Combination Chemotherapy for Pediatric Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Jessica Gartrell

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: St. Jude Children's Research Hospital

Must not be taking: Investigational drugs

Disqualifiers: Pregnant, Breastfeeding, Thrombosis, others

No Placebo Group

Breakthrough Therapy

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}

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

Trial 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 (Monoclonal Antibodies)
• Bevacizumab (Monoclonal Antibodies)
• Cyclophosphamide (Alkylating agents)
• Sorafenib (Kinase Inhibitor)

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

St. Jude Children's Research Hospital Memphis, TN

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital Lead Sponsor

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] Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children.

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] To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of sorafenib, bevacizumab, and low-dose oral cyclophosphamide in children and young adults with recurrent/refractory solid tumors.

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] Pre-clinical findings suggest that combination treatment with bevacizumab and temsirolimus could be effective against malignant pediatric central nervous system (CNS) tumors.

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

A phase 1 trial of everolimus and bevacizumab in children with recurrent solid tumors. [2021] The prognosis for children with recurrent solid tumors generally is poor. Targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor A with everolimus and bevacizumab, respectively, synergistically improves progression-free survival and is well tolerated in adults with solid tumors.

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] Children and adolescents with recurrent and metastatic solid tumors have a poor outcome. A previous phase 1 study (ANGIO1) targeting angiogenesis with bevacizumab, sorafenib, and cyclophosphamide, demonstrated a signal of activity in a subset of patients. Here we report the results of a cohort of pediatric and young adult patients treated at the recommended phase 2 doses.

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

Dexrazoxane exposure and risk of secondary acute myeloid leukemia in pediatric oncology patients. [2022] Dexrazoxane may reduce anthracycline-associated cardiotoxicity in pediatric cancer patients. However, concerns of secondary acute myeloid leukemia (AML) have led to restrictions on pediatric dexrazoxane use in Europe. Published data about dexrazoxane-associated secondary AML are limited and conflicting. We sought to estimate the secondary AML risk in children receiving dexrazoxane after anthracycline exposure.

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] Dexrazoxane reduces the risk of anthracycline-related cardiotoxicity. In a study of children with Hodgkin lymphoma, the addition of dexrazoxane may have been associated with a higher risk for developing second malignant neoplasms (SMNs) including acute myelogenous leukaemia (AML) and myelodysplastic syndrome (MDS). We determined the incidence of SMNs in children and adolescents with acute lymphoblastic leukaemia (ALL) who were treated with dexrazoxane.

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] Dexrazoxane is a drug used to prevent anthracycline-induced cardiotoxicity. A recent report found an association between the use of dexrazoxane and the risk of developing secondary malignant neoplasms (SMNs) in children with Hodgkin's disease. We report the absence of an association of SMNs in children with acute lymphoblastic leukemia (ALL) treated on Dana-Farber Cancer Institute ALL Consortium Protocol 95-01.

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

Cardiotoxicity in childhood cancer survivors: strategies for prevention and management. [2023] Advances in cancer treatment have greatly improved survival rates of children with cancer. However, these same chemotherapeutic or radiologic treatments may result in long-term health consequences. Anthracyclines, chemotherapeutic drugs commonly used to treat children with cancer, are known to be cardiotoxic, but the mechanism by which they induce cardiac damage is still not fully understood. A higher cumulative anthracycline dose and a younger age of diagnosis are only a few of the many risk factors that identify the children at increased risk of developing cardiotoxicity. While cardiotoxicity can develop at anytime, starting from treatment initiation and well into adulthood, identifying the best cardioprotective measures to minimize the long-term damage caused by anthracyclines in children is imperative. Dexrazoxane is the only known agent to date, that is associated with less cardiac dysfunction, without reducing the oncologic efficacy of the anthracycline doxorubicin in children. Given the serious long-term health consequences of cancer treatments on survivors of childhood cancers, it is essential to investigate new approaches to improving the safety of cancer treatments.

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

[Anthracycline-induced cardiotoxicity: report of fatal cases]. [2017] Anthracyclines are effective drugs in pediatrics cancer treatment. However, anthracycline-induced cardiotoxicity (AIC) is a serious adverse drug reaction that affects the survival in patients treated for childhood cancer.

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

Availability of Essential Medicines for Pediatric Oncology in Armenia [2020] Background: One of the main contributors in low survival rate in LMIC is the lack of availability of cancer medications for curative, supportive and palliative care. In many developing countries access to cytotoxic medicine is a major challenge. The information about the availability of essential medicines for pediatric cancer in the country is not known. The main objective of this study was to determine whether the medications used during the treatment of pediatric cancer are available in Armenia. Methods: In summer 2016 we conducted a survey in the 3 main pharmacies in Yerevan, which import pediatric cancer medications to Armenia to evaluate whether medications used during cancer treatment are officially registered and available in the country. In addition, the information on official registration was cross-checked with the Ministry of Health of the Republic of Armenia (MOH). Simultaneously, detailed information about the drugs, on type of produced drug company, doses and price intervals was confined from the price lists of the national drug importer companies. Results: The survey included 64 agents in three classes of medication: anti-neoplastics, anti-microbials, and drugs used in supportive care. All of these medications were included in the recent version of the WHO model list of essential medicines. From 30 anti-neoplastic medications on the essential medicines list 22 (73%) were officially registered in Armenia; from 19 anti-microbial drugs all were registered except caspofungin and from 15 supportive care agents 13 (87%) were registered. From registered anti-neoplastic drugs 18% and from antimicrobial drugs 33% were not available in the drug stores. Conclusion: This study showed that not all the drugs from the SIOP PODC Essential Medication list for pediatric oncology are officially registered and available in Armenia, and effective drug regulation focusing on the childhood cancer care medicine is needed for improving the situation in the country.

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] In preclinical models, temozolomide, and vincristine are additive or synergistic with irinotecan. We examined this three-drug combination in children with relapsed solid tumors. Patients received orally administered irinotecan together with temozolomide and vincristine on two different schedules, using cefixime to reduce irinotecan-associated diarrhea.

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] To evaluate maximum tolerated dose and recommended dose (RD) for phase II studies of topotecan (TPT) combined with temozolomide (TMZ) (TOTEM) in children and adolescents with relapsed or refractory solid malignancies.