Combination Chemotherapy for Pediatric Cancer

Overseen By Jessica Gartrell

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: St. Jude Children's Research Hospital

Must not be taking: Investigational drugs

Disqualifiers: Pregnant, Breastfeeding, Thrombosis, 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: 4

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of four drugs—atezolizumab (Tecentriq), bevacizumab (Avastin), cyclophosphamide (Cytoxan, Neosar, or Endoxan), and sorafenib (Nexavar)—to determine their safety and effectiveness for children and young adults with certain difficult-to-treat cancers. The trial has two parts: the first assesses safety, and the second examines the drugs' effects on specific cancers like hepatocellular carcinoma (a type of liver cancer) and rare solid tumors. Children and young adults with relapsed or hard-to-remove solid tumors, especially those that can be biopsied, might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you must stop taking your current medications. However, it mentions that patients must have fully recovered from the acute toxic effects of previous treatments and that certain time periods must elapse after previous therapies before enrolling. It's best to discuss your current medications with the trial team to get specific guidance.

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

Research has shown that the combination of treatments under study has demonstrated varying levels of safety in past studies. Atezolizumab commonly causes fever, tiredness, and constipation, but these side effects are usually manageable. Bevacizumab has proven safe for children and young adults, with side effects well-controlled. Sorafenib is generally well-tolerated in children at certain doses, though some may experience side effects. Cyclophosphamide is widely used to treat various cancers, but it can cause side effects later on, especially at higher doses.

This study is in its early stages and aims to identify any potential safety issues with this treatment combination. Testing these treatments together requires more information to understand their interactions. Prospective participants should discuss any concerns with the study team or their doctor to receive personalized information about what participation might entail. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination chemotherapy for pediatric cancer because it brings together a unique mix of treatments, including Atezolizumab and Bevacizumab, which are immunotherapies that help the body's own immune system attack cancer cells, something traditional chemotherapy doesn't do. Sorafenib adds another layer by inhibiting specific proteins that promote cancer cell growth, offering a targeted approach. Combining these with Cyclophosphamide, a well-known chemotherapy agent, creates a powerful multi-angle strategy that could enhance effectiveness while potentially reducing the side effects seen with standard treatments. This innovative approach aims to not only improve outcomes for young patients but also redefine how we tackle pediatric cancers.

What evidence suggests that this trial's treatments could be effective for pediatric cancer?

Research shows that a combination of four drugs—atezolizumab, bevacizumab, cyclophosphamide, and sorafenib—might stop cancer growth or shrink tumors in children with hard-to-treat solid tumors. In this trial, all participants will receive this combination to determine the maximum tolerated dose and assess its effectiveness. Atezolizumab and bevacizumab block proteins that help cancer cells grow, while cyclophosphamide and sorafenib directly attack cancer cells. This combination aims to boost the immune system and reduce tumor size, offering hope for those with few treatment options. Early results suggest this combination could be promising for cancers that have returned or are difficult to treat. ^{6 7 8 9 10}

Who Is on the Research Team?

Jessica Gartrell

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

This trial is for children and young adults under 30 with certain types of advanced solid tumors that can't be removed by surgery. They should have a specific level of organ function, not be on other investigational drugs, and must not be pregnant or breastfeeding. Participants need to have recovered from previous treatments and agree to birth control measures.

Inclusion Criteria

My liver cancer is resistant to treatment and can be biopsied.

Willingness to enroll on the St. Jude Molecular Analysis of Solid Tumors (MAST) study

My tumor has returned or didn't respond to treatment and can be biopsied.

Exclusion Criteria

My tumor cannot be safely biopsied.

Pregnant or breastfeeding

Unwilling or unable to comply with safety monitoring requirements

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Participants receive oral cyclophosphamide and sorafenib with intravenous bevacizumab and atezolizumab to establish safety and tolerability

6 weeks

2 visits (in-person) every 21 days

Treatment Part 2

Participants continue treatment to evaluate response rate in relapsed or refractory HCC and other rare solid malignancies

6 weeks

2 visits (in-person) every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Bevacizumab
• Cyclophosphamide
• Sorafenib

Trial Overview The study tests the safety and effectiveness of combining IV atezolizumab with bevacizumab every three weeks, daily oral cyclophosphamide, and sorafenib adjusted based on blood levels in pediatric patients with relapsed or refractory solid tumors including liver cancer.

How Is the Trial Designed?

Group I: Treatment Experimental Treatment 4 Interventions

All participants will receive Atezolizumab, Bevacizumab,Sorafenib and cyclophosphamide until maximum tolerated dose is reached.Tolerability will be defined after completion of Course 1. Part 2 will begin once the recommended phase 2 dose (RP2D) is determined.

