What side effects are associated with this type of intervention?

Common treatments for Langerhans Cell Histiocytosis (LCH) that involve enzyme inhibition, similar to Tovorafenib (DAY101), include various kinase inhibitors. These treatments often aim to block specific enzymes necessary for cancer cell growth. Known side effects of such treatments typically include gastrointestinal issues like nausea and vomiting, skin reactions such as rash and dermatitis, fatigue, and respiratory symptoms like dyspnea. Additionally, patients may experience more severe adverse effects such as increased risk of infections and potential organ toxicity, depending on the specific inhibitor used.

What prior FDA approvals exist?

There have been limited FDA approvals specifically for the treatment of Langerhans Cell Histiocytosis (LCH). Historically, treatments have included chemotherapy agents and targeted therapies. One notable FDA-approved drug for LCH is vemurafenib, a BRAF inhibitor, which targets the BRAF V600E mutation found in some LCH patients. This mechanism is somewhat similar to Tovorafenib (DAY101), which aims to inhibit enzymes necessary for cancer cell growth. Other treatments have included corticosteroids and vinblastine, but these do not work through enzyme inhibition.

What other types of research exist?

A promising novel alternative to Tovorafenib (DAY101) for Langerhans Cell Histiocytosis patients is Vemurafenib, a BRAF inhibitor. It has shown rapid clinical improvement and complete resolution of symptoms in a newborn with multisystem LCH.

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Kinase Inhibitor

DAY101 for Langerhans Cell Histiocytosis

Q: What is the mechanism of action of this treatment?

The most common treatments for Langerhans Cell Histiocytosis (LCH) often involve enzyme inhibitors like Tovorafenib (DAY101), which work by blocking specific enzymes required for cancer cell growth and proliferation. This approach is significant for LCH patients as it directly targets the underlying cellular mechanisms driving the disease, potentially leading to more effective control and reduction of tumor formation and tissue damage.

Phase 2

Recruiting

Led By Michelle L Hermiston

Research Sponsored by National Cancer Institute (NCI)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Patients aged 180 days to < 22 years at time of study enrollment

Patients must not have received myelosuppressive chemotherapy within 14 days of entry onto this study

Must not have

History of significant bowel resection or other significant malabsorptive disease

Major surgical procedure or significant traumatic injury within 14 days prior to study enrollment

Timeline

Screening 3 weeks

Treatment Varies

Follow Up at 1 and 2 years

Awards & highlights

No Placebo-Only Group

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects include reactions related to immune system activation such as inflammation in various organs but specifics are not provided; however, participants will be closely monitored for any adverse reactions during the study.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am between 6 months and 21 years old.

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

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I can take medicine by mouth.

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My brain-related side effects are mild.

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My cancer has worsened or returned after chemotherapy.

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I am mostly able to care for myself and carry out daily activities.

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I can take care of myself but might not be able to do heavy physical work.

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My LCH has come back or spread, and it can be measured.

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My kidney function tests are within the required range for my age and gender.

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My cancer has a known harmful gene mutation.

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I don't have shortness of breath at rest, can exercise, and my oxygen levels are above 94%.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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

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

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I have only one bone lesion.

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I have never been treated with MAPK pathway inhibitors.

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I do not have any untreated serious infections.

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I have LCH with another blood cancer or a history of a different cancer.

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My condition only affects my skin.

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I have had a solid organ or bone marrow transplant.

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My cancer has a MAP2K1 mutation.

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I have not had a serious brain bleed or any brain bleed in the last 28 days.

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I am currently pregnant.

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My condition involves brain degeneration due to LCH without any brain or systemic lesions.

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I have a high level of CPK in my blood causing symptoms.

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I have severe, uncontrolled nausea or problems absorbing food, or I have an external biliary shunt.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ at 1 and 2 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~at 1 and 2 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and at 1 and 2 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Frequency of dose limiting toxicity (DLT) (dose finding phase)

Overall response rate (ORR) (phase II)

Secondary study objectives

Duration of response rate

Event free survival rate (EFS)

Overall survival rate (OS)

+1 more

Other study objectives

Percent peripheral blood mononuclear cells (PBMC) with mutated allele

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (tovorafenib)Experimental Treatment9 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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Lumbar Puncture

2016

Completed Phase 3

~510

Biospecimen Collection

2004

Completed Phase 3

~2030

Bone Marrow Aspiration

2011

Completed Phase 2

~1740

Bone Marrow Biopsy

2021

Completed Phase 3

~230

Computed Tomography

2017

Completed Phase 2

~2790

Echocardiography

2013

Completed Phase 4

~11580

Multigated Acquisition Scan

2015

Completed Phase 3

~270

0 / 25Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Langerhans Cell Histiocytosis (LCH) often involve enzyme inhibitors like Tovorafenib (DAY101), which work by blocking specific enzymes required for cancer cell growth and proliferation. This approach is significant for LCH patients as it directly targets the underlying cellular mechanisms driving the disease, potentially leading to more effective control and reduction of tumor formation and tissue damage.

First-line Advanced Cutaneous Melanoma Treatments: Where Do We Stand?Tofacitinib enhances delivery of antibody-based therapeutics to tumor cells through modulation of inflammatory cells.The Systemic Management of Advanced Melanoma in 2016.