DAY101 for Brain Tumor

(FIREFLY-1 Trial)

Recruiting at 43 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called tovorafenib (also known as DAY101) to determine its safety and effectiveness for children with brain tumors or advanced solid tumors. It targets those with low-grade glioma or advanced tumors that have specific genetic changes known as BRAF or RAF fusions. Participants should have experienced a return or worsening of their condition despite previous treatments. This study might be suitable for individuals with a brain tumor or solid tumor that has recurred or progressed after treatment and has specific genetic mutations. As a Phase 2 trial, it measures how well the treatment works in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that tovorafenib, also known as DAY101, may help treat certain childhood brain tumors and advanced solid tumors. In a previous study, most patients tolerated the treatment well, though some side effects occurred. Specifically, 37% of patients experienced bleeding, with 26% having nosebleeds and some experiencing bleeding in the tumor.

The FDA has granted tovorafenib fast-track approval for certain childhood brain tumors, indicating some confidence in its safety for these conditions. While more studies are needed to confirm its safety for other types of tumors, these findings provide insight into its safety profile. Those considering this treatment should discuss the possible risks and benefits with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for brain tumors?

Unlike the standard treatments for low-grade glioma, which often include surgery, radiation, and sometimes chemotherapy, DAY101 offers a novel approach. DAY101, also known as tovorafenib, specifically targets cancer cell growth by inhibiting a protein called RAF. This targeted action could mean fewer side effects compared to traditional therapies and potentially more effective control of tumor growth. Researchers are particularly excited because this targeted therapy could offer a new option for patients with recurrent or progressive tumors who have limited choices.

What evidence suggests that DAY101 might be an effective treatment for low-grade glioma or advanced solid tumors?

Research has shown that tovorafenib (DAY101) yields promising results for treating certain brain tumors. In one study involving 77 children, nearly 70% experienced significant tumor shrinkage or disappearance, particularly in cases of low-grade glioma with specific genetic changes. This trial includes an arm for participants with recurrent or progressive low-grade glioma who will receive tovorafenib. Another study on advanced solid tumors found that about half of the participants experienced tumor shrinkage. This trial also includes an arm for participants with advanced solid tumors receiving tovorafenib. Tovorafenib blocks certain proteins called RAF, which aid tumor growth. These findings offer hope that tovorafenib could benefit patients with these difficult-to-treat tumors. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

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]

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]

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]

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]

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]

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]

Citations

1. ir.dayonebio.com ir.dayonebio.com/news-releases/news-release-details/day-ones-ojemdatm-tovorafenib-receives-us-fda-accelerated

Day One's OJEMDA™ (tovorafenib) Receives US FDA ... The accelerated approval of OJEMDA is based on data from the Company's pivotal open-label Phase 2 FIREFLY-1 trial, which enrolled a total of 137 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04985604

Study Details | NCT04985604 | Tovorafenib (DAY101) ... This is a Phase 2, multi-center, open-label to evaluate the efficacy and safety of tovorafenib (DAY101) in participants ≥12 years of age with recurrent or ...

3. ojemdahcp.com ojemdahcp.com/resources/OJEMDA-Clinical-Overview-Brochure.pdf

Clinical Overview - OJEMDA™ (tovorafenib) Increased bilirubin occurred in. 23% of patients, including Grade 3 increased bilirubin in 0.6% of patients (n=1) treated with OJEMDA. Hyperbilirubinemia ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11996598/

Tovorafenib for Relapsed or Refractory BRAF-altered ... ... advanced or metastatic solid tumor with an activating RAF fusion. Results from the efficacy population demonstrated an ORR of 51% (95% CI: 40, 63) ...

5. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2024/217700Orig1s000,%20218033Orig1s000MultidisciplineR.pdf

217700Orig1s000 218033Orig1s000 - accessdata.fda.gov Safety analyses were further supported by data from monotherapy studies. C28001 in adult patients with advanced solid tumors and the investigator-sponsored ...

6. ojemdahcp.com ojemdahcp.com/safety

Safety | OJEMDA™ (tovorafenib) The safety population described in warnings and precautions reflects exposure to OJEMDA taken orally once weekly at a dosage based on body surface area.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2024/217700s000lbl.pdf

OJEMDA (tovorafenib) tablets, for oral ... - accessdata.fda.gov In the pooled safety population [see Adverse Reactions (6.1)], hemorrhagic events occurred in. 37% of patients, including epistaxis in 26% and intratumoral ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04985604

Study Details | NCT04985604 | Tovorafenib (DAY101) ... This is a Phase 2, multi-center, open-label to evaluate the efficacy and safety of tovorafenib (DAY101) in participants ≥12 years of age with recurrent or ...

9. asco.org asco.org/abstracts-presentations/ABSTRACT379812

FIREFLY-1 (PNOC 026): A phase 2 study to evaluate the ... FIREFLY-1 (PNOC 026): A phase 2 study to evaluate the safety and efficacy of tovorafenib (DAY101) in pediatric patients with RAF-altered recurrent or ...