DAY101 for Brain Tumor

Not currently recruiting at 16 trial locations

Overseen By Karen Wright, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Karen D. Wright, MD

Must not be taking: Strong CYP2C inducers, Gemfibrozil

Disqualifiers: NF1, Major disease, Cardiovascular, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new drug, Tovorafenib (DAY101), for treating low-grade brain tumors unresponsive to other treatments. The drug targets a specific pathway (RAS/RAF/MEK/ERK) that can cause tumor growth. Researchers seek participants under 25 years old with a brain or solid tumor that persists or worsens despite treatment. Participants will take the medication once a week and must have a tumor measurable on scans. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

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

The trial requires that any previous chemotherapy, hormone therapy, immunotherapy, monoclonal antibody use, and MEK or BRAF inhibitors be stopped for a certain period before starting the study drug. Specifically, chemotherapy and hormone therapy must be stopped at least 4 weeks or 4 half-lives prior, immunotherapy and monoclonal antibodies at least 4 weeks or 4 half-lives prior, and MEK or BRAF inhibitors at least 7 days prior. Additionally, certain medications like strong CYP2C inducers and gemfibrozil must be stopped 14 days before the first dose of the study drug.

Is there any evidence suggesting that Tovorafenib/DAY101 is likely to be safe for humans?

Research has shown that tovorafenib/DAY101 has been tested in patients with brain tumors. In these studies, some patients experienced side effects, with about 36% facing serious side effects related to the treatment. These side effects were grade 3 or higher, indicating greater severity. However, research also suggests that tovorafenib might be effective for certain brain tumors with specific genetic changes.

This treatment remains under study, particularly regarding long-term safety. Researchers are examining its effects on growth and development in young patients, as well as any potential impacts on the reproductive system. This information helps balance understanding the potential benefits with the risks. Participants considering this treatment in a trial should discuss these aspects with their doctors. ^{1 2 3 4 5}

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

Unlike the standard treatments for brain tumors, which often focus on chemotherapy and radiation, Tovorafenib (DAY101) targets a specific pathway involved in tumor growth: the RAS/RAF/MEK/ERK pathway. This is particularly exciting because it offers a more targeted approach, potentially leading to fewer side effects and better outcomes for patients. Tovorafenib is taken orally once a week, which is more convenient compared to some existing treatments that require more frequent administration or hospital visits. Researchers are hopeful that this novel approach will provide a more effective option for young patients with difficult-to-treat tumors.

What evidence suggests that Tovorafenib/DAY101 might be an effective treatment for low-grade glioma?

Research has shown that Tovorafenib (also known as DAY101) may help treat certain brain tumors. In one study with patients who had difficult-to-treat brain tumors, 67% saw their tumors shrink, and 93% experienced some improvement in their condition. The drug targets a specific pathway that often causes tumors to grow. In this trial, participants will receive Tovorafenib in one of two treatment arms based on body surface area. These findings suggest that Tovorafenib could be a useful option for those with brain tumors that haven't responded to other treatments. ^{3 5 6 7 8}

Who Is on the Research Team?

Karen D. Wright, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for pediatric patients aged 1-25 with recurrent or progressive brain tumors (gliomas) not responding to other treatments, and whose tumors are linked to a specific cellular pathway (RAS/RAF/MEK/ERK). Participants must have adequate organ function, be able to swallow pills, and agree to effective contraception. Excluded are those with certain genetic conditions (NF1), recent major surgery, uncontrolled heart issues, active infections, or inadequate blood counts.

Inclusion Criteria

My previous treatments for my condition did not work.

I am between 1 and 25 years old.

My cancer has a mutation in the RAS/RAF/MEK/ERK pathway.

Exclusion Criteria

I have certain eye or skin conditions.

I have no current infections or serious health conditions.

History of any major disease that might interfere with safe protocol participation

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive DAY101 once a week in 28-day cycles to determine the appropriate dose and assess safety

28 days per cycle

Weekly visits for dosing

Follow-up

Participants are monitored for safety and effectiveness after treatment

48 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Tovorafenib/DAY101

Trial Overview The study tests Tovorafenib/DAY101 as a treatment for low-grade glioma that's come back or worsened despite previous therapies. It focuses on children and young adults who've had no success with standard care options. The drug targets a specific growth-related pathway in cancer cells.

How Is the Trial Designed?

