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

64 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase I/II study to evaluate the safety of combining intravenous (IV) atezolizumab and bevacizumab every three weeks, with daily oral cyclophosphamide and pharmacokinetic (PK)-guided sorafenib in children and adolescent and young adults (AYA) with relapsed or refractory solid malignancies (Part 1), and then evaluate the response rate of this combination in children, AYA with relapsed or refractory hepatocellular carcinoma (HCC) and other rare solid malignancies (Part 2). Primary Objectives Part 1 * To establish the safety associated with the administration of the combination of cyclophosphamide, PK-guided sorafenib, bevacizumab and atezolizumab in children and AYA with relapsed or refractory solid tumors * To determine if sorafenib systemic exposure can be successfully targeted to an AUC between 20 and 55 hr·µg/mL by Day 21 of cycle 1 in 60% of evaluable patients, when given in combination with cyclophosphamide, bevacizumab, and atezolizumab in children and AYA with relapsed or refractory solid tumors Part 2 * To evaluate the response rate (CR+PR) of the combination of cyclophosphamide, PK-guided sorafenib, bevacizumab and atezolizumab in children and AYA with relapsed or refractory HCC following two cycles of therapy * To determine if the use of PK-guided sorafenib dosing to maintain a systemic exposure between 20 and 55 reduces the interpatient pharmacokinetic variability of sorafenib and the incidence of sorafenib- induced skin toxicities in children and AYA with relapsed or refractory HCC and other rare solid tumors Parts 1 \& 2 * To determine if the combination of cyclophosphamide, PK-guided sorafenib and atezolizumab will result in increased intratumoral T-cell infiltration of CD8+C45RO+ cells between baseline and following two courses of therapy in pediatric children and AYA with relapsed or refractory solid tumors following two cycles of therapy * To characterize the pharmacokinetics of atezolizumab in combination with cyclophosphamide, PK-guided sorafenib and bevacizumab in children and AYA with relapsed or refractory solid tumors * To assess the feasibility of performing contrast enhanced ultrasound and explore the correlation between quantitative CEUS parameters and clinical response. Secondary Objectives Part 1 • To describe the response rate (CR+PR) of the combination of cyclophosphamide, PK-guided sorafenib, bevacizumab and atezolizumab in children and AYA with relapsed or refractory solid tumors following two cycles of therapy Part 2 • To describe the response rate (CR+PR) of the combination of cyclophosphamide, PK-guided sorafenib, bevacizumab and atezolizumab in children and AYA with relapsed or refractory fibrolamellar carcinoma, desmoplastic small round cell tumor, malignant rhabdoid tumor, and other rare solid tumors following two cycles of therapy Parts 1\&2 * To describe the number of children with liver tumors, initially judged unresectable at diagnosis, that can have their primary tumor resected after treatment with oral cyclophosphamide and sorafenib with intravenous bevacizumab and atezolizumab * To describe changes in immune cells in the peripheral blood at periodic times before and after treatment with this combination chemoimmunotherapy * To describe the PFS, EFS, and OS in patients treated with the combination of cyclophosphamide, PK-guided sorafenib, bevacizumab, and atezolizumab in patients with relapsed or refractory HCC, DSRCT, MRT, FL-HCC and other rare solid tumors

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.

What data supports the effectiveness of the drug combination Atezolizumab, Tecentriq, Bevacizumab, Avastin, Cyclophosphamide, Cytoxan, Neosar, Endoxan, Sorafenib, Nexavar for pediatric cancer?

Research shows that combining bevacizumab, sorafenib, and cyclophosphamide has provided clinical benefits for children with certain types of recurrent or hard-to-treat tumors, suggesting potential effectiveness of these drugs in similar combinations. ^{1 2 3 4 5}

Is the combination chemotherapy for pediatric cancer generally safe in humans?

The research articles provided do not contain specific safety data for the combination chemotherapy involving Atezolizumab, Tecentriq, Bevacizumab, Avastin, Cyclophosphamide, Cytoxan, Neosar, Endoxan, Sorafenib, or Nexavar. They focus on dexrazoxane, which is used to reduce heart damage from other cancer drugs, but may increase the risk of other cancers in some cases. ^{6 7 8 9 10}

What makes the combination chemotherapy with Atezolizumab, Bevacizumab, Cyclophosphamide, and Sorafenib unique for pediatric cancer?

This combination therapy is unique because it includes Atezolizumab, an immunotherapy drug that helps the immune system attack cancer cells, and Bevacizumab, which blocks blood supply to tumors, alongside traditional chemotherapy agents Cyclophosphamide and Sorafenib. This multi-faceted approach targets cancer through different mechanisms, potentially offering a more comprehensive treatment strategy for pediatric cancer. ^{1 3 11 12 13}

Research Team

Jessica Gartrell

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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 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]

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 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]

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 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]

References

1. United States 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. [2019]

2. 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]

3. Greece pubmed.ncbi.nlm.nih.gov

Pediatric patients with refractory central nervous system tumors: experiences of a clinical trial combining bevacizumab and temsirolimus. [2022]

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

A phase 1 trial of everolimus and bevacizumab in children with recurrent solid tumors. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Bevacizumab, With Sorafenib and Cyclophosphamide Provides Clinical Benefit for Recurrent or Refractory Osseous Sarcomas in Children and Young Adults. [2022]

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

Dexrazoxane exposure and risk of secondary acute myeloid leukemia in pediatric oncology patients. [2022]

7. England 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. [2022]

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

Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Cardiotoxicity in childhood cancer survivors: strategies for prevention and management. [2023]

10. Mexico pubmed.ncbi.nlm.nih.gov

[Anthracycline-induced cardiotoxicity: report of fatal cases]. [2017]

11. Thailand pubmed.ncbi.nlm.nih.gov

Availability of Essential Medicines for Pediatric Oncology in Armenia [2020]

12. United States 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. [2021]

13. England pubmed.ncbi.nlm.nih.gov

Phase I study of topotecan in combination with temozolomide (TOTEM) in relapsed or refractory paediatric solid tumours. [2023]