating metastasizing osteosarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antimetastatic activity of honokiol in osteosarcoma. Steinmann, P., Walters, DK., Arlt, MJ., et al.[2012]

Immunotherapy using antibody-drug conjugates shows promise for treating osteosarcoma (OS), with preclinical studies indicating encouraging results in targeting OS surface antigens.

Clinical trials involving glembatumumab vedotin may provide valuable insights into the efficacy of these treatments, potentially improving patient selection and outcomes in OS therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunoconjugates for Osteosarcoma Therapy: Preclinical Experiences and Future Perspectives. Mercatelli, D., Bortolotti, M., Bazzocchi, A., et al.[2020]

Osteosarcoma (OS) is a highly aggressive bone tumor with a low 5-year survival rate due to tumor recurrence and metastasis, highlighting the need for more effective treatments beyond standard therapies like MAP chemotherapy.

The ErbB receptor family, which is linked to cancer growth and poor prognosis, presents a promising target for new therapies in OS, with ongoing clinical trials exploring monoclonal antibodies and inhibitors aimed at these receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advanced development of ErbB family-targeted therapies in osteosarcoma treatment. Wang, W., Zhao, HF., Yao, TF., et al.[2020]

Osteosarcoma (OS) treatment has improved overall survival rates to 60-75% with surgery and chemotherapy, but patients with pulmonary metastasis face a much lower 5-year survival rate of about 20%.

There is a pressing need for novel targeted therapies for relapsed and metastatic osteosarcoma, as current options are limited and often involve additional cytotoxic treatments, highlighting ongoing research efforts to enhance patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of TKI for Metastatic Osteogenic Sarcoma. Duffaud, F.[2021]

The study developed improved mouse models of osteosarcoma (OS) using the low metastatic Dunn cell line and its highly metastatic LM8 subline, which allow for the visualization of single metastatic cells in organs, aiding in the understanding of metastasis mechanisms.

These models, which maintain the tumorigenic and metastatic properties of the cells, will be crucial for testing new drugs that target metastasizing cells and for developing advanced imaging technologies for early detection of metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LacZ transgene expression in the subcutaneous Dunn/LM8 osteosarcoma mouse model allows for the identification of micrometastasis. Arlt, MJ., Banke, IJ., Walters, DK., et al.[2011]

In a study of 66 patients with recurrent bone tumors, regorafenib and cabozantinib showed meaningful activity, with median overall survival ranging from 8.1 to 18.2 months depending on the tumor type.

The treatment was generally well-tolerated, with 42.4% of patients requiring dose reductions due to side effects, indicating that these targeted therapies can be effective with manageable toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience of tyrosine kinase inhibitors in children, adolescents and adults with relapsed or refractory bone tumours: A Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) study. Peretz Soroka, H., Vora, T., Noujaim, J., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03811886?term=natalizumab&rank=10

Natalizumab in Recurrent, Refractory or Progressive ... The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure.

2. withpower.com withpower.com/trial/phase-2-osteosarcoma-8-2021-49431

Natalizumab for Metastatic Osteosarcoma Safety data from the STRATA MS Study indicates long-term safety over 240 weeks. Natalizumab was reapproved for relapsing forms of MS after initial concerns ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8998815/

Recent and Ongoing Research into Metastatic ... Median survival for patients with unresectable metastases was 13 months and 31 months for those who underwent successful metastasectomy [37]. Trial data to date ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03811886

Study Details | NCT03811886 | Natalizumab in Recurrent, ... The purpose of this study is to evaluate the safety and tolerability of Natalizumab in children, adolescent and young adult patients with pulmonary ...

5. uhhospitals.org uhhospitals.org/for-clinicians/articles-and-news/articles/2021/11/deploying-immunotherapy-against-metastatic-osteosarcoma

Deploying Immunotherapy Against Metastatic Osteosarcoma “The outcomes for metastatic osteosarcoma are pretty abysmal,” says pediatric oncologist Alex Huang, MD, PhD, Director of the new Pediatric ...

6. tysabrihcp.com tysabrihcp.com/en_us/home/clinical-trials/observational-program.html

10-Year Safety & Efficacy Results | TYSABRI® (natalizumab ... 10-YEAR SAFETY DATA. TYSABRI had a sustained impact on disability progression ... Based on animal data, TYSABRI may cause fetal harm. TYSABRI should be ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7279201/

Long-term safety and effectiveness of natalizumab treatment ... Overall, 829 patients (13.5%) experienced ≥1 serious adverse event (SAE), with infection the most common (4.1%). Fifty-three patients (0.9%) had ...