Cobimetinib for Langerhans Cell Histiocytosis

(NACHO-COBI Trial)

Recruiting at 11 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

Trial Summary

What is the purpose of this trial?

This is a research study of a drug called cobimetinib in children and adults diagnosed with Langerhans cell histiocytosis (LCH), and other histiocytic disorders that has returned or does not respond to treatment. Cobimetinib blocks activation of a protein called Mitogen-activated protein kinase (MEK) that is part of incorrect growth signals in histiocytosis cells. Four different groups of patients will be enrolled.

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.

What data supports the effectiveness of the drug Cobimetinib for treating Langerhans Cell Histiocytosis?

In a reported case, a patient with Langerhans Cell Histiocytosis and Erdheim-Chester disease showed a dramatic and rapid response to Cobimetinib, remaining disease-free for 3 years. This suggests Cobimetinib may be effective for similar conditions involving mutations in the MAPK pathway. ^{1 2 3 4 5}

Is cobimetinib safe for treating Langerhans Cell Histiocytosis?

In a reported case, cobimetinib was used as a treatment for a patient with mixed histiocytosis, including Langerhans Cell Histiocytosis, and resulted in a dramatic and rapid disease response with the patient remaining disease-free for 3 years, suggesting it was well-tolerated and safe in this instance. ^{3 4 5 6 7}

How is the drug cobimetinib unique in treating Langerhans Cell Histiocytosis?

Cobimetinib is unique because it is a MEK inhibitor that has shown a dramatic and rapid response in treating Langerhans Cell Histiocytosis, especially in cases where other treatments like trametinib were not effective. It targets the MAPK pathway, which is often involved in this condition, and has been successful in cases with specific genetic mutations. ^{3 4 5 7 8}

Research Team

Carl E Allen, MD, PhD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

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.

I have LCH or a related disease, with treatment failure or recent worsening.

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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 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]

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]

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 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]

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]

References

1. China pubmed.ncbi.nlm.nih.gov

[BRAF V600E Mutation in Chinese Patients with Langerhans Cell Histiocytosis and Its Clinical Significance]. [2022]

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

Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes. [2019]

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

Clinical resistance associated with a novel MAP2K1 mutation in a patient with Langerhans cell histiocytosis. [2019]

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

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

5. Canada pubmed.ncbi.nlm.nih.gov

Dramatic Response After Switching MEK Inhibitors in a Patient With Refractory Mixed Histiocytosis. [2022]

6. Italy pubmed.ncbi.nlm.nih.gov

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

7. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of vemurafenib in Langerhans cell histiocytosis (LCH): A systematic review and meta-analysis. [2023]

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

Progressive nodular histiocytosis in a 9-year-old boy treated with cobimetinib. [2023]