DAY101 for Brain Tumor

Recruiting at 14 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

44 Participants Needed

Trial Summary

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.

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

Research from the FIREFLY-1 trial shows that Tovorafenib, a drug targeting specific genetic changes in tumors, was effective in treating a type of brain tumor called pediatric low-grade glioma, with a 67% response rate and an average response lasting over a year. ^{1 2 3 4 5}

What safety data is available for the treatment Tovorafenib/DAY101 in humans?

In a study of Tovorafenib for pediatric low-grade glioma, common side effects included changes in hair color, increased levels of a muscle enzyme, and anemia. Serious side effects occurred in 42% of patients, and 7% stopped treatment due to side effects. ^{1 2 6 7 8}

How is the drug tovorafenib unique for treating brain tumors?

Tovorafenib is unique because it is an oral drug specifically designed to target BRAF alterations, which are common in certain brain tumors like pediatric low-grade glioma. It is a type II RAF inhibitor that can penetrate the central nervous system, offering a targeted approach for relapsed or refractory cases. ^{1 6 9 10 11}

What is the purpose of this trial?

This research study is studying a drug Tovorafenib/DAY101 (formerly TAK-580, MLN2480) as a possible treatment a low-grade glioma that has not responded to other treatments. The name of the study drug involved in this study is: • Tovorafenib/DAY101 (formerly TAK-580, MLN2480)

Research Team

Karen D. Wright, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 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]

References

1. 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]

2. England 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. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Neurocognitive functioning and quality of life in patients with recurrent malignant gliomas treated on a phase Ib trial evaluating topotecan by convection-enhanced delivery. [2020]

4. England pubmed.ncbi.nlm.nih.gov

A randomized feasibility study evaluating temozolomide circadian medicine in patients with glioma. [2023]

5. Germany pubmed.ncbi.nlm.nih.gov

Cetuximab and circadian chronomodulated chemotherapy as salvage treatment for metastatic colorectal cancer (mCRC): safety, efficacy and improved secondary surgical resectability. [2018]

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

Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma. [2022]

7. 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]

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

RTOG 0211: a phase 1/2 study of radiation therapy with concurrent gefitinib for newly diagnosed glioblastoma patients. [2022]

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

Phase I trial of tipifarnib (R115777) concurrent with radiotherapy in patients with glioblastoma multiforme. [2016]

10. England pubmed.ncbi.nlm.nih.gov

Wee1 kinase inhibitor adavosertib with radiation in newly diagnosed diffuse intrinsic pontine glioma: A Children's Oncology Group phase I consortium study. [2023]

11. United States 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. [2023]