DAY101 for Langerhans Cell Histiocytosis

Recruiting at 98 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP2C8 inducers/inhibitors, BCRP substrates

Disqualifiers: Other malignancy, MAP2K1 mutation, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

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

Compensation: Varies

Number of Visits: 4

48 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking strong inducers or inhibitors of CYP2C8 and medications that are breast cancer resistant protein (BCRP) substrates with a narrow therapeutic index for 14 days before starting the study drug and throughout the trial. You may continue taking low-dose steroids, but other anticancer therapies must be stopped 14 days before starting the trial.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting the study. Specifically, you must not take strong inducers or inhibitors of CYP2C8 and medications that are breast cancer resistant protein (BCRP) substrates with a narrow therapeutic index for 14 days before starting the trial and during the study. Other medications are not specifically mentioned, so it's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug Tovorafenib (DAY101) for treating Langerhans Cell Histiocytosis?

Research shows that drugs targeting the MAPK pathway, like trametinib and vemurafenib, have been effective in treating Langerhans Cell Histiocytosis, especially in cases with specific genetic mutations. These drugs have shown favorable responses in patients, suggesting that similar treatments like Tovorafenib may also be effective. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Tovorafenib (DAY101) for treating Langerhans Cell Histiocytosis?

Research shows that drugs targeting the MAP kinase pathway, like trametinib and vemurafenib, have been effective in treating Langerhans Cell Histiocytosis, especially in cases with specific genetic mutations. These drugs have shown favorable responses in patients, suggesting that similar treatments targeting the same pathway could be effective. ^{1 2 3 4 5}

Is DAY101 (Tovorafenib) safe for humans?

There is no specific safety data available for DAY101 (Tovorafenib) in the provided research articles. However, similar treatments like dabrafenib and trametinib, which target the same pathway, have been shown to be generally safe and well-tolerated in children with Langerhans Cell Histiocytosis, with common side effects including vomiting, fever, and skin issues. ^{1 2 3 5 6}

What is the purpose of this trial?

This trial tests the safety and effectiveness of tovorafenib (DAY101) in children and young adults with Langerhans cell histiocytosis that is worsening, has returned, or does not respond to other treatments. Tovorafenib is taken orally and works by blocking enzymes needed for cancer cell growth. The study aims to find the best dose and observe the response and side effects over time.

Research Team

Michelle L Hermiston

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for patients aged 6 months to under 22 years with progressive, relapsed, or refractory Langerhans cell histiocytosis who've had prior chemotherapy. They must have a certain level of organ function and performance status, no severe CNS toxicity, controlled infections or seizures, and not be pregnant or breastfeeding. Patients can't join if they've had recent surgeries, uncontrolled diseases, specific drug allergies or previous MAPK inhibitor therapy.

Inclusion Criteria

I am between 6 months and 21 years old.

It's been over 2 weeks since my last long-acting growth factor dose.

I haven't had chemotherapy that lowers my blood cell counts in the last 14 days.

Exclusion Criteria

I have had major surgery on my intestines or have a disease that affects how I absorb nutrients.

I have not had major surgery or a serious injury in the last 14 days.

I have only one bone lesion.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Patients receive tovorafenib orally once weekly on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

12 months

4 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up visits occur at 28 days, months 3, 6, 9, and 12, and then at 2 years post cycle 12.

Up to 2 years

Multiple visits (in-person)

Treatment Details

Interventions

• Tovorafenib

Trial Overview The trial tests the safety and effectiveness of tovorafenib (DAY101) in young patients with Langerhans cell histiocytosis that's worsening or not responding to treatment. It aims to find the best dose while monitoring how well it stops cancer cells by blocking enzymes needed for their growth.

Participant Groups

Group I: Treatment (tovorafenib) Experimental Treatment 9 Interventions

Patients receive tovorafenib PO QW on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MUGA or ECHO scans, and FDG-PET or CT throughout the trial, and collection of blood samples on study. Patients with suspicion of bone marrow and/or central nervous system involvement will also undergo bone marrow biopsy and aspiration and lumbar puncture on study and during follow up.