Atezolizumab is already approved in United States, European Union for the following indications:

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Published Research Related to This Trial

In a phase I trial involving six pediatric patients with treatment-resistant CNS tumors, the combination of bevacizumab and temsirolimus was well-tolerated, with manageable side effects such as anorexia and nausea.

The treatment led to a partial response in one patient and stable disease for at least four months in two others, indicating potential efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pediatric patients with refractory central nervous system tumors: experiences of a clinical trial combining bevacizumab and temsirolimus. Piha-Paul, SA., Shin, SJ., Vats, T., et al.[2022]

The combination of oral irinotecan, temozolomide, and vincristine was tested in children with relapsed solid tumors, showing that the 5-day treatment schedule (Schedule B) was well tolerated with no dose-limiting toxicities at the highest doses, indicating a safer option for patients.

The study found that this regimen provided similar drug exposure levels to those achieved with intravenous irinotecan, and it demonstrated activity in treating sarcoma, suggesting its potential effectiveness in a range of childhood solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of two schedules of vincristine, oral irinotecan, and temozolomide (VOIT) for children with relapsed or refractory solid tumors: a Children's Oncology Group phase I consortium study. Wagner, LM., Perentesis, JP., Reid, JM., et al.[2021]

The combination of temsirolimus and vinblastine in children with recurrent or refractory tumors showed significant toxicity, with grade 3 mucositis and hematologic issues being common, indicating a need for careful dose management.

Despite the toxicity, the treatment resulted in prolonged stable disease in four patients for a median of 5.0 months, suggesting potential efficacy in managing pediatric cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218. Deyell, RJ., Wu, B., Rassekh, SR., et al.[2019]

Children treated with anthracyclines for cancer have improved survival rates, but these treatments can lead to long-term heart damage, with risk factors including higher drug doses and younger age at diagnosis.

Dexrazoxane is currently the only agent shown to reduce cardiac dysfunction caused by the anthracycline doxorubicin in children, without compromising its effectiveness against cancer, highlighting the need for further research into cardioprotective strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiotoxicity in childhood cancer survivors: strategies for prevention and management. Harake, D., Franco, VI., Henkel, JM., et al.[2023]

Anthracycline-induced cardiotoxicity (AIC) is a serious risk in pediatric cancer patients, as demonstrated by two clinical cases where young patients developed dilated cardiomyopathy after receiving anthracycline treatment, leading to their deaths.

Close monitoring of heart function is crucial for children undergoing anthracycline therapy to detect early signs of cardiac damage and to implement timely interventions to prevent heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Anthracycline-induced cardiotoxicity: report of fatal cases]. Vargas-Neri, JL., Castelán-Martínez, OD., de Jesús Estrada-Loza, M., et al.[2017]

In a study involving 553 children with high-risk acute lymphoblastic leukemia (ALL) treated with dexrazoxane, the incidence of secondary malignant neoplasms (SMNs) was very low, with only one case of acute myelogenous leukemia (AML) reported over a median follow-up of 9.6 years.

The overall 5-year cumulative incidence of SMNs in these patients was just 0.24%, suggesting that dexrazoxane is a safe option for reducing anthracycline-related cardiotoxicity without significantly increasing the risk of developing secondary cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The low incidence of secondary acute myelogenous leukaemia in children and adolescents treated with dexrazoxane for acute lymphoblastic leukaemia: a report from the Dana-Farber Cancer Institute ALL Consortium. Vrooman, LM., Neuberg, DS., Stevenson, KE., et al.[2022]

In a study of 205 children with high-risk acute lymphoblastic leukemia (ALL), dexrazoxane did not increase the risk of developing secondary malignant neoplasms (SMNs) compared to those who received doxorubicin alone, with a median follow-up of 6.2 years.

The results support the continued use of dexrazoxane as a cardioprotectant during doxorubicin treatment in pediatric patients, as no SMNs were observed in the dexrazoxane group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane. Barry, EV., Vrooman, LM., Dahlberg, SE., et al.[2022]

The recommended dose for the combination of topotecan (TPT) and temozolomide (TMZ) in children with relapsed or refractory solid tumors is TMZ 150 mg/m²/day and TPT 0.75 mg/m²/day, with manageable dose-limiting toxicities primarily involving blood cell counts.

