Genetic Testing-Directed Therapy for Pediatric Cancer

Recruiting in Palo Alto (17 mi)

+180 other locations

Overseen by Donald W Parsons

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Waitlist Available

Sponsor: National Cancer Institute (NCI)

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This Pediatric MATCH screening and multi-sub-study phase II trial studies how well treatment that is directed by genetic testing works in pediatric patients with solid tumors, non-Hodgkin lymphomas, or histiocytic disorders that have progressed following at least one line of standard systemic therapy and/or for which no standard treatment exists that has been shown to prolong survival. Genetic tests look at the unique genetic material (genes) of patients' tumor cells. Patients with genetic changes or abnormalities (mutations) may benefit more from treatment which targets their tumor's particular genetic mutation, and may help doctors plan better treatment for patients with solid tumors or non-Hodgkin lymphomas.

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.

What data supports the idea that Genetic Testing-Directed Therapy for Pediatric Cancer is an effective treatment?

The available research does not provide specific data on Genetic Testing-Directed Therapy for Pediatric Cancer. However, it does highlight the effectiveness of other targeted therapies for pediatric cancers. For example, the FDA approved dabrafenib combined with trametinib for treating low-grade glioma in children with a specific mutation, showing a higher response rate compared to traditional treatments. Additionally, a case study showed that using a targeted ALK inhibitor, crizotinib, in combination with chemotherapy led to complete remission in a child with a rare cancer. These examples suggest that targeted therapies, which are a part of genetic testing-directed approaches, can be effective in treating pediatric cancers. ^{1 2 3 4 5}

What safety data is available for genetic testing-directed therapy in pediatric cancer?

Safety data for genetic testing-directed therapy in pediatric cancer includes studies on drugs like larotrectinib and dabrafenib. Larotrectinib has been shown to be well tolerated in children, including newborns, with NTRK fusion-positive cancers, with cases reporting no adverse events. Dabrafenib, often used in combination with trametinib, has been studied in pediatric patients with BRAF V600 mutations, showing common adverse reactions such as pyrexia, rash, headache, and fatigue. These studies indicate that while these therapies can be effective, they may also have side effects that need to be managed. ^{2 6 7 8 9}

Is the drug Erdafitinib, Larotrectinib, Olaparib, Palbociclib, Selpercatinib, Selumetinib, Tazemetostat, Tipifarnib, Ulixertinib, or Vemurafenib promising for treating pediatric cancer?

The drug Vemurafenib, also known as Zelboraf, is promising for treating pediatric cancer, especially for those with specific genetic mutations like BRAF V600E. It has been studied and approved for use in certain pediatric cancers, showing positive results in clinical trials. ^{1 2 3 8 10}

Research Team

Donald W Parsons

Principal Investigator

Children's Oncology Group

Eligibility Criteria

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.

Treatment Details

Interventions

• Erdafitinib (Kinase Inhibitor)
• Larotrectinib (Kinase Inhibitor)
• Larotrectinib Sulfate (Kinase Inhibitor)
• Olaparib (PARP Inhibitor)
• Palbociclib (CDK4/6 Inhibitor)
• Selpercatinib (Kinase Inhibitor)
• Selumetinib Sulfate (Kinase Inhibitor)
• Tazemetostat (Histone Methyltransferase Inhibitor)
• Tipifarnib (Farnesyltransferase Inhibitor)
• Ulixertinib (MAPK Inhibitor)
• Vemurafenib (BRAF Inhibitor)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Evaluation of gefitinib for treatment of refractory solid tumors and central nervous system malignancies in pediatric patients. [2018]

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

FDA Approval Summary: Dabrafenib in combination with trametinib for BRAF V600E mutation-positive low-grade glioma. [2023]

3. England 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. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

Educational paper. The development of new therapies for pediatric oncology. [2021]

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

STRN-ALK rearranged pediatric malignant peritoneal mesothelioma - Functional testing of 527 cancer drugs in patient-derived cancer cells. [2021]

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

Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma. [2023]

7. Japan 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]. [2020]

8. United States 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. [2023]

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

A newborn with a large NTRK fusion positive infantile fibrosarcoma successfully treated with larotrectinib. [2021]

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

Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Children's Oncology Group Study. [2018]