Group I: DAY101 (formerly TAK-580, MLN2480) BSA > 1.5m^2 Experimental Treatment 1 Intervention

Phase I Part B BSA \> 1.5m\^2 * Patients (\< 25 years) with radiographically recurrent or radiographically progressive non-hematologic malignancies (Central Nervous System (CNS) or solid tumors) associated with activation of the RAS/RAF/MEK/ERK pathway will be eligible with the exception of patients with NF1 * Study treatment cycle lasts 28 days, oral, once a week

Group II: DAY101 (formerly TAK-580, MLN2480) BSA </= 1.5m^2 Experimental Treatment 1 Intervention

Phase I Part B BSA \</= 1.5m\^2 * Patients (\< 25 years) with radiographically recurrent or radiographically progressive non-hematologic malignancies (Central Nervous System (CNS) or solid tumors) associated with activation of the RAS/RAF/MEK/ERK pathway will be eligible with the exception of patients with NF1 * Study treatment cycle lasts 28 days, oral, once a week

Who Is Running the Clinical Trial?

Karen D. Wright, MD

Lead Sponsor

Trials

1

Recruited

40+

Karen D. Wright MD

Lead Sponsor

Trials

2

Recruited

100+

PLGA Fund at Pediatric Brain Tumor Foundation

Collaborator

Trials

1

Recruited

40+

Pacific Pediatric Neuro-Oncology Consortium

Collaborator

Trials

16

Recruited

840+

Team Jack Foundation

Collaborator

Trials

2

Recruited

100+

Day One Biopharmaceuticals, Inc.

Industry Sponsor

Trials

8

Recruited

1,100+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Vandetanib, administered at a maximum tolerated dose of 145 mg/m² per day, showed a manageable safety profile in children with diffuse intrinsic pontine glioma, with only one patient experiencing a dose-limiting toxicity of grade 3 diarrhea.

The study found that higher baseline levels of vascular endothelial growth factor (VEGF) were associated with longer progression-free survival, while increases in VEGF during treatment correlated with shorter progression-free survival, indicating the importance of monitoring VEGF levels during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma. Broniscer, A., Baker, JN., Tagen, M., et al.[2022]

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 phase II clinical trial involving 158 patients with newly diagnosed glioblastoma, cediranib combined with radiation and temozolomide significantly improved 6-month progression-free survival (PFS) to 46.6% compared to 24.5% for the placebo group (P = 0.005).

Although cediranib showed efficacy in prolonging PFS, it was associated with a higher incidence of grade ≥3 adverse events compared to placebo (P = 0.02), and there was no significant difference in overall survival between the two treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma. Batchelor, TT., Won, M., Chakravarti, A., 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 case series of 4 patients with BRAF V600E primary brain tumors, dual therapy with dabrafenib and trametinib led to near-complete or complete clinical responses in three patients after 8 weeks, demonstrating significant efficacy.

The combination therapy not only showed greater effectiveness than dabrafenib alone but also helped reduce skin-related side effects, such as keratosis, highlighting its potential to improve patient tolerability during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual BRAF/MEK therapy in BRAF V600E-mutated primary brain tumors: a case series showing dramatic clinical and radiographic responses and a reduction in cutaneous toxicity. Bernstein, A., Mrowczynski, OD., Greene, A., et al.[2023]

Citations

1. ir.dayonebio.com ir.dayonebio.com/news-releases/news-release-details/day-one-announces-new-firefly-1-data-tovorafenib-day101-and

Day One Announces New FIREFLY-1 Data for Tovorafenib ... Overall response rate (ORR) of 67% and clinical benefit rate (CBR) of 93% in 69 heavily pretreated RANO-HGG evaluable patients.

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

Tovorafenib for Relapsed or Refractory BRAF-altered ... The primary efficacy data supporting approval of tovorafenib were derived from 76 patients enrolled in Arm 1 of FIREFLY-1, an open-label, multicenter trial ...

3. 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 ...

4. nature.com nature.com/articles/s41591-023-02668-y

The type II RAF inhibitor tovorafenib in relapsed/refractory ... These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG.

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.TPS10067

LOGGIC/FIREFLY-2: A phase 3, randomized trial of ... The study is evaluating the efficacy, safety, and tolerability of tovorafenib vs. standard of care (SoC) chemotherapy in patients < 25 years old with pLGG ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03429803

NCT03429803 | DAY101 In Gliomas and Other Tumors The purpose of this study is to test the safety DAY101 in children and adolescent participants with brain tumors. The investigators want to find out what ...

7. ir.dayonebio.com ir.dayonebio.com/news-releases/news-release-details/day-one-announces-positive-initial-data-pivotal-firefly-1-trial

Release Details - Investor Relations Treatment-related AEs of grade 3 or greater occurred in nine patients (36%). “These initial findings underscore the potential of tovorafenib ...

8. trials.braintumor.org trials.braintumor.org/trials/NCT04775485

A Study to Evaluate Tovorafenib in Pediatric and Young Adult ... This is a Phase 2, multi center, open-label study to evaluate the safety and efficacy of Type II RAF (tovorafenib) in pediatric participants with low-grade ...