Sorafenib + Cyclophosphamide/Topotecan for Neuroblastoma

(N2013-02 Trial)

Recruiting at 11 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: New Approaches to Neuroblastoma Therapy Consortium

Must not be taking: Anticoagulants, Antihypertensives, Antiarrhythmics, Enzyme inducers

Disqualifiers: Pregnancy, Infection, Allogeneic transplant, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 5 days per course, repeated over 2 years

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will combine three drugs: sorafenib, cyclophosphamide and topotecan. Adding sorafenib to cyclophosphamide and topotecan may increase the effectiveness of this combination. The investigators first need to find out the highest dose of sorafenib that can be given safely together with cyclophosphamide and topotecan. This is the first study to test giving these three drugs together and will help determine the highest dose of sorafenib that can safely be given together with cyclophosphamide and topotecan to patients with resistant/relapsed neuroblastoma.

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

The trial protocol does not specify if you need to stop all current medications, but you cannot take certain medications like anti-cancer agents, investigational drugs, enzyme inducers, anti-coagulation, anti-arrhythmic, or anti-hypertensive medications during the study. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug combination Sorafenib, Cyclophosphamide, and Topotecan for treating neuroblastoma?

Research shows that the combination of topotecan and cyclophosphamide has been used in children with neuroblastoma, particularly in cases where the disease has returned or is resistant to other treatments. This combination has been studied for its ability to help manage the disease and improve outcomes in these challenging cases. ^{1 2 3 4 5}

Is the combination of Sorafenib, Cyclophosphamide, and Topotecan safe for humans?

The combination of Cyclophosphamide and Topotecan has been studied in children with neuroblastoma, showing some toxicities (side effects) but generally considered manageable. These studies focused on neuroblastoma, so while they provide some safety information, they may not fully represent the safety profile for other conditions or when combined with Sorafenib. ^{1 2 3 4 6}

What makes the drug combination of Sorafenib, Cyclophosphamide, and Topotecan unique for treating neuroblastoma?

This treatment is unique because it combines Sorafenib, a drug that targets cancer cell growth, with Cyclophosphamide and Topotecan, which are used in other regimens for neuroblastoma, potentially offering a novel approach to improve outcomes in high-risk patients. ^{1 2 3 4 5}

Eligibility Criteria

This trial is for patients under 30 with high-risk neuroblastoma that's come back or didn't respond to treatment. They should have a certain level of bone marrow activity, no recent other cancer treatments, and be able to perform daily activities at least half the time. Not eligible if pregnant, breastfeeding, had an allogeneic transplant, uncontrolled infections or certain heart conditions.

Inclusion Criteria

Serum albumin > 2.5 g/dl

I am not on blood thinners.

My cancer has come back, hasn't responded well, or still exists after initial treatment.

Exclusion Criteria

I or my close family had blood clots before 40, but only if not caused by a central line.

Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events

I do not have any active or uncontrolled infections.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sorafenib in combination with cyclophosphamide and topotecan to determine the maximum tolerated dose

5 days per course, repeated over 2 years

Multiple visits for dose escalation and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Cyclophosphamide
• Sorafenib
• Topotecan

Trial Overview The study tests combining sorafenib with cyclophosphamide and topotecan in children and young adults with relapsed/refractory neuroblastoma. It aims to find the highest safe dose of sorafenib when used with these drugs for this specific condition.

Participant Groups

Group I: Sorafenib and Cyclophosphamide/Topotecan Experimental Treatment 3 Interventions

Sorafenib and Cyclophosphamide/Topotecan with growth factor support.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

New Approaches to Neuroblastoma Therapy Consortium

Lead Sponsor

Trials

19

Recruited

1,700+

Cook Children's Health Care System

Collaborator

Trials

11

Recruited

5,001,000+

Dana-Farber Cancer Institute

Collaborator

Trials

1,128

Recruited

382,000+

University of Michigan

Collaborator

Trials

1,891

Recruited

6,458,000+

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

Children's Healthcare of Atlanta

Collaborator

Trials

172

Recruited

108,000+

Seattle Children's Hospital

Collaborator

Trials

319

Recruited

5,232,000+

Children's Hospital Medical Center, Cincinnati

Collaborator

Trials

844

Recruited

6,566,000+

The Hospital for Sick Children

Collaborator

Trials

724

Recruited

6,969,000+

Lucile Packard Children's Hospital

Collaborator

Trials

16

Recruited

2,800+

Findings from Research

In a phase II trial involving 119 children with relapsed/refractory neuroblastoma, the combination of topotecan and cyclophosphamide (TOPO/CTX) showed a higher response rate (32%) compared to single-agent topotecan (19%), indicating that TOPO/CTX may be more effective in achieving initial responses.

While TOPO/CTX resulted in significantly better progression-free survival (PFS), there was no difference in overall survival (OS) between the two treatments after adjusting for subsequent therapies, suggesting that while TOPO/CTX may delay disease progression, it does not necessarily improve long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a Children's Oncology Group study. London, WB., Frantz, CN., Campbell, LA., et al.[2022]

In a study of 107 high-risk neuroblastoma patients, an induction regimen combining topotecan and cyclophosphamide resulted in favorable treatment responses, with no patients experiencing stable disease or progression after the fifth cycle.

The treatment was well tolerated, with febrile neutropenia being the most common side effect, indicating that this regimen could be a safe and effective option for managing high-risk neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes and prognostic factors to predict treatment response in high risk neuroblastoma patients receiving topotecan and cyclophosphamide containing induction regimen: a prospective multicenter study. Rujkijyanont, P., Photia, A., Traivaree, C., et al.[2020]

In a Phase II trial involving 25 children with advanced neuroblastoma, the combination of topotecan, vincristine, and doxorubicin showed a promising overall response rate of 64%, with 4 complete responses and 12 partial responses.

The treatment was generally well tolerated, with limited toxicity primarily affecting the hematopoietic system, and only one patient experiencing dose-limiting Grade 4 liver toxicity, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of topotecan with vincristine and doxorubicin in children with recurrent/refractory neuroblastoma. Garaventa, A., Luksch, R., Biasotti, S., et al.[2020]

References

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

Camptothecin analogs (irinotecan or topotecan) plus high-dose cyclophosphamide as preparative regimens for antibody-based immunotherapy in resistant neuroblastoma. [2021]

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

Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a Children's Oncology Group study. [2022]

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

Clinical outcomes and prognostic factors to predict treatment response in high risk neuroblastoma patients receiving topotecan and cyclophosphamide containing induction regimen: a prospective multicenter study. [2020]

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

Treatment with topotecan plus cyclophosphamide in children with first relapse of neuroblastoma. [2013]

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

A phase II study of topotecan with vincristine and doxorubicin in children with recurrent/refractory neuroblastoma. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Short topotecan-based induction regimen in newly diagnosed high-risk neuroblastoma. [2013]