Cabozantinib + Ifosfamide for Bone Cancer

Recruiting at 4 trial locations

Overseen By James Robinson, MSW, MPH

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Children's Hospital of Philadelphia

Must not be taking: CYP3A4 drugs, QTc drugs

Disqualifiers: Brain metastases, Cardiovascular disease, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

30 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to better understand how safe and effective the drug cabozantinib in combination with high-dose ifosfamide is in the treatment of children and adults with relapsed/refractory Ewing sarcoma and osteosarcoma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does exclude certain medications like strong CYP3A4 inducers or inhibitors, and some anticoagulants. It's best to discuss your current medications with the study team to see if they are allowed.

What data supports the effectiveness of the drug Cabozantinib for bone cancer?

Research shows that Cabozantinib has been effective in reducing tumor size in patients with bone metastases from various cancers, including sarcoma, and has improved overall survival rates. In a study, it decreased the risk of death by 53% in patients with bone metastases compared to standard treatments. ^{1 2 3 4 5}

Is the combination of Cabozantinib and Ifosfamide safe for treating bone cancer?

Cabozantinib has been studied for safety in various cancers, including bone cancers like osteosarcoma and Ewing sarcoma. Common side effects include fatigue, diarrhea, and high blood pressure, with some serious risks like cerebral hemorrhage. Dose adjustments are often needed to manage these side effects. ^{1 2 6 7 8}

How is the drug Cabozantinib + Ifosfamide unique for treating bone cancer?

Cabozantinib, when combined with Ifosfamide, offers a novel approach for bone cancer by potentially targeting cancer growth through different mechanisms, as Cabozantinib is known to inhibit certain pathways involved in tumor growth and blood vessel formation, which is different from traditional chemotherapy regimens that primarily focus on killing rapidly dividing cells. ^{9 10 11 12 13}

Research Team

Theodore W. Laetsch

Principal Investigator

Children's Hospital of Philadelphia

Eligibility Criteria

This trial is for children and adults with relapsed/refractory Ewing sarcoma or osteosarcoma who have had prior chemotherapy. Participants must be able to swallow tablets, not pregnant, use contraception, and have a certain body surface area. They should have measurable disease progression but limited previous treatments and good organ function.

Inclusion Criteria

My cancer can be measured by scans according to specific criteria.

Hematopoietic function: Absolute neutrophil count > 1,000/uL (without hematopoietic growth factor within the time frame noted below). Hemoglobin > 8 g/dL (without transfusion in the last 7 days). Platelets > 100,000/uL (without transfusion in the last 7 days).

My kidney function is normal based on tests.

Exclusion Criteria

Other clinically significant disorders that would preclude safe study participation, including: Cavitating pulmonary lesion. Serious non-healing wound/ulcer/bone fracture. Uncompensated/symptomatic hypothyroidism. Moderate to severe hepatic impairment (Child-Pugh B or C). Recipient of solid organ transplant, known human immunodeficiency virus (HIV) seropositivity, and other non-treatment related immunodeficiencies. Severe or uncontrolled infection or systemic disease. Inadequate electrolyte balance, defined as abnormal levels of serum potassium, calcium, magnesium, and phosphorous and causing clinically significant symptoms, acid-base disturbances, or changes in ECG. Women who are currently pregnant or breastfeeding.

I have had severe bladder inflammation from cancer treatment.

I am not taking any strong medication that affects liver enzymes or prolongs the QT interval.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cabozantinib in combination with high-dose ifosfamide to evaluate safety and antitumor activity

6 months

Periodic visits for disease progression assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Extension

Participants may continue treatment to further evaluate long-term safety and efficacy

Long-term

Treatment Details

Interventions

• Cabozantinib

Trial Overview The study tests the safety and effectiveness of cabozantinib combined with high-dose ifosfamide in treating specific sarcomas. It aims to understand how well this drug combination works when other treatments haven't been successful.

Participant Groups

Group I: Treatment Experimental Treatment 1 Intervention

Cabozantinib

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

Approved in European Union as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in United States as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Canada as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Japan as Cabometyx for:

• Renal cell carcinoma

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

Children's Hospital Colorado

Collaborator

Trials

121

Recruited

5,135,000+

Alex's Lemonade Stand Foundation

Industry Sponsor

Trials

9

Recruited

1,500+

Exelixis

Industry Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

Findings from Research

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]

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]

Cabozantinib, an oral medication, was found to be safe and effective in treating bone metastases in 37 patients with various solid tumors, with no skeletal-related events observed during the study.

Among the 20 patients with measurable disease, 4 showed a partial response and 12 had a decrease in tumor burden, indicating that cabozantinib may be particularly effective for patients with metastatic sarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Cabozantinib in Patients With Bone Metastasis. Choy, E., Cote, GM., Michaelson, MD., et al.[2022]

In a phase II study involving 52 women with hormone receptor-positive breast cancer and bone metastases, cabozantinib showed a 38% partial response rate on bone scans, indicating its potential effectiveness in this patient population.

The treatment resulted in a median progression-free survival of 4.3 months and a median overall survival of 19.6 months, with manageable side effects, primarily hypertension and anorexia, suggesting that cabozantinib could be a viable option for patients with this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Trial of Cabozantinib in Hormone Receptor-Positive Breast Cancer with Bone Metastases. Xu, J., Higgins, MJ., Tolaney, SM., et al.[2021]

Cabozantinib significantly improves overall survival in cancer patients, reducing the risk of death by 53% for those with bone metastases and by 44% for those without, based on a systematic review of randomized trials.