Tovorafenib 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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of two pediatric patients with Langerhans cell histiocytosis (LCH) and confirmed MAPK pathway mutations, treatment with trametinib led to complete resolution of the disease in both cases.

Trametinib, a MAP2K inhibitor, was well-tolerated with no adverse effects reported, suggesting it may be a safe and effective second-line treatment option for LCH driven by specific genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Success of Trametinib in the Treatment of Langerhans Cell Histiocytosis With Novel MAPK Pathway Mutations. Orr, K., Hustak, S., Beaudoin, R., et al.[2023]

In a study of 34 patients with various histiocytoses, including LCH, treatment with BRAF and MEK inhibitors (dabrafenib and trametinib) resulted in sustained favorable responses in 94% of patients with recurrent or refractory disease over a median duration of 4.3 years.

The inhibitors were also effective as first-line treatment for 18 patients, all of whom showed sustained favorable responses over a median duration of 2.5 years, indicating that these targeted therapies can be a safe and effective alternative to traditional chemotherapy for children with histiocytoses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib and trametinib in Langerhans cell histiocytosis and other histiocytic disorders. Cournoyer, E., Ferrell, J., Sharp, S., et al.[2023]

Vemurafenib (VMF) was found to be safe and effective in treating refractory childhood Langerhans cell histiocytosis (LCH) with the BRAFV600E mutation, showing significant therapeutic responses in 54 patients over a median follow-up of 22 months.

The treatment led to a substantial decrease in Disease Activity Score from diagnosis to treatment, with 38 complete and 16 partial responses observed at 8 weeks, although skin rash was a common side effect affecting 74% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study. Donadieu, J., Larabi, IA., Tardieu, M., et al.[2020]

Vemurafenib, a BRAF inhibitor, showed substantial and rapid clinical improvement in 3 patients with refractory Erdheim-Chester disease carrying the BRAFV600E mutation, indicating its potential efficacy in treating this rare condition.

The treatment led to confirmed tumor responses through imaging techniques within one month, suggesting that vemurafenib could be a viable option for severe cases of BRAFV600E histiocytoses, especially when the disease poses a life-threatening risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Haroche, J., Cohen-Aubart, F., Emile, JF., et al.[2022]

Dabrafenib shows promising effectiveness in treating children with BRAFV600E-mutated Langerhans cell histiocytosis, achieving a 65% objective response rate and a 75% disease control rate in a study of 20 children over a median follow-up of 30.8 months.

The treatment was generally safe, with only five patients experiencing grade 2 or 3 adverse effects, and 60% of patients showed negative circulating levels of BRAFV600E within 3 months, indicating a strong response to the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and Safety of Dabrafenib in the Treatment of 20 Chinese Children with BRAFV600E-Mutated Langerhans Cell Histiocytosis. Yang, Y., Wang, D., Cui, L., et al.[2022]

Dabrafenib, either alone or in combination with trametinib, showed significant clinical efficacy in treating pediatric patients with BRAF V600-mutant Langerhans cell histiocytosis (LCH), with response rates of 76.9% for monotherapy and 58.3% for combination therapy, and most responses were ongoing at the end of the studies.

The treatment was generally well-tolerated, with manageable side effects similar to those seen in other pediatric and adult conditions, although some patients discontinued due to adverse events like vomiting and increased blood creatinine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib, alone or in combination with trametinib, in BRAF V600-mutated pediatric Langerhans cell histiocytosis. Whitlock, JA., Geoerger, B., Dunkel, IJ., et al.[2023]

References

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

Success of Trametinib in the Treatment of Langerhans Cell Histiocytosis With Novel MAPK Pathway Mutations. [2023]

2. Italy pubmed.ncbi.nlm.nih.gov

Dabrafenib and trametinib in Langerhans cell histiocytosis and other histiocytic disorders. [2023]

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

Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study. [2020]

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

Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. [2022]

5. Korea (South) pubmed.ncbi.nlm.nih.gov

Effectiveness and Safety of Dabrafenib in the Treatment of 20 Chinese Children with BRAFV600E-Mutated Langerhans Cell Histiocytosis. [2022]

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

Dabrafenib, alone or in combination with trametinib, in BRAF V600-mutated pediatric Langerhans cell histiocytosis. [2023]