Alectinib for Pediatric Brain Cancer

Recruiting at 43 trial locations

Overseen By Reference Study ID Number: GO42286 https://forpatients.roche.com/

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Hoffmann-La Roche

Must not be taking: Alk inhibitors

Disqualifiers: Substance abuse, Organ transplant, HIV, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: Ongoing 28-day cycles

42 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will evaluate the safety, pharmacokinetics, and efficacy of alectinib in children and adolescents with ALK fusion-positive solid or CNS tumors for whom prior treatment has proven to be ineffective or for whom there is no satisfactory standard treatment available.

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

The trial does not specify if you need to stop taking your current medications, but you cannot take other anti-cancer therapies while participating. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Alectinib for pediatric brain cancer?

While there is no direct data on Alectinib for pediatric brain cancer, similar drugs like ceritinib, which also targets ALK (a protein that can be involved in cancer growth), have shown some effectiveness in treating high-risk pediatric brain tumors. This suggests that Alectinib might also be beneficial, but more specific research is needed. ^{1 2 3 4 5}

Is alectinib safe for use in humans?

Alectinib has been generally well tolerated in clinical trials for non-small cell lung cancer, with common side effects including fatigue, constipation, and muscle pain. Serious side effects were rare, and most issues could be managed by adjusting the dose. ^{6 7 8 9 10}

What makes the drug Alectinib unique for treating pediatric brain cancer?

Alectinib is unique because it specifically targets and inhibits the ALK (anaplastic lymphoma kinase) protein, which can be involved in the growth of cancer cells. This targeted approach is different from traditional chemotherapy, which affects both cancerous and healthy cells. ^{1 2 4 11 12}

Research Team

Clinical Trials

Principal Investigator

Hoffmann-LaRoche

Eligibility Criteria

This trial is for children and adolescents with ALK fusion-positive brain or solid tumors that haven't responded to previous treatments or have no other satisfactory treatment options. Participants must be in a certain health status, agree to use contraception if of childbearing potential, and not have any conditions that could interfere with the study.

Inclusion Criteria

I can provide a recent tumor sample or am willing to have a biopsy before joining the study.

For females of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined by the protocol

I agree to not have sex or use birth control and not donate sperm as per the study's rules.

Exclusion Criteria

I am not planning any surgeries during the study, except those allowed by the study.

Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the participant in this study

Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; such conditions should be discussed with the participant before trial entry

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Confirmation

Part 1 is a dose-confirmation phase to confirm the recommended phase 2 dose (RP2D)

4 weeks

1 visit (in-person) per cycle

Treatment

Participants receive alectinib at the RP2D on Days 1-28 of each 28-day cycle

Ongoing 28-day cycles

1 visit (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Alectinib

Trial Overview The trial is testing Alectinib's safety, how it's processed by the body (pharmacokinetics), and its effectiveness in treating pediatric patients with specific types of tumors. It includes those who've had ineffective prior treatments or lack standard treatment options.

Participant Groups

Group I: ALK-Fusion Positive Experimental Treatment 1 Intervention

Part 1 is a dose-confirmation phase to confirm the recommended phase 2 dose (RP2D). In Parts 2 and 3, participants will receive alectinib at the RP2D on Days 1-28 of each 28-day cycle

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

Approved in United States as Alecensa for:

• Metastatic ALK-positive non-small cell lung cancer (NSCLC)
• Adjuvant treatment following tumor resection in patients with ALK-positive NSCLC

Approved in European Union as Alecensa for:

• Metastatic ALK-positive non-small cell lung cancer (NSCLC)
• Adjuvant treatment following tumor resection in patients with ALK-positive NSCLC

Who Is Running the Clinical Trial?

Hoffmann-La Roche

Lead Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

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]

In a study involving 32 pediatric patients with BRAF V600-mutant low-grade glioma, dabrafenib showed a 44% objective response rate and an impressive 85% one-year progression-free survival rate, indicating its effectiveness in treating this type of brain tumor.

The treatment was generally well-tolerated, with 91% of patients experiencing treatment-related adverse events, primarily fatigue, and only 28% experiencing severe (grade 3/4) side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation-Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study. Hargrave, DR., Bouffet, E., Tabori, U., et al.[2023]

In a study of 64 children with solid tumors or anaplastic large-cell lymphoma, the pharmacokinetics of oral crizotinib were characterized, showing that the drug reaches peak plasma concentration in about 4 hours and has a half-life of approximately 36 hours.

At the maximum tolerated dose of 280 mg/m2, the steady-state trough concentrations of crizotinib in children were found to exceed levels that inhibit cancer cell growth, indicating potential efficacy in treating ALCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-dose and steady-state pharmacokinetics of orally administered crizotinib in children with solid tumors: a report on ADVL0912 from the Children's Oncology Group Phase 1/Pilot Consortium. Balis, FM., Thompson, PA., Mosse, YP., et al.[2018]

Molecular analysis of a pediatric high-grade glioma revealed actionable mutations and amplifications, including TP53 and MYCN, which guided the selection of targeted therapies.

In vivo testing in a patient-derived xenograft (PDX) model showed that the mTOR inhibitor temsirolimus and the PLK1 inhibitor BI2536 significantly improved survival compared to standard therapies, highlighting the potential of precision medicine in treating pediatric brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integration of genomics, high throughput drug screening, and personalized xenograft models as a novel precision medicine paradigm for high risk pediatric cancer. Tsoli, M., Wadham, C., Pinese, M., et al.[2020]

Precision oncology, which tailors cancer treatment based on the genomic profile of a patient's tumor, is showing promise in effectively treating some children with cancer, supported by recent clinical trials and case reports.

