Genetic Testing-Directed Therapy for Pediatric Cancer

Not currently recruiting at 190 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Investigational drugs

Disqualifiers: Pregnancy, Uncontrolled infection, Organ transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 1

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if treatments guided by genetic testing can better assist children with certain cancers that have not responded to standard treatments. By examining specific genes in tumor cells, doctors aim to match patients with treatments targeting their unique genetic mutations. The trial tests several treatments, including Erdafitinib (Balversa), on different groups based on the genetic changes in their tumors. Children with solid tumors, non-Hodgkin lymphomas, or similar conditions that have resisted other treatments might be suitable for this trial if they have specific genetic mutations. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group, offering a chance to potentially benefit from targeted therapies.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot take other investigational drugs or anticancer agents while on the study. If you're on corticosteroids, you must be on a stable or decreasing dose for at least 7 days before enrolling in a subprotocol. It's best to discuss your specific medications with the study team.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, certain medications like corticosteroids and investigational drugs have specific requirements, such as being on a stable dose for at least 7 days before enrollment. It's best to discuss your current medications with the study team.

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

A previous study found erdafitinib safe for children, though all participants experienced at least one side effect. Larotrectinib is known to be safe and well-tolerated in children with TRK fusion cancer. Similarly, olaparib was well-tolerated in children with certain tumors, but other studies reported serious side effects like bone marrow problems.

Palbociclib has been shown to be safe when combined with chemotherapy in children with certain blood cancers, with no major unexpected side effects. Selpercatinib was safely used in children as young as two with changes in the RET gene. Selumetinib is approved for children with a specific genetic condition, and its wider use has revealed no new safety concerns.

Tazemetostat is considered safe for teenagers over 16, but its safety in younger children remains uncertain. A previous study found that tipifarnib did not increase severe side effects in children. Ulixertinib is still under research, but early results suggest it is promising and manageable in terms of side effects. Vemurafenib has shown good safety results in children with certain brain tumors, although it may cause skin cancer in some cases.

These treatments have been studied at different stages. While research shows they can be tolerated, discussing potential risks with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for pediatric cancer because they leverage genetic testing to tailor therapies based on specific gene mutations. Unlike traditional chemotherapy, which targets rapidly dividing cells indiscriminately, these treatments are precision medicines that target specific genetic alterations. For example, vemurafenib targets the BRAF V600 mutation, while larotrectinib sulfate addresses NTRK gene fusions. This personalized approach not only enhances effectiveness but also minimizes side effects, offering a more precise and potentially less harmful treatment option for young patients.

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

Research has shown that genetic testing can identify effective cancer treatments by targeting specific tumor changes. In this trial, participants with various genetic mutations will receive targeted treatments. For instance, those with NTRK gene changes will receive larotrectinib, which demonstrated an 87% response rate, leading to significant tumor shrinkage. Participants with certain gene changes will receive olaparib, which has proven effective for tumors and shown promising results in children. Those with RET gene changes will receive selpercatinib, which provided lasting benefits with a 92% response rate after 12 months. Lastly, vemurafenib will be administered to individuals with the BRAF V600E gene change, showing promise for treating brain tumors and being well-tolerated in children. These treatments target specific genetic changes, potentially improving outcomes for patients with these mutations. ^{2 3 6 7 8}

Who Is on the Research Team?

Donald W Parsons

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for pediatric patients aged 12 months to 21 years with advanced solid tumors, non-Hodgkin lymphomas, or histiocytic disorders that have worsened after treatment or lack standard survival-prolonging treatments. They must have recovered from previous therapies' side effects, be able to swallow pills, and meet specific blood count and organ function criteria.

Inclusion Criteria

My bilirubin levels are within the normal range for my age.

Your platelet count is at least 100,000 per cubic millimeter.

I have a recurring or hard-to-treat tumor, including in the brain, lymph system, or other solid tumors.

Exclusion Criteria

I have been on a stable or decreasing dose of corticosteroids for at least 7 days.

