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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if metronomic chemotherapy (a low-dose, continuous drug treatment) can benefit children with high-risk solid tumors who have completed their initial treatment and are in remission. It targets tumors such as rhabdomyosarcoma, osteosarcoma, and Ewing sarcoma. The study tests a combination of drugs, including Bevacizumab (Avastin) and Cyclophosphamide (Cytoxan, Neosar, or Endoxan), to assess their ability to prevent cancer recurrence. Children who have finished their first round of treatment, are in remission, and have an expected progression in less than two years might be suitable candidates. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the treatments in this trial, including bevacizumab, cyclophosphamide, valproic acid, and temsirolimus, have varied safety records in children.

Bevacizumab has been used in children, but some studies indicate it can increase the risk of bleeding, such as nosebleeds. Cyclophosphamide is known to be safe and effective for children, though concerns exist about higher drug exposure in very young children. Valproic acid has been well-tolerated in pediatric trials, with manageable side effects. Temsirolimus has been used in some cases, but limited safety data exist for children, although it has shown an acceptable safety profile in certain cancer types.

This trial is in an early phase, meaning research is still ongoing to confirm how well these treatments are tolerated in children. However, previous use in pediatric settings provides some context for their potential safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment because it uses a metronomic chemotherapy approach, which involves administering low doses of chemotherapy drugs like Cyclophosphamide continuously over an extended period. This strategy is believed to minimize side effects while effectively targeting cancer cells, unlike traditional high-dose chemotherapy regimens. Additionally, the combination of Bevacizumab, which inhibits blood vessel growth in tumors, and Temsirolimus, an mTOR inhibitor, offers a novel mechanism of action that disrupts cancer cell growth and survival pathways. This multi-pronged approach could potentially improve outcomes for children with high-risk cancers compared to current standard treatments.

What evidence suggests that metronomic chemotherapy could be effective for pediatric high-risk cancer?

Research has shown that metronomic therapy, which involves administering lower doses of drugs continuously, successfully treats childhood leukemias. In this trial, all participants will receive a combination of Bevacizumab, Cyclophosphamide, Valproic Acid, and Temsirolimus as part of the metronomic therapy regimen. Bevacizumab has controlled disease in more than half of children with certain brain tumors for over six months. Cyclophosphamide has been effective, with many children surviving and responding well to treatment for various cancers. Valproic Acid, when combined with other treatments, has been well-tolerated and helpful in treating difficult brain and solid tumors in children. Temsirolimus has shown some positive effects in children with certain high-risk tumors, although results vary. Overall, these treatments have different levels of success in treating various types of childhood cancers, suggesting potential benefits for high-risk cases. ^{1 6 7 8 9}

Who Is on the Research Team?

Ted Zwerdling, MD

Principal Investigator

Miller Children's and Women's Hospital Long Beach

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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 (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]

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]

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]

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]

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