An emerging regulatory framework is helping to speed up clinical trials for pediatric cancer treatments, while also addressing unique challenges in drug development for young patients, particularly for cancers driven by hard-to-target proteins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ushering in the next generation of precision trials for pediatric cancer. DuBois, SG., Corson, LB., Stegmaier, K., et al.[2020]

Alectinib is a highly effective treatment for ALK fusion-gene positive advanced non-small cell lung cancer (NSCLC), with a 93.5% objective response rate in a phase 1-2 study involving ALK inhibitor-naive patients.

The drug is well tolerated, showing no grade 4 adverse events, and has a promising safety profile, with a 76% two-year progression-free survival rate and no progression of CNS lesions in patients with known metastases during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alectinib: a review of its use in advanced ALK-rearranged non-small cell lung cancer. McKeage, K.[2022]

Alectinib, approved by the FDA for ALK-positive metastatic non-small cell lung cancer, showed an objective response rate of 38% to 44% in two trials involving 225 patients, with median durations of response lasting between 7.5 and 11.2 months.

The treatment had a manageable safety profile, with common side effects including fatigue and constipation, and only 6% of patients discontinued due to adverse reactions, indicating a favorable benefit-risk profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval: Alectinib for the Treatment of Metastatic, ALK-Positive Non-Small Cell Lung Cancer Following Crizotinib. Larkins, E., Blumenthal, GM., Chen, H., et al.[2022]

Alectinib, when administered as an oral suspension, showed significantly higher exposure levels compared to the capsule form in healthy adults, indicating that this formulation may be more effective, especially in fasted conditions.

Both the suspension and capsule forms of alectinib were well tolerated with no safety concerns, suggesting that the suspension could be a safe alternative for pediatric patients who cannot swallow capsules.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relative bioavailability and food effect study of an oral suspension of alectinib in healthy volunteers using venipuncture and capillary microsampling. Liu, SN., Agarwal, P., Heinig, K., et al.[2023]

Alectinib has been shown to significantly improve progression-free survival and overall survival compared to crizotinib in patients with advanced ALK-positive non-small-cell lung cancer, as demonstrated in the phase III ALEX study and confirmed in subsequent studies in Japanese and Asian populations.

The safety profile of alectinib is manageable, with most adverse events being treatable through dose reduction, and no new safety concerns have emerged during long-term follow-up, reinforcing its recommendation as a preferred first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience and management of adverse events in patients with advanced ALK-positive non-small-cell lung cancer receiving alectinib. Dziadziuszko, R., Peters, S., Ruf, T., et al.[2023]

Alectinib, administered at a dose of 600 mg twice daily, shows a median overall survival of 29.1 months in patients with crizotinib-resistant ALK-positive non-small-cell lung cancer, indicating its robust efficacy.

The study found no significant relationship between drug exposure levels and overall survival or adverse events, confirming that the 600 mg BID dose maintains a well-tolerated safety profile while providing effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer. Morcos, PN., Nueesch, E., Jaminion, F., et al.[2019]

Recent advances in molecular diagnostics have identified specific genetic alterations in pediatric low-grade gliomas (pLGGs), such as BRAF mutations, which have led to the development of targeted therapies like BRAF and MEK inhibitors that are currently being tested in phase III clinical trials.

Immunotherapy for pediatric brain tumors faces challenges due to lower mutational burdens and less active immune environments compared to adult tumors, but ongoing trials are exploring various strategies, including vaccines and CAR T-cell therapies, to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pediatric brain tumors: the era of molecular diagnostics, targeted and immune-based therapeutics, and a focus on long term neurologic sequelae. Plant-Fox, AS., O'Halloran, K., Goldman, S.[2021]

Ribociclib and everolimus were found to be well-tolerated in a study involving 22 pediatric patients, with a recommended phase II dose established at 120 mg/m2 for ribociclib and 1.2 mg/m2 for everolimus, indicating their potential safety for use in children with brain tumors.

The study demonstrated that ribociclib achieved significantly higher concentrations in tumor tissue compared to plasma, with a mean tumor-to-plasma ratio of 19.8, suggesting effective delivery of the drug to the site of the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I and Surgical Study of Ribociclib and Everolimus in Children with Recurrent or Refractory Malignant Brain Tumors: A Pediatric Brain Tumor Consortium Study. DeWire, MD., Fuller, C., Campagne, O., 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

Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation-Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study. [2023]

3. Germany pubmed.ncbi.nlm.nih.gov

First-dose and steady-state pharmacokinetics of orally administered crizotinib in children with solid tumors: a report on ADVL0912 from the Children's Oncology Group Phase 1/Pilot Consortium. [2018]

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

Integration of genomics, high throughput drug screening, and personalized xenograft models as a novel precision medicine paradigm for high risk pediatric cancer. [2020]

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

Ushering in the next generation of precision trials for pediatric cancer. [2020]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Alectinib: a review of its use in advanced ALK-rearranged non-small cell lung cancer. [2022]

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

FDA Approval: Alectinib for the Treatment of Metastatic, ALK-Positive Non-Small Cell Lung Cancer Following Crizotinib. [2022]

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

Relative bioavailability and food effect study of an oral suspension of alectinib in healthy volunteers using venipuncture and capillary microsampling. [2023]

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

Clinical experience and management of adverse events in patients with advanced ALK-positive non-small-cell lung cancer receiving alectinib. [2023]

10. Germany pubmed.ncbi.nlm.nih.gov

Exposure-response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer. [2019]

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

Pediatric brain tumors: the era of molecular diagnostics, targeted and immune-based therapeutics, and a focus on long term neurologic sequelae. [2021]

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

A Phase I and Surgical Study of Ribociclib and Everolimus in Children with Recurrent or Refractory Malignant Brain Tumors: A Pediatric Brain Tumor Consortium Study. [2023]