I do not have any infections that are currently uncontrolled.

You have had an organ transplant in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive targeted therapy based on genetic testing results, with cycles repeating every 28 days for up to 2 years

Up to 2 years

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 4 years

Periodic follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Erdafitinib
• Larotrectinib
• Larotrectinib Sulfate
• Olaparib
• Palbociclib
• Selpercatinib
• Selumetinib Sulfate
• Tazemetostat
• Tipifarnib
• Ulixertinib
• Vemurafenib

Trial Overview The Pediatric MATCH trial tests if targeted therapy based on genetic testing can effectively treat children's cancers. It involves various interventions like imaging scans and biopsies to identify mutations in tumor genes, followed by matching patients with medications targeting those mutations.

How Is the Trial Designed?

Group I: Subprotocol N (activating RET mutations) Experimental Treatment 11 Interventions

Patients with activating RET gene alterations receive selpercatinib PO BID on days 1-28. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients may also undergo PET, CT, MRI, PET/CT, PET/MRI, and/or CT/MRI, scintigraphy, and x-ray imaging throughout the trial.

Group II: Subprotocol J (MAPK pathway mutations) Experimental Treatment 6 Interventions

Patients with MAPK pathway mutations receive ulixertinib PO BID. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Group III: Subprotocol I (Rb positive, alterations in cell cycle genes) Experimental Treatment 6 Interventions

Patients with Rb positive advanced solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with activating alterations in cell cycle genes receive palbociclib PO QD on days 1-21. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Group IV: Subprotocol H (ATM, BRCA1, BRCA2, RAD51C, RAD51D mutations) Experimental Treatment 6 Interventions

Patients deleterious ATM, BRCA1, BRCA2, RAD51C, or RAD51D gene mutations receive olaparib PO BID on days 1-28. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

Group V: Subprotocol G (BRAF V600 gene mutation) Experimental Treatment 6 Interventions

Patients with a BRAF V600 gene mutation receive vemurafenib PO BID on days 1-28. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

Group VI: Subprotocol F (ALK or ROS1 gene alteration) Experimental Treatment 13 Interventions

Patients with an ALK or ROS1 gene alteration receive ensartinib PO BID on days 1-28. Cycles repeat every 28 days for 2 years (up to 26 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo an x-ray, CT scan, MRI, PET scan, radionuclide imaging, and/or bone scan, as well as a bone marrow aspiration and/or biopsy during screening and on study. Patients also undergo blood sample collection on study.

Group VII: Subprotocol E (activating MAPK pathway gene mutation) Experimental Treatment 6 Interventions

Patients with an activating MAPK pathway gene mutation receive selumetinib sulfate PO BID on days 1-28. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

Group VIII: Subprotocol D (TSC1, TSC2, or PI3K/mTOR gene mutation) Experimental Treatment 6 Interventions

Patients with a TSC1, TSC2, or PI3K/mTOR gene mutations receive PI3K/mTOR inhibitor LY3023414 PO BID on days 1-28. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

Group IX: Subprotocol C (EZH2, SMARCB1, or SMARCA4 gene mutation) Experimental Treatment 6 Interventions

Patients with an EZH2, SMARCB1, or SMARCA4 gene mutation receive tazemetostat PO BID on days 1-28. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

Group X: Subprotocol B (FGFR1, FGFR2, FGFR3, or FGFR4 gene mutation) Experimental Treatment 12 Interventions

Patients with a FGFR1, FGFR2, FGFR3, or FGFR4 gene mutation receive erdafitinib PO QD on days 1-28 of each cycle. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients undergo an x-ray, CT scan, MRI, radionuclide imaging, and/or bone scan, as well as a bone marrow aspiration and/or biopsy during screening and on study. Patients also undergo blood sample collection on study.

Group XI: Subprotocol A (NTRK1, NTRK2, or NTRK3 gene fusion) Experimental Treatment 6 Interventions

Patients with a NTRK1, NTRK2, or NTRK3 gene fusion receive larotrectinib sulfate PO or via nasogastric- or gastric-tube BID on days 1-28. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

Group XII: Subprotcol M (HRAS gene alterations) Experimental Treatment 6 Interventions

Patients receive tipifarnib PO or via nasogastric or gastric tube BID on days 1-7 and 15-21. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as Balversa for:

• Locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 genetic alterations

Approved in European Union as Balversa for:

• Locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 genetic alterations

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The FDA approved the combination of dabrafenib and trametinib for treating pediatric patients with low-grade glioma (LGG) with a BRAFV600E mutation, marking the first systemic therapy approved for this condition.

In a clinical trial with 110 patients, the combination therapy showed a significantly higher overall response rate of 47% compared to 11% for the standard treatment of carboplatin and vincristine, along with longer progression-free survival of 20.1 months versus 7.4 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Dabrafenib in combination with trametinib for BRAF V600E mutation-positive low-grade glioma. Barbato, MI., Nashed, J., Bradford, D., et al.[2023]

Gefitinib, an EGFR inhibitor, has been well tolerated in children with refractory solid tumors and CNS malignancies, showing a safety profile similar to that of adults.

The pharmacokinetics of gefitinib in children are comparable to adults, suggesting its potential effectiveness in pediatric oncology, although further research is needed to identify the most suitable tumor types and patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of gefitinib for treatment of refractory solid tumors and central nervous system malignancies in pediatric patients. Freeman, BB., Daw, NC., Geyer, JR., et al.[2018]

An 8-year-old girl with a recurrent NTRK fusion low-grade sarcoma achieved complete radiographic remission after 3 months of treatment with larotrectinib, a selective TRK inhibitor, demonstrating its efficacy in pediatric patients.

Larotrectinib was well tolerated with no adverse events reported, and after 6 months of treatment, a local resection confirmed pathological complete remission, with no signs of relapse 4 months post-surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A Case of Pediatric Soft Tissue Sarcoma with LMNA-NTRK1 Gene Fusion Treated with Larotrectinib under Single Patient Expanded Access System]. Kato, S., Fujimura, J., Nozaki, Y., et al.[2020]

In a phase I trial involving 25 children with refractory solid tumors, gefitinib was found to be well tolerated, with a maximum-tolerated dose established at 400 mg/m2/d and manageable side effects like rash and dry skin.

One patient showed a partial response to gefitinib, and disease stabilization was observed in several others, indicating potential efficacy, especially when considering future combinations with chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Children's Oncology Group Study. Daw, NC., Furman, WL., Stewart, CF., et al.[2018]

In a phase I/II study involving 139 pediatric patients with relapsed/refractory malignancies, trametinib was found to have a recommended dose of 0.032 mg/kg for children under 6 years and 0.025 mg/kg for those 6 years and older, with manageable safety profiles and no dose-limiting toxicities when combined with dabrafenib.

Among 49 patients with BRAF V600-mutant low-grade gliomas, the combination therapy of dabrafenib and trametinib showed a higher objective response rate of 25% compared to 15% for trametinib alone, indicating improved efficacy with the combination treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma. Bouffet, E., Geoerger, B., Moertel, C., et al.[2023]

Ceritinib, at a recommended dose of 500 mg/m2 once daily, demonstrated promising antitumor activity in pediatric patients with ALK-positive malignancies, particularly in inflammatory myofibroblastic tumors (IMT) and anaplastic large cell lymphoma (ALCL), as well as in some cases of neuroblastoma.

The safety profile of ceritinib was manageable, with 81% of patients experiencing grade 3 or 4 adverse events, primarily increases in liver enzymes, indicating that while the treatment can have serious side effects, it is consistent with what has been observed in adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ceritinib in paediatric patients with anaplastic lymphoma kinase-positive malignancies: an open-label, multicentre, phase 1, dose-escalation and dose-expansion study. Fischer, M., Moreno, L., Ziegler, DS., et al.[2022]

A 5-year-old patient with aggressive malignant peritoneal mesothelioma (MPeM) driven by an ALK gene rearrangement achieved complete remission for over 3 years after treatment with the ALK inhibitor crizotinib combined with conventional chemotherapy.

