Cabozantinib + Ifosfamide for Bone Cancer

Recruiting at 4 trial locations

Overseen By Meghan Donnelly, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a new treatment for individuals with Ewing sarcoma and osteosarcoma, types of bone cancer that have returned or resisted treatment. The study examines the combined use of two drugs, cabozantinib (Cabometyx) and high-dose ifosfamide, to determine if they can more effectively combat these cancers. Ideal candidates are those whose bone cancer has progressed after traditional chemotherapy and have undergone no more than two prior treatments. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

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

Research has shown that cabozantinib has been tested in patients with bone cancers, such as Ewing sarcoma and osteosarcoma. In these studies, some patients experienced unwanted side effects from the drug. For example, one study found that 75% of patients reported at least one side effect. However, other studies did not find any new safety concerns, suggesting that the drug's safety is generally consistent.

Previous trials identified common serious side effects, including pneumonia and issues detected in lab tests. While side effects can occur, cabozantinib has proven effective in fighting tumors in these types of cancers. This suggests the drug might still be helpful even if side effects happen. Prospective trial participants should discuss potential risks and benefits with a healthcare professional. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for bone cancer?

Cabozantinib is unique because it targets multiple pathways involved in bone cancer growth, unlike standard treatments that often focus on just one. This multi-target approach can potentially slow down tumor progression more effectively. Researchers are excited about cabozantinib because it also inhibits the MET and VEGFR2 pathways, which are crucial for cancer cell survival and blood supply, offering a promising new strategy against bone cancer.

What evidence suggests that cabozantinib in combination with high-dose ifosfamide might be an effective treatment for bone cancer?

Research has shown that cabozantinib, which participants in this trial will receive, may help treat bone cancers like Ewing sarcoma and osteosarcoma. One study found cabozantinib effective in fighting tumors in patients with advanced stages of these cancers. Another study found that while no patients were completely cured, many experienced stable disease, meaning their cancer did not worsen for a while. Cabozantinib also affects the bone environment, which might help slow down osteosarcoma. These findings suggest that cabozantinib could be a useful option for managing bone cancers that have returned or are difficult to treat. ^{1 3 5 6 7}

Who Is on the Research Team?

Theodore W. Laetsch

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

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 condition worsened after initial treatment including chemotherapy, with no more than 2 prior chemotherapy treatments.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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 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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9918141/

Real-World Data on Cabozantinib in Advanced Osteosarcoma ... No objective response was noted, and 9/16 patients exhibited stable disease outcomes. Progression-free survival varied from 1 to 8 (median; 5) ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8763616/

Cabozantinib in Advanced Ewing Sarcomas and osteosarcomas In this study, cabozantinib showed marked antitumor activity in patients with advanced Ewing sarcoma and osteosarcoma and may represent a new ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.535

Evaluating the efficacy of cabozantinib in patients with ... Conclusions: Cabozantinib demonstrated favorable clinical effects on bone metastasis in patients with aRCC, as suggested by a high DCR. Our ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05691478

NCT05691478 | A Study to Test the Addition of the Drug ... This phase II/III trial tests the safety, side effects, and best dose of the drug cabozantinib in combination with standard chemotherapy.

5. nature.com nature.com/articles/s41598-018-22469-5

Cabozantinib Affects Osteosarcoma Growth Through A ... The present study aimed to evaluate the effect of c-MET inhibitor cabozantinib (CBZ) on OS both directly and through its action on bone microenvironment.

6. cabometyxhcp.com cabometyxhcp.com/rcc-treatment/monotherapy/safety

CABOSUN & METEOR show similar safety results for ... Grade 3-4 adverse reactions (ARs) occurring in >1% of patients who received CABOMETYX in the CABOSUN trial · Laboratory-related Grade 3-4 ARs occurring in ≥1% of ...

7. ema.europa.eu ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf

Cabometyx, INN-Cabozantinib - EMA Cabozantinib as monotherapy Summary of safety profile The most common serious adverse drug reactions in the RCC population (≥1% incidence) are pneumonia, ...