DAY101 for Brain Tumor

(FIREFLY-1 Trial)

Recruiting at 37 trial locations

Overseen By Day One Biopharmaceuticals, Inc.

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Day One Biopharmaceuticals, Inc.

Disqualifiers: Neurofibromatosis type 1, 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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 48 months

141 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new pill called DAY101 in young patients with certain brain tumors or advanced cancers. The pill works by blocking proteins that help cancer cells grow. The goal is to see if this treatment can control the disease in patients who have specific genetic changes.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What safety data exists for the treatment Tovorafenib (DAY101) in humans?

In the FIREFLY-1 trial for pediatric low-grade glioma, Tovorafenib (DAY101) was generally safe but had some side effects. Common side effects included changes in hair color, increased levels of a muscle enzyme, and anemia (low red blood cell count). More severe side effects occurred in 42% of patients, and 7% of patients stopped treatment due to these effects. ^{1 2 3 4 5}

What makes the drug DAY101 (Tovorafenib) unique for treating brain tumors?

DAY101 (Tovorafenib) is unique because it is an oral drug specifically targeting BRAF alterations, which are common in pediatric low-grade gliomas. Unlike standard chemotherapy, it is a selective type II RAF inhibitor that penetrates the central nervous system, offering a targeted approach for tumors with BRAF mutations. ^{2 6 7 8 9}

What data supports the effectiveness of the drug DAY101 (Tovorafenib) for brain tumors?

Research shows that Tovorafenib, a part of the DAY101 treatment, has been effective in treating pediatric low-grade glioma with BRAF alterations, achieving a 67% response rate in a clinical trial. This suggests it could be a promising option for brain tumors with similar genetic changes. ^{2 4 9 10 11}

Eligibility Criteria

This trial is for young patients aged 6 months to 25 years with relapsed or progressive low-grade glioma (LGG) or advanced solid tumors that have a specific BRAF gene change. Participants must have at least one measurable tumor and, for certain arms of the study, must have tried at least one other treatment before joining.

Inclusion Criteria

My cancer is advanced or has spread, and tests show a RAF fusion.

I am between 6 months and 25 years old.

My low-grade glioma has returned or worsened with a known BRAF mutation.

Exclusion Criteria

There may be additional criteria for participation in the study as specified in the protocol.

I feel my cancer is getting worse even though scans don't show it.

I have been diagnosed with or suspected to have neurofibromatosis type 1.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tovorafenib weekly according to dose rounding guidelines and their baseline body surface area

48 months

End of Treatment (EOT) Visit

Participants undergo assessments to evaluate the end of treatment outcomes

Safety Follow-up

Participants are monitored for safety after the end of treatment

4 weeks

Long-term Follow-up

Participants are monitored for long-term safety and efficacy outcomes

48 months

Treatment Details

Interventions

• DAY101

Trial Overview The FIREFLY-1 study is testing DAY101, an oral medication designed to inhibit a protein called pan-RAF which may be involved in tumor growth. The goal is to see if it's safe and effective in children and young adults with brain tumors or other solid tumors with BRAF alterations.

Participant Groups

Group I: Arm 3: Advanced Solid Tumor Experimental Treatment 1 Intervention

Participants with advanced solid tumors will receive 420 mg/m\^2) of tovorafenib weekly according to dose rounding guidelines and according to their baseline BSA.

Group II: Arm 2: Low-Grade Glioma Expanded Access Experimental Treatment 1 Intervention

Participants with recurrent or progressive low-grade glioma will receive 420 mg/m\^2 of tovorafenib weekly according to dose rounding guidelines and according to their baseline BSA.

Group III: Arm 1: Low-Grade Glioma Experimental Treatment 1 Intervention

Participants with recurrent or progressive low-grade glioma will receive 420 milligrams/meters square (mg/m\^2) of tovorafenib weekly according to dose rounding guidelines and according to their baseline body surface area (BSA).

DAY101 is already approved in United States for the following indications:

Approved in United States as Ojemda for:

• Pediatric low-grade glioma with BRAF gene mutations

Who Is Running the Clinical Trial?

Day One Biopharmaceuticals, Inc.

Lead Sponsor

Trials

8

Recruited

1,100+

Pacific Pediatric Neuro-Oncology Consortium

Collaborator

Trials

16

Recruited

840+

Findings from Research

In a phase 2 trial involving 110 pediatric patients with low-grade glioma and BRAF V600 mutations, the combination of dabrafenib and trametinib resulted in a significantly higher overall response rate (47%) compared to standard chemotherapy (11%).

Dabrafenib plus trametinib also demonstrated a longer median progression-free survival (20.1 months) and a better safety profile, with fewer severe adverse events (47% vs. 94% for chemotherapy), making it a promising first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations. Bouffet, E., Hansford, JR., Garrè, ML., et al.[2023]

In the phase 2 FIREFLY-1 trial, tovorafenib demonstrated a high overall response rate of 67% in treating pediatric low-grade glioma (pLGG) with BRAF alterations, with a median duration of response of 16.6 months.

While tovorafenib shows promise as an effective therapy, it is associated with notable treatment-related adverse events, including hair color changes (76%) and elevated creatine phosphokinase (56%), with 42% of patients experiencing grade ≥3 adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. Kilburn, LB., Khuong-Quang, DA., Hansford, JR., 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]

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]

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 trial involving 37 children and adolescents with relapsed or refractory solid tumors, the maximum tolerated dose (MTD) of adavosertib combined with irinotecan was determined to be 85 mg/m2 and 90 mg/m2, respectively, with common side effects including hematologic and gastrointestinal issues.

The combination treatment showed promising results, with one patient achieving a partial response and two others maintaining stable disease for at least six cycles, indicating potential efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Clinical Trial of the Wee1 Inhibitor Adavosertib (AZD1775) with Irinotecan in Children with Relapsed Solid Tumors: A COG Phase I Consortium Report (ADVL1312). Cole, KA., Pal, S., Kudgus, RA., et al.[2021]

A two-year-old girl with a low-grade glioma and a BRAF-V600E mutation showed significant improvement and near-complete tumor resolution after being treated with the targeted therapy dabrafenib, following failure of standard chemotherapy.

This case suggests that children with low-grade gliomas harboring BRAF-V600E mutations may benefit more from targeted therapies like BRAF inhibitors rather than traditional chemotherapy, highlighting the need for further clinical trials to compare these treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Inoperable Supra-Sellar Low-Grade Glioma With BRAF Mutation in Young Children. Howden, K., Chapman, S., Serletis, D., et al.[2023]

References

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

Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations. [2023]

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

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. [2023]

3. 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]

4. 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]

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

Response to the BRAF/MEK inhibitors dabrafenib/trametinib in an adolescent with a BRAF V600E mutated anaplastic ganglioglioma intolerant to vemurafenib. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Effect of early adverse events on response and survival outcomes of advanced melanoma patients treated with vemurafenib or vemurafenib plus cobimetinib: A pooled analysis of clinical trial data. [2020]

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

Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial. [2023]

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

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

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

Phase I Clinical Trial of the Wee1 Inhibitor Adavosertib (AZD1775) with Irinotecan in Children with Relapsed Solid Tumors: A COG Phase I Consortium Report (ADVL1312). [2021]

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

Management of Inoperable Supra-Sellar Low-Grade Glioma With BRAF Mutation in Young Children. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Topoisomerase I inhibitors for the treatment of brain tumors. [2018]