Functional precision oncology profiling identified not only ALK inhibitors but also MEK/ERK and Bcl-xl inhibitors as effective treatments, suggesting that combining these therapies could enhance efficacy and overcome drug resistance in rare pediatric cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

STRN-ALK rearranged pediatric malignant peritoneal mesothelioma - Functional testing of 527 cancer drugs in patient-derived cancer cells. Murumägi, A., Ungureanu, D., Arjama, M., et al.[2021]

Dabrafenib was found to be well tolerated in pediatric patients aged 1 to 17 years with advanced BRAF V600-mutated cancers, with a median treatment duration of 75.6 weeks and no dose-limiting toxicities observed.

The study achieved target drug exposure levels comparable to those seen in adults, indicating that dabrafenib can be safely administered to children at specific doses based on age, which is crucial for its potential use in treating these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients with Recurrent or Refractory BRAF V600 Mutation-Positive Solid Tumors. Kieran, MW., Geoerger, B., Dunkel, IJ., et al.[2023]

Larotrectinib, a selective TRK inhibitor, has shown to be effective and well tolerated in treating infantile fibrosarcoma (IFS) in a newborn, indicating its potential for use in very young patients.

The patient exhibited a rapid clinical and radiographic response to larotrectinib, suggesting that this treatment could be a promising option for IFS when surgical resection is not feasible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A newborn with a large NTRK fusion positive infantile fibrosarcoma successfully treated with larotrectinib. Caldwell, KJ., De La Cuesta, E., Morin, C., et al.[2021]

Cure rates for children with cancer have plateaued around 70%, highlighting the need for new drug approaches, especially for hard-to-treat cancers like stage IV neuroblastoma and relapsed leukemia.

Novel agents, including cell cycle inhibitors like clofarabine and nelarabine, as well as targeted therapies such as tyrosine kinase inhibitors and monoclonal antibodies, show promise in improving treatment outcomes for high-risk pediatric cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Educational paper. The development of new therapies for pediatric oncology. Horton, TM., Berg, SL.[2021]

Citations

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Use of BALVERSA in Pediatric Patients Efficacy was evaluated at a data cutoff of December 4, 2023, with a median follow-up of 9.7 months. Investigator-assessed ORR was 9.1% (1/11; 95 ...

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Efficacy and safety of erdafitinib in pediatric patients with ... Results: 11 pts (median age 13 years; range, 6-16; 64% female) received erdafitinib. Median follow-up was 9.7 months at data cutoff. Histologies ...

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Rare FGFR Oncogenic Alterations in Sequenced Pediatric ... After seven cycles of chemotherapy, insurance approval was obtained for erdafitinib, which has pediatric toxicity data and guidelines for administration as a ...

4. meetings.asco.org meetings.asco.org/abstracts-presentations/218016

Erdafitinb in patients with FGFR-altered tumors Conclusions: Erdafitinib was generally well tolerated in this heavily pre-treated cohort of children with relapsed tumors harboring FGFR alterations.

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Efficacy and safety of erdafitinib in pediatric patients with ... Here we report on Final Analysis of efficacy and safety results from the. Pediatric Cohort of the RAGNAR study. Methods: Pediatric pts $6 years with advanced ...

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BALVERSA (erdafitinib) tablets, for oral use - accessdata.fda.gov Safety and effectiveness of BALVERSA in pediatric patients have not been established. In 4 and 13-week repeat-dose toxicology studies in rats and dogs, ...

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product monograph including patient medication information The safety data described below reflect exposure to BALVERSA® in Cohort 1 of Study. BLC3001. This was a Phase 3 study that included patients ...

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Efficacy and safety of erdafitinib in pediatric patients with ... Here we report on Final Analysis of efficacy and safety results from the Pediatric Cohort of the RAGNAR study. Methods: Pediatric pts ≥6 years with advanced ...