Cobimetinib for Langerhans Cell Histiocytosis
(NACHO-COBI Trial)
Recruiting in Palo Alto (17 mi)
+11 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Carl Allen
Must not be taking: CYP3A4 inducers/inhibitors, Anticoagulants
Disqualifiers: Other malignancy, Infection, Cardiac dysfunction, others
No Placebo Group
Prior Safety Data
Approved in 5 Jurisdictions
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.
12345Is 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.
34567How 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.
34578Eligibility 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.
+7 more
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.
+20 more
Trial 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
Participant Groups
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.
4Treatment groups
Experimental Treatment
Group I: Patients ≥ 21 years with LCH/histiocytic disorders (Grp4)Experimental Treatment1 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 Treatment1 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 Treatment1 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 Treatment1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Dana Farber Cancer Institute, Boston Children'sBoston, MA
Arkansas Children's HospitalLittle Rock, AR
Memorial Sloan Kettering Cancer CenterNew York, NY
Children's Medical Center- UTSWDallas, TX
More Trial Locations
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Who Is Running the Clinical Trial?
Carl AllenLead Sponsor
North American Consortium for HistiocytosisCollaborator
Baylor College of MedicineCollaborator
Genentech, Inc.Industry Sponsor
References
Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes. [2019]Many patients with histiocytic disorders such as Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) have treatment-refractory disease or suffer recurrences. Recent findings of gene mutations in histiocytoses have generated options for targeted therapies. We sought to determine the utility of prospective sequencing of select genes to further characterize mutations and identify targeted therapies for patients with histiocytoses. Biopsies of 72 patients with a variety of histiocytoses underwent comprehensive genomic profiling with targeted DNA and RNA sequencing. Fifteen patients (21%) carried the known BRAF V600E mutation, and 11 patients (15%) carried various mutations in MAP2K1, which we confirm induce constitutive activation of extracellular signal-regulated kinase (ERK) and were sensitive to inhibitors of mitogen-activated protein kinase kinase (MEK, the product of MAP2K1). We also identified recurring ALK rearrangements, and 4 LCH patients with an uncommon in-frame deletion in BRAF (N486_P490del or N486_T491>K), resulting in constitutive activation of ERK with resistance to V600E-specific inhibitors. We subsequently describe clinical cases where patients with aggressive multisystem LCH experience dramatic and sustained responses to monotherapy with either dabrafenib or trametinib. These findings support our conclusion that comprehensive genomic profiling should be regularly applied to these disorders at diagnosis, and can positively impact clinical care.
[BRAF V600E Mutation in Chinese Patients with Langerhans Cell Histiocytosis and Its Clinical Significance]. [2022]To investigate the BRAF V600E mutation in Chinese patients with langerhans cell histiocytosis (LCH) and its clinical significance.
Clinical resistance associated with a novel MAP2K1 mutation in a patient with Langerhans cell histiocytosis. [2019]Patients with Langerhans cell histiocytosis (LCH) harbor BRAF V600E and activating mutations of MAP2K1/MEK1 in 50% and 25% of cases, respectively. We evaluated a patient with treatment-refractory LCH for mutations in the RAS-RAF-MEK-ERK pathway and identified a novel mutation in the MAP2K1 gene resulting in a p.L98_K104 > Q deletion and predicted to be auto-activating. During treatment with the MEK inhibitor trametinib, the patient's disease showed significant progression. In vitro characterization of the MAP2K1 p.L98_K104 > Q deletion confirmed its effect on cellular activation of the ERK pathway and drug resistance.
Success of Trametinib in the Treatment of Langerhans Cell Histiocytosis With Novel MAPK Pathway Mutations. [2023]Approximately a third of patients with Langerhans cell histiocytosis (LCH) experience recurrence of disease. Genomic analysis has revealed that this condition is often driven by oncogenic mutations in the MAP kinase (MAPK) pathway, and agents that target components of this pathway have been explored as a second-line treatment for LCH. Here, we examine 2 pediatric patients with LCH and confirmed but rarely reported MAPK pathway mutations treated with trametinib, a MAP2K inhibitor approved to treat several cancers with a BRAFV600E mutation. Each patient achieved or maintained complete resolution of disease and remain on the drug with no adverse effects.
