Metronomic Chemotherapy for Pediatric High-Risk Cancer

(Metronomic Trial)

Recruiting at 1 trial location

Overseen By Ted Zwerdling, MD

Age: < 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Miller Children's & Women's Hospital Long Beach

Must be taking: Metronomic therapy

Disqualifiers: Pregnancy, CNS tumor, Relapsed, 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

Compensation: Varies

Number of Visits: 21

Duration: 60 weeks

20 Participants Needed

Trial Summary

What is the purpose of this trial?

Most pediatric patients with solid tumors respond to initial high-dose, intensive therapy and complete treatment in remission. High-risk patients however, frequently have recurrent disease which is then treated with ad hoc regimens or early phase therapies with little benefit to the patient. Metronomic therapy (MC), defined as lower dose continuous drug exposure, has been successfully tested in pediatric leukemias with excellent results in terms of improved outcome, toxicity profiles, and cost. MC has been applied to solid tumors with little success, but has been implemented usually in the relapsed setting at a time of high tumor burden and disease resistance.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug combination used in metronomic chemotherapy for pediatric high-risk cancer?

Research shows that metronomic chemotherapy, which involves giving low doses of drugs frequently, can be effective in children with recurrent or progressive cancer. In one study, 40% of patients completed 6 months of therapy and remained disease-free for a prolonged period, suggesting that this approach can help control cancer growth. ^{1 2 3 4 5}

Is metronomic chemotherapy safe for children with high-risk cancer?

Research shows that metronomic chemotherapy, which involves giving low doses of drugs like cyclophosphamide over time, is generally well tolerated in children with recurrent or progressive cancer. Some side effects, like bone marrow suppression (a decrease in blood cell production), were reversible with dose adjustments, and the treatment was considered safe enough to continue studying in clinical trials. ^{1 2 4 6 7}

How is the drug metronomic chemotherapy with Bevacizumab and Cyclophosphamide unique for pediatric high-risk cancer?

This treatment is unique because it uses metronomic chemotherapy, which involves giving low doses of drugs frequently without long breaks, aiming to stop the growth of blood vessels that feed tumors. This approach can reduce side effects and improve the quality of life for children, making it a promising option for high-risk pediatric cancers. ^{3 4 8 9 10}

Research Team

Ted Zwerdling, MD

Principal Investigator

Miller Children's and Women's Hospital Long Beach

Eligibility Criteria

This trial is for pediatric patients aged 12 months to less than 31 years with specific solid tumors like rhabdomyosarcoma and osteosarcoma, who are in remission but at high risk of recurrence. They must have completed initial therapy, be within six weeks post-treatment, not pregnant or breastfeeding, and willing to use contraception if applicable.

Inclusion Criteria

All patients or their parents/legal guardian will have signed an informed consent document

Patients must have had histologic verification of malignancy at original diagnosis

Normal liver tests (ALT/AST/total bilirubin/triglycerides/cholesterol)

Exclusion Criteria

Lactating females are not eligible unless they have agreed to discontinue breastfeeding

I have a brain tumor.

I am using effective birth control during the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive metronomic therapy consisting of bevacizumab, cyclophosphamide, valproic acid, and temsirolimus over 10 cycles of 42 days each

60 weeks

Regular visits every 21 days for evaluation and treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to five years

Treatment Details

Interventions

• Bevacizumab
• Cyclophosphamide
• Temsirolimus
• Valproic Acid

Trial Overview The study tests metronomic therapy using lower doses of Bevacizumab, Cyclophosphamide, Valproic Acid, and Temsirolimus continuously on children with solid tumors. It aims to see if this approach can prevent cancer from coming back while being less toxic and more cost-effective.

Participant Groups

Group I: Metronomic Therapy Experimental Treatment 4 Interventions

There is only one arm in this study. All subjects receive the same therapy for a period of 420 days (42 day cycles x 10 cycles). 1. Bevacizumab: IV, 10 mg/kg, Days 1, 8 2. Cyclophosphamide: PO, 25 mg/m2 Days 1-14 (max dose = 50mg/dose) 3. Valproic Acid: PO, 5 mg/kg, three times per day (TID), Days 22-35 4. Temsirolimus: IV, 25 mg/m2, Days 22, 29

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

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

Miller Children's & Women's Hospital Long Beach

Lead Sponsor

Trials

2

Recruited

120+

Children's Hospital of Orange County

Collaborator

Trials

38

Recruited

5,700+

Findings from Research

The maximum tolerated dose (MTD) for the combination of sirolimus, cyclophosphamide, and topotecan in pediatric patients with relapsed/refractory solid tumors was established, with sirolimus levels targeted at 8-12.0 ng/mL, indicating a safe dosing strategy for this population.

While no objective responses were observed, the treatment was well tolerated, and biomarker analyses showed significant reductions in angiogenesis-related factors, suggesting potential modulation of tumor growth pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors. Vo, KT., Karski, EE., Nasholm, NM., et al.[2021]

In a phase II study involving 101 children with recurrent or progressive cancer, a 5-drug oral regimen was generally well tolerated, with hematologic toxicities being the most common side effects.

Out of the participants, 25% completed 27 weeks of therapy without disease progression, with notable responses in certain tumor types, particularly ependymoma and low-grade glioma, indicating potential efficacy of the treatment in specific cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer. Robison, NJ., Campigotto, F., Chi, SN., et al.[2022]

Metronomic chemotherapy (MC) offers a promising treatment approach for pediatric cancer, allowing for frequent, low-dose drug administration that minimizes toxicity while maintaining efficacy, which is crucial for improving the quality of life for young patients.