While cabozantinib is an effective treatment option for patients with bone metastases, its benefits do not differ significantly from those seen in patients without bone metastases, suggesting that the presence of bone metastases should not be the primary factor in choosing this drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A metanalysis on cabozantinib and bone metastases: true story or commercial gimmick? Bersanelli, M., Buti, S., Ghidini, A., et al.[2021]

Cabozantinib is an oral multitargeted tyrosine kinase inhibitor approved for advanced renal cell carcinoma and progressive metastatic medullary thyroid cancer, showing potential advantages over single-receptor TKIs.

The article reviews clinical trial data and management strategies for common adverse events associated with cabozantinib, highlighting its expanding use in treating various cancers such as prostate, hepatocellular, and lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib: A Multitargeted Oral Tyrosine Kinase Inhibitor. Markowitz, JN., Fancher, KM.[2019]

Cabozantinib is an effective treatment for advanced hepatocellular carcinoma (HCC) after failure of sorafenib, showing significant improvement in overall survival and progression-free survival compared to placebo in the phase 3 CELESTIAL trial.

Common side effects of cabozantinib include palmar-plantar erythrodysesthesia, hypertension, fatigue, and diarrhea, which are important to manage in patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib for the Treatment of Advanced Hepatocellular Carcinoma: Current Data and Future Perspectives. Trojan, J.[2021]

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]

In a study of 30 patients under 30 years old with metastatic osteosarcoma, the ifosfamide-containing chemotherapy regimen resulted in a 5-year survival rate of 53.3% and an event-free survival rate of 46.7%, indicating its effectiveness in treating this aggressive cancer.

The treatment was generally well-tolerated, with mild hematopoietic toxicity reported, although some patients experienced renal toxicity. However, the study suggests that improved treatment strategies are needed, especially for patients with multiple lung metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study. Harris, MB., Gieser, P., Goorin, AM., et al.[2017]

A combination chemotherapy regimen of ifosfamide, doxorubicin, and cisplatin was assessed in 103 patients with primary osteosarcoma, showing a clinical response in 36% of primary tumors and 33% of pulmonary metastases.

Despite the regimen's activity, it did not demonstrate superior efficacy compared to the existing two-drug cisplatin-doxorubicin treatment, with five-year survival rates of 62% for non-metastatic limb tumors, 41% for axial skeletal tumors, and only 16% for limb metastatic cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of cisplatin, ifosfamide and doxorubicin in operable primary, axial skeletal and metastatic osteosarcoma. European Osteosarcoma Intergroup (EOI). Voûte, PA., Souhami, RL., Nooij, M., et al.[2020]

In a study of 69 patients with untreated osteosarcoma, the combination of carboplatin and ifosfamide showed a 67.7% clinical and radiographic response rate, significantly reducing the rate of disease progression compared to historical data using only ifosfamide.

Patients receiving carboplatin/ifosfamide experienced comparable survival rates to those treated with cisplatin-based therapies, but with reduced long-term renal toxicity and ototoxicity, indicating a safer treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin/ifosfamide window therapy for osteosarcoma: results of the St Jude Children's Research Hospital OS-91 trial. Meyer, WH., Pratt, CB., Poquette, CA., et al.[2017]

The combination of etoposide and high-dose ifosfamide resulted in a 59% overall response rate in patients with newly diagnosed metastatic osteosarcoma, indicating its effectiveness as an induction chemotherapy.

Despite its efficacy, the treatment was associated with significant toxicity, including severe myelosuppression (83% of patients experienced grade 4 neutropenia) and complications such as sepsis and renal toxicity, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. Goorin, AM., Harris, MB., Bernstein, M., et al.[2017]

In a study of 86 osteosarcoma patients, the combination of liposome doxorubicin and ifosfamide resulted in a higher total effective rate and 2-year survival rate compared to conventional doxorubicin and ifosfamide, indicating improved efficacy.

Patients receiving liposome doxorubicin experienced fewer adverse effects, such as liver and kidney function injuries and cardiotoxicity, while also showing better quality of life scores, suggesting a safer treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of ifosfamide combined with liposome doxorubicin on osteosarcoma and its effects on serum IL-10, TNF-α, and IFN-γ in patients with osteosarcoma. Huang, G., Hua, S., Liu, H., et al.[2022]

References

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

Phase 1 study of cabozantinib in combination with topotecan-cyclophosphamide for patients with relapsed Ewing sarcoma or osteosarcoma. [2023]

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

Anticancer Activity of the Combination of Cabozantinib and Temozolomide in Uterine Sarcoma. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Phase II Study of Cabozantinib in Patients With Bone Metastasis. [2022]

4. England pubmed.ncbi.nlm.nih.gov

A Phase II Trial of Cabozantinib in Hormone Receptor-Positive Breast Cancer with Bone Metastases. [2021]

5. England pubmed.ncbi.nlm.nih.gov

A metanalysis on cabozantinib and bone metastases: true story or commercial gimmick? [2021]

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

Cabozantinib: A Multitargeted Oral Tyrosine Kinase Inhibitor. [2019]

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

Cabozantinib for the Treatment of Advanced Hepatocellular Carcinoma: Current Data and Future Perspectives. [2021]

8. Switzerland 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. [2023]

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

Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study. [2017]

10. England pubmed.ncbi.nlm.nih.gov

A phase II study of cisplatin, ifosfamide and doxorubicin in operable primary, axial skeletal and metastatic osteosarcoma. European Osteosarcoma Intergroup (EOI). [2020]

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

Carboplatin/ifosfamide window therapy for osteosarcoma: results of the St Jude Children's Research Hospital OS-91 trial. [2017]

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

Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. [2017]

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

Efficacy of ifosfamide combined with liposome doxorubicin on osteosarcoma and its effects on serum IL-10, TNF-α, and IFN-γ in patients with osteosarcoma. [2022]