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

Trial Summary

What is the purpose of this trial?

This trial tests if Natalizumab, a drug that changes how the immune system works, can help young patients with a specific type of lung-spread bone cancer that hasn't responded to other treatments.

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.

What data supports the idea that Natalizumab for Metastatic Osteosarcoma is an effective treatment?

The available research does not provide specific data supporting the effectiveness of Natalizumab for Metastatic Osteosarcoma. Instead, it discusses other treatments like tyrosine kinase inhibitors and ErbB-targeted therapies, which are being explored for this condition. These alternatives are being prioritized for clinical trials due to the lack of progress in improving survival rates for metastatic osteosarcoma with existing treatments. ^{1 2 3 4 5}

What safety data exists for Natalizumab (Tysabri)?

Natalizumab, also known as Tysabri, has been studied for its safety in multiple sclerosis (MS) and Crohn's disease. It has been associated with progressive multifocal leukoencephalopathy (PML), a serious brain infection, in some patients. The drug is generally well tolerated but carries an increased risk of infections, such as influenza. Due to the risk of PML, its use is restricted under the TOUCH program in the USA. 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 about PML. ^{6 7 8 9 10}

Is the drug Natalizumab a promising treatment for metastatic osteosarcoma?

Based on the provided research articles, there is no specific mention of Natalizumab as a promising treatment for metastatic osteosarcoma. The articles discuss other potential treatments and targets, but Natalizumab is not highlighted among them. ^{4 11 12 13 14}

Research Team

Kristen VanHeyst, DO

Principal Investigator

University Hospitals Cleveland Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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 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]

References

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

Role of TKI for Metastatic Osteogenic Sarcoma. [2021]

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

LacZ transgene expression in the subcutaneous Dunn/LM8 osteosarcoma mouse model allows for the identification of micrometastasis. [2011]

3. United States 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. [2023]

4. United States 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. [2022]

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

Advanced development of ErbB family-targeted therapies in osteosarcoma treatment. [2020]

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

Long-term safety and effectiveness of natalizumab redosing and treatment in the STRATA MS Study. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Natalizumab for the treatment of Crohn's disease. [2015]

8. England 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. [2021]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Impact of natalizumab on patient-reported outcomes in a clinical practice setting: a cross-sectional survey. [2021]

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

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

11. Italy pubmed.ncbi.nlm.nih.gov

Targeted antiosteosarcoma methotrexate-bisphosphonate conjugate induces apoptosis of osteosarcoma cells in vitro. [2014]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Identification of therapeutic targets for osteosarcoma by integrating single-cell RNA sequencing and network pharmacology. [2023]

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

Antimetastatic activity of honokiol in osteosarcoma. [2012]

14. Switzerland pubmed.ncbi.nlm.nih.gov

Immunoconjugates for Osteosarcoma Therapy: Preclinical Experiences and Future Perspectives. [2020]