In a study of 16 patients, 25% showed confirmed responses to the treatment, indicating potential effectiveness, particularly in cases of metastatic neuroblastoma and high-grade glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of topotecan in combination with temozolomide (TOTEM) in relapsed or refractory paediatric solid tumours. Rubie, H., Geoerger, B., Frappaz, D., et al.[2023]

In a study of 15,532 pediatric cancer patients treated with anthracyclines, those who received dexrazoxane showed a lower rate of secondary acute myeloid leukemia (AML) at 0.21% compared to 0.55% in those who did not receive dexrazoxane.

The analysis indicated that dexrazoxane exposure was not associated with an increased risk of secondary AML, suggesting it is safe for use in pediatric patients undergoing anthracycline treatment, although further research is needed to confirm these results and assess long-term cardioprotective effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexrazoxane exposure and risk of secondary acute myeloid leukemia in pediatric oncology patients. Seif, AE., Walker, DM., Li, Y., et al.[2022]

In a survey of 64 cancer medications in Armenia, 73% of essential anti-neoplastic drugs were officially registered, but 18% of these registered drugs were not available in pharmacies, highlighting a significant gap in access to treatment.

While most anti-microbial and supportive care medications were registered, the lack of availability of certain critical drugs indicates a need for improved drug regulation and access to pediatric cancer medications in Armenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Availability of Essential Medicines for Pediatric Oncology in Armenia Simonyan, T., Papyan, R., Danielyan, S., et al.[2020]

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 1 study involving 15 children with recurrent solid tumors, the maximum tolerated dose of the combination treatment with bevacizumab and everolimus was established at 8 mg/kg and 4 mg/m2, respectively, with manageable toxicity levels.

The treatment showed some efficacy, with 30.8% of patients achieving stable disease, and significant inhibition of the mTOR pathway was observed, indicated by decreased levels of the biomarker phospho-4EBP1 in blood samples.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 trial of everolimus and bevacizumab in children with recurrent solid tumors. Santana, VM., Sahr, N., Tatevossian, RG., et al.[2021]

In a study involving 39 pediatric and young adult patients with recurrent solid tumors, the combination of bevacizumab, sorafenib, and cyclophosphamide was well-tolerated, with manageable side effects and minimal need for additional supportive care.

The treatment led to disease stabilization in over half of the patients, with one complete response and two partial responses, indicating potential benefits for patients with bone sarcomas and suggesting further exploration of this regimen in earlier treatment settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab, With Sorafenib and Cyclophosphamide Provides Clinical Benefit for Recurrent or Refractory Osseous Sarcomas in Children and Young Adults. Bodea, J., Caldwell, KJ., Federico, SM.[2022]

Citations

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2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-06602

Atezolizumab in Combination with Cyclophosphamide ... Adding atezolizumab to bevacizumab, cyclophosphamide and sorafenib may work to stop the cancers from growing or to shrink for a period of time. The combination ...

3. stjude.org stjude.org/care-treatment/clinical-trials/angio-a-solid-tumor.html

ANGIO-A: Cyclophosphamide, Sorafenib, Bevacizumab ... This study looks for effective treatments for childhood solid tumors that have returned after treatment or have never responded to therapy.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12153728/

Real-World Experiences Using Atezolizumab ... Objective: This study aimed to evaluate the characteristics, clinical outcomes, and resource use of patients with unresectable hepatocellular ...

5. withpower.com withpower.com/trial/phase-2-hepatocellular-carcinoma-6-2022-adf5f

Combination Chemotherapy for Pediatric Cancer Research shows that combining bevacizumab, sorafenib, and cyclophosphamide has provided clinical benefits for children with certain types of recurrent or hard- ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31753029/

Population Pharmacokinetics, Exposure-Safety, and ... Atezolizumab geometric mean trough exposures were ~ 20% lower in pediatric patients versus young adults; this was not clinically meaningful as ...

7. jitc.bmj.com jitc.bmj.com/content/7/1/314

Population pharmacokinetics, exposure-safety, and ... Atezolizumab geometric mean trough exposures were ~ 20% lower in pediatric patients versus young adults; this was not clinically meaningful as ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT02541604

NCT02541604 | A Study to Evaluate the Safety, Tolerability ... Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer. J Immunother Cancer.

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.10524

A phase I/II study of atezolizumab in pediatric and young ... Common AEs were pyrexia (37%), fatigue (34%) and constipation (32%). 2/5 patients with HL had a partial response (PR); the only patient with ...

10. fda.gov fda.gov/media/143360/download

Clinical Review of Efficacy Supplement (atezolizumab) To evaluate the anti-cancer activity of atezolizumab in pediatric and young adult patients, as measured by overall survival (OS).