DAY101 for Langerhans Cell Histiocytosis

Recruiting at 116 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

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 effectiveness for people with Langerhans cell histiocytosis, a condition where certain white blood cells accumulate and cause damage. The trial targets individuals whose disease is worsening, has returned after treatment, or isn't responding to existing treatments. The goal is to identify the safest, most effective dose and assess its impact on the disease. Suitable candidates for this trial have Langerhans cell histiocytosis that has relapsed, progressed, or is not responding to treatment. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that tovorafenib (DAY101) is likely to be safe for humans?

Research has shown that tovorafenib, the treatment being tested in this trial, has been studied for its safety and side effects in patients with Langerhans cell histiocytosis. In these studies, patients generally tolerated tovorafenib well. Some reported side effects included mild to moderate symptoms like tiredness, nausea, and skin rash, while serious side effects were less common.

The trial's advanced stage indicates that earlier studies found the treatment safe enough to continue testing. If tovorafenib were unsafe, it would not have reached this stage. Additionally, independent scientists monitor the trial to ensure the treatment remains safe as it progresses. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Langerhans Cell Histiocytosis, which often involve chemotherapy and steroids, tovorafenib targets a specific pathway that is crucial for the growth and survival of the diseased cells. Tovorafenib is a type of targeted therapy that inhibits a protein called BRAF, which is commonly mutated in this condition. Researchers are excited about tovorafenib because it offers a more precise approach, potentially leading to fewer side effects compared to conventional treatments. Additionally, its once-weekly oral administration is more convenient and less invasive than traditional therapies, making it a promising option for patients.

What evidence suggests that DAY101 might be an effective treatment for Langerhans cell histiocytosis?

Research shows that tovorafenib, also known as DAY101, might help treat difficult-to-treat Langerhans cell histiocytosis (LCH), meaning it has returned or doesn't respond to other treatments. This trial will evaluate tovorafenib, which blocks certain proteins that cancer cells need to grow. Previous studies have found that similar treatments, called MAPK inhibitors, effectively treat children with recurrent or resistant LCH. These findings suggest that tovorafenib may slow down or stop the growth of these cancer cells. ^{1 2 3 6 7}

Who Is on the Research Team?

Michelle L Hermiston

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

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 never been treated with MAPK pathway inhibitors.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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 and urine 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+

Published Research Related to This Trial

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, 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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05828069

NCT05828069 | A Study With Tovorafenib (DAY101) as ... This phase II trial tests the safety, side effects, best dose and activity of tovorafenib (DAY101) in treating patients with Langerhans cell histiocytosis ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05828069?term=AREA%5BBasicSearch%5D(TOVORAFENIB)&rank=6

A Study With Tovorafenib (DAY101) as a Treatment Option for ... There are three types of expanded access: Individual Patients: Allows a single patient, with a serious disease or condition who cannot participate in a clinical ...

3. uvahealth.com uvahealth.com/clinicaltrials/study-tovorafenib-day101-treatment-option-progressive-relapsed-or-refractory

A Study With Tovorafenib (DAY101) as a Treatment Option ... This phase II trial tests the safety, side effects, best dose and activity of tovorafenib (DAY101) in treating patients with Langerhans cell histiocytosis.

4. orlandohealth.com orlandohealth.com/clinical-trials-and-research/find-a-clinical-trial/anhl2121-phase-2-study-of-tovorafenib-day101-in-relapsed

Phase 2 Study of Tovorafenib (DAY101) in Relapsed and ... To determine overall response rate (ORR) for children and young adults with relapsed or refractory Langerhans cell histiocytosis (LCH) treated with tovorafenib ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10985455/

First-line MAPK inhibition in pediatric histiocytosis A few studies have shown the effectiveness of MAPK inhibitors in children with relapsed/refractory LCH or neuro-degenerative disease.

6. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2023-0369.html

COG: Phase 2 study of Tovorafenib (DAY101) in relapsed ... This phase II trial tests the safety, side effects, best dose and activity of tovorafenib (DAY101) in treating patients with Langerhans cell histiocytosis ...

7. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/langerhans-cell-histiocytosis

Langerhans Cell Histiocytosis clinical trials at UCSF This phase II trial tests the safety, side effects, best dose and activity of tovorafenib (DAY101) in treating patients with Langerhans cell histiocytosis.