MC not only enhances comfort through oral administration and home-based treatment but also has the potential to reduce the economic burden of cancer therapy in children, making it a valuable option in both high- and low-income settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metronomic Chemotherapy in Pediatric Oncology: From Preclinical Evidence to Clinical Studies. Banchi, M., Fini, E., Crucitta, S., et al.[2022]

A 6-month metronomic chemotherapy regimen using oral thalidomide, celecoxib, etoposide, and cyclophosphamide was well tolerated in 20 children with recurrent or progressive cancer, despite some patients experiencing reversible bone marrow suppression and other toxicities.

Forty percent of the patients completed the full 6 months of therapy, with some achieving prolonged disease-free status, and 16% showing a partial response, indicating potential efficacy of this antiangiogenic approach in pediatric cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer. Kieran, MW., Turner, CD., Rubin, JB., et al.[2019]

The study involved 18 pediatric patients with recurrent and refractory solid and brain tumors, testing the combination of sirolimus and metronomic chemotherapy, which was found to be well tolerated with a recommended phase II dose of 2 mg/m2.

While the best response observed was stable disease in eight patients and a partial response in one, the treatment effectively inhibited a key cancer-related pathway, as indicated by the inhibition of phospho-S6 kinase in all patients during the first cycle.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of sirolimus in combination with metronomic therapy (CHOAnome) in children with recurrent or refractory solid and brain tumors. Qayed, M., Cash, T., Tighiouart, M., et al.[2020]

The combination of low dose metronomic topotecan and pazopanib significantly improved antitumor activity and survival in pediatric solid tumor mouse models compared to using either drug alone.

In vitro studies showed that topotecan effectively reduced cell viability in various cancer cell lines, while pazopanib did not, indicating that the combination therapy enhances antiangiogenic effects without adverse drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor. Kumar, S., Mokhtari, RB., Sheikh, R., et al.[2021]

In a study involving 19 children and young adults with recurrent solid tumors, the combination of sorafenib, bevacizumab, and low-dose cyclophosphamide showed promising antitumor activity, with 5 out of 17 evaluable patients achieving partial responses and 5 stabilizing their disease.

The recommended doses for further studies were established as sorafenib at 90 mg/m² twice daily, bevacizumab at 15 mg/kg every 3 weeks, and cyclophosphamide at 50 mg/m² daily, with manageable toxicities including neutropenia and rashes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children and young adults with refractory/recurrent solid tumors. Navid, F., Baker, SD., McCarville, MB., et al.[2021]

Metronomic chemotherapy, which involves giving low doses of chemotherapy frequently without long breaks, shows promise in controlling advanced cancer, particularly in children, by targeting angiogenesis—the process that tumors use to grow.

This approach not only helps in killing resistant cancer cells but also significantly reduces the side effects typically associated with traditional chemotherapy, making it a potentially safer option for young patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Metronomic chemotherapy in pediatric oncology: hype or hope?]. André, N., Pasquier, E., Verschuur, A., et al.[2009]

A four-drug metronomic chemotherapy regimen showed anti-tumor activity in pediatric patients with low-grade gliomas (LGG), with 2 partial responses and 6 stable disease outcomes observed after two cycles.

The treatment was generally well-tolerated, with acceptable toxicity levels, although five patients experienced grade 3/4 adverse effects, indicating that while effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metronomic Four-Drug Regimen Has Anti-tumor Activity in Pediatric Low-Grade Glioma; The Results of a Phase II Clinical Trial. Verschuur, A., Heng-Maillard, MA., Dory-Lautrec, P., et al.[2020]

Metronomic chemotherapy, which involves administering low doses of chemotherapy drugs frequently without long breaks, is emerging as a promising strategy for treating advanced and high-risk cancers, particularly in pediatric oncology.

Despite its potential, the development of metronomic chemotherapy in children is still in early stages due to a lack of large-scale clinical trials and a limited understanding of its complex mechanisms, highlighting the need for further research and collaboration in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moving forward with metronomic chemotherapy: meeting report of the 2nd International Workshop on Metronomic and Anti-Angiogenic Chemotherapy in Paediatric Oncology. Pasquier, E., Kieran, MW., Sterba, J., et al.[2021]

References

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

Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors. [2021]

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

A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Metronomic Chemotherapy in Pediatric Oncology: From Preclinical Evidence to Clinical Studies. [2022]

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

A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer. [2019]

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

A phase I study of sirolimus in combination with metronomic therapy (CHOAnome) in children with recurrent or refractory solid and brain tumors. [2020]

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

Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor. [2021]

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

Phase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children and young adults with refractory/recurrent solid tumors. [2021]

8. France pubmed.ncbi.nlm.nih.gov

[Metronomic chemotherapy in pediatric oncology: hype or hope?]. [2009]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Metronomic Four-Drug Regimen Has Anti-tumor Activity in Pediatric Low-Grade Glioma; The Results of a Phase II Clinical Trial. [2020]

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

Moving forward with metronomic chemotherapy: meeting report of the 2nd International Workshop on Metronomic and Anti-Angiogenic Chemotherapy in Paediatric Oncology. [2021]