Dramatic Response After Switching MEK Inhibitors in a Patient With Refractory Mixed Histiocytosis. [2022]We report the case of a patient with progressive multisystem mixed histiocytosis associating Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) involving the bone marrow, whose lesions harbored the MAP2K1 E102-I103del. After initial improvement under the MEK inhibitor trametinib, the treatment was only partially efficient and poorly tolerated. Eventually, although the trough blood level of trametinib at steady state was within expected ranges, the disease progressed to a life-threatening situation, with peritoneal involvement and anasarca. Switching to the MEK inhibitor cobimetinib as a salvage therapy resulted in a dramatic, rapid disease response, and the patient remains disease-free 3 years later with the treatment. The load of the MAP2K1 deletion in peripheral blood was correlated with the disease activity and strongly declined with cobimetinib, although it remained detectable at the last follow-up.
Dabrafenib and trametinib in Langerhans cell histiocytosis and other histiocytic disorders. [2023]Standard treatment for Langerhans Cell Histiocytosis (LCH) is chemotherapy, with high failure rates. Since MAP-kinase activating mutations are found in most cases, BRAF- and MEKinhibitors have been used successfully to treat patients with refractory or relapsed disease. However, data on long-term responses in children are limited and no data exist on their use as first-line therapy. We treated thirty-four patients (26 LCH, 2 Juvenile Xanthogranuloma, 2 Rosai-Dorfman Disease, 4 presumed single site-CNS histiocytosis) with either dabrafenib and/or trametinib, either as first line or after relapse or failure of chemotherapy. Sixteen patients aged 1.3-21 years, had disease that was recurrent or refractory to chemotherapy, 9 of whom had multisystem LCH with risk-organ involvement. With a median treatment duration of 4.3 years, 15 (94%) patients have sustained favorable responses. Eighteen patients aged 0.2-45 years received the inhibitor as first-line treatment. All of these have had sustained favorable responses, with a median treatment duration of 2.5 years. Three patients with presumed isolated CNS/pituitary-stalk histiocytosis demonstrated stabilization or improvement of disease. Overall, inhibitors were well tolerated. Five patients with single system LCH discontinued therapy and remain off therapy without recurrence. In contrast, all 4 patients with multisystem disease that discontinued therapy were restarted. Our data suggest that children suffering from histiocytoses can be treated safely, and effectively with dabrafenib or trametinib. Additional studies are needed however to determine the long term safety and optimal duration of therapy.
Efficacy and safety of vemurafenib in Langerhans cell histiocytosis (LCH): A systematic review and meta-analysis. [2023]Almost half of the patients with Langerhans cell histiocytosis (LCH) are refractory to primary induction chemotherapy or undergo reactivation. The ideal treatment modality for refractory/relapsed LCH is yet not evidenced. This review aimed to determine the efficacy and safety of vemurafenib (a BRAF pathway inhibitor) in LCH, particularly the refractory/relapsed cases. The literature search was conducted using PubMed, Embase, CENTRAL, and abstracts published in the SIOP meetings. Studies that described the outcome of patients of LCH being treated with vemurafenib, alone or in combination, were included. A total of 416 studies were screened, and after applying exclusion criteria, 22 studies (n = 107) were included in the final analysis. The first-line therapy was prednisolone plus vinblastine for most patients (n = 92, 86%), and vemurafenib was started upfront in 3 patients (3%). The median time to first clinical response with vemurafenib was one week. The median time to best response was 5.25 months. Out of 107 patients, 62 patients (58%) had ultimately no active disease (NAD) while 39 (36%) had active disease better (ADB), making the overall response rate (ORR) of 101/107, ie, 94.4% (CI 0.88; 0.98). The main adverse effects of vemurafenib were rash or photosensitivity (47%) and other cutaneous adverse events (15%). Vemurafenib is highly efficