Cobimetinib for Langerhans Cell Histiocytosis

(NACHO-COBI Trial)

Recruiting at 12 trial locations

Overseen By Olive Eckstein, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Carl Allen

Must not be taking: CYP3A4 inducers/inhibitors, Anticoagulants

Disqualifiers: Other malignancy, Infection, Cardiac dysfunction, 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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores cobimetinib (also known as Cotellic) for treating conditions like Langerhans cell histiocytosis (LCH) and similar disorders. The goal is to determine if cobimetinib, which blocks signals causing abnormal cell growth, can help when these diseases return or resist other treatments. The trial includes individuals with biopsy-confirmed LCH or related disorders unresponsive to standard therapy, encompassing both children and adults, with specific groups for different conditions. Participants must be able to take medicine orally and have measurable active disease.

As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications that affect the CYP3A4 enzyme, such as erythromycin or grapefruit juice, at least 14 days before joining. If you're on other treatments like chemotherapy or immunotherapy, you need to finish those at least 28 days before starting the trial. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatment is likely to be safe?

Research has shown that cobimetinib, a drug under study for Langerhans cell histiocytosis (LCH) and related disorders, has undergone safety testing in people. In earlier studies, patients who took cobimetinib experienced some common side effects, including diarrhea in 75% of patients, a skin rash in 50%, and imbalances in body minerals in 37.5%.

Despite these common side effects, cobimetinib is being studied for its potential effectiveness in some patients. Anyone considering joining a clinical trial should discuss the possible risks and benefits with a healthcare provider. This discussion can help them understand how the treatment might affect their health. ^{1 2 3 4 5}

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

Unlike the standard treatments for Langerhans Cell Histiocytosis, which often involve chemotherapy or targeted therapies like vemurafenib, cobimetinib stands out because it specifically inhibits MEK, a key protein in the signaling pathway that drives the growth of histiocytic cells. This unique mechanism of action offers a more targeted approach, potentially leading to fewer side effects and improved patient outcomes. Additionally, cobimetinib has shown promise in treating other histiocytic disorders, expanding its potential benefits beyond just LCH. Researchers are particularly excited about cobimetinib's ability to target the disease at a molecular level, which could lead to breakthroughs in treatment efficacy and safety.

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

Research has shown that cobimetinib can help treat certain histiocytic disorders, such as Langerhans Cell Histiocytosis (LCH). In one study, about 62.5% of patients experienced some symptom improvement, though symptoms did not completely disappear. Another study found that 83.3% of patients responded positively, which is very encouraging. Cobimetinib blocks a protein called MEK, which is involved in the signals that promote the growth of these disorders. While effective, some patients experienced side effects, including blood clots and eye problems. This trial will evaluate cobimetinib in different groups: children and young adults with recurrent LCH, adults with LCH or other histiocytic disorders, and patients with LCH Neurodegenerative Disease (LCH-ND). These findings suggest cobimetinib could be a helpful option for those with hard-to-treat histiocytic disorders. ^{1 2 3 4 6}

Who Is on the Research Team?

Carl E Allen, MD, PhD

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

This trial is for children and adults with Langerhans cell histiocytosis (LCH) or other histiocytic disorders that are resistant to treatment. Participants must have proper blood, kidney, liver, and heart function, not be pregnant or breastfeeding, agree to use contraception if applicable, and be able to take oral medication. Specific age groups are targeted for different parts of the study.

Inclusion Criteria

My heart's pumping ability is confirmed to be good by a recent heart scan.

I can take medicine by mouth or through a feeding tube.

My blood counts meet the required levels without recent medical help.

Exclusion Criteria

Patient has received treatment with investigational therapy within 4 weeks prior to initiation of study drug.

I have no other active cancer or a history of another cancer.

I have a history of serious heart problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Cobimetinib to assess safety and efficacy in treating histiocytic disorders

12 months

Regular visits for response assessment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cobimetinib

Trial Overview

The drug cobimetinib is being tested on patients with various histiocytic disorders including LCH. Cobimetinib works by blocking a protein involved in abnormal cell growth signals. The study will include four distinct patient groups based on their specific conditions.

How Is the Trial Designed?

Group I: Patients ≥ 21 years with LCH/histiocytic disorders (Grp4) Experimental Treatment 1 Intervention

Adults (≥21 years) with LCH or other histiocytic disorder with recurrent active lesions (may also have LCH-ND).

Group II: Patients of any age with LCH-ND (Grp2) Experimental Treatment 1 Intervention

Patients of any age (≥ 6 months) with progressive LCH Neurodegenerative Disease (LCH-ND) without other sites of active LCH.

Group III: Patients <21 years with other histiocytic disorders (Grp3) Experimental Treatment 1 Intervention

Newly diagnosed or relapsed/refractory children (≥ 6 months) and young adults (\<21 years) with other histiocytic disorders including juvenile xanthogranuloma, Erdheim-Chester disease, histiocytic sarcoma and Rosai-Dorfman disease.

Group IV: Patients < 21 years with recurrent LCH (Grp1) Experimental Treatment 1 Intervention

Children (≥ 6 months) and young adults (\<21 years) with recurrent active LCH lesions (may also have LCH-ND).

Cobimetinib is already approved in European Union, United States, Canada, Switzerland, Japan for the following indications:

Approved in European Union as Cotellic for:

• Melanoma

Approved in United States as Cotellic for:

• Melanoma

Approved in Canada as Cotellic for:

• Melanoma

Approved in Switzerland as Cotellic for:

• Melanoma

Approved in Japan as Cotellic for:

• Melanoma

Who Is Running the Clinical Trial?

Carl Allen

Lead Sponsor

Trials

1

Recruited

90+

North American Consortium for Histiocytosis

Collaborator

Trials

5

Recruited

1,700+

Baylor College of Medicine

Collaborator

Trials

1,044

Recruited

6,031,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

In a study of 50 Chinese patients with Langerhans cell histiocytosis (LCH), the BRAF V600E mutation was found in 58% of cases, indicating that LCH may be a clonal disease associated with this mutation.

The presence of the BRAF V600E mutation did not significantly correlate with patient age, sex, clinical stage, or survival outcomes, suggesting that while the mutation is common in LCH, its clinical significance remains unclear and requires further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[BRAF V600E Mutation in Chinese Patients with Langerhans Cell Histiocytosis and Its Clinical Significance]. Cheng, XY., Li, Y., Zhou, J., et al.[2022]

A novel mutation in the MAP2K1 gene was identified in a patient with treatment-refractory Langerhans cell histiocytosis (LCH), which is predicted to cause auto-activation of the ERK pathway.

Despite treatment with the MEK inhibitor trametinib, the patient's disease progressed significantly, indicating that this mutation may contribute to drug resistance in LCH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical resistance associated with a novel MAP2K1 mutation in a patient with Langerhans cell histiocytosis. Azorsa, DO., Lee, DW., Wai, DH., et al.[2019]

A patient with a severe form of mixed histiocytosis showed initial improvement with the MEK inhibitor trametinib, but the treatment was only partially effective and poorly tolerated, leading to disease progression.

Switching to the MEK inhibitor cobimetinib resulted in a dramatic and rapid response, allowing the patient to remain disease-free for 3 years, highlighting the potential of cobimetinib as an effective salvage therapy for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dramatic Response After Switching MEK Inhibitors in a Patient With Refractory Mixed Histiocytosis. Roeser, A., Jouenne, F., Vercellino, 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]

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, a BRAF pathway inhibitor, shows high efficacy in treating refractory or relapsed Langerhans cell histiocytosis (LCH), with an overall response rate of 94.4% in a review of 22 studies involving 107 patients.

The median time to first clinical response was just one week, indicating rapid effectiveness, although common side effects included rash and photosensitivity in nearly half of the patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of vemurafenib in Langerhans cell histiocytosis (LCH): A systematic review and meta-analysis. Mohapatra, D., Gupta, AK., Haldar, P., et al.[2023]

In a study of 72 patients with histiocytic disorders, comprehensive genomic profiling revealed that 21% had the BRAF V600E mutation and 15% had mutations in MAP2K1, which can be targeted with specific therapies.

Patients with aggressive Langerhans cell histiocytosis (LCH) showed significant and lasting responses to targeted treatments like dabrafenib or trametinib, highlighting the importance of genetic testing in guiding effective therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes. Lee, LH., Gasilina, A., Roychoudhury, J., et al.[2019]

A 9-year-old boy with severe progressive nodular histiocytosis, which is resistant to standard chemotherapy, was successfully treated with the MEK inhibitor cobimetinib, highlighting a potential new treatment option for this rare condition.

This case is significant as it represents the first documented use of MEK inhibition for treating this specific subtype of histiocytosis in a pediatric patient, suggesting that targeted therapies may be effective in similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progressive nodular histiocytosis in a 9-year-old boy treated with cobimetinib. Buján, MM., Sánchez La Rosa, C., Galluzzo Mutti, ML., et al.[2023]

Citations

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clinicaltrials.gov

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Study Details | NCT04079179 | Cobimetinib in Refractory ...

The purpose of this research study is to learn whether cobimetinib is safe and effective in subjects diagnosed with LCH, LCH-ND, RDD, JXG and ECD which may have ...

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Treatment of Cerebral Histiocytosis With Low Dose of ...

Treatment with the MEK inhibitor cobimetinib brought the disease to a complete halt. However, side effects such as thrombosis and serous macular ...

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Phase 2 Trial of Single-Agent Cobimetinib for Adults with ...

Response rates are listed in Table 1 and PRC responses are presented in Figure 1. The ORR by PRC was 83.3% (95% CI 62.62-95.26), in the PRC- ...

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journals.lww.com

journals.lww.com/hemasphere/fulltext/2022/06003/p1097__mek_inhibitors_in_treatment_of_langerhans.987.aspx

mek-inhibitors in treatment of langerhans cell histiocytosis

Results: Complete response to cobimetinib was not achieved in any patient. Partial response was established in 62,5% cases. One patient was diagnosed with ...

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histio.org

histio.org/breakthrough-for-histiocytosis-cobimetinib-approval-by-the-fda/

Breakthrough for Histiocytosis: Cobimetinib Approval by ...

This research is exciting as it has led to better patient outcomes, higher percentages of survivorship, and has brought about much hope for the ...

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trialx.com

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Cobimetinib in Refractory Langerhans Cell Histiocytosis ...

The purpose of this research study is to learn whether cobimetinib is safe and effective in subjects diagnosed with LCH, LCH-ND, RDD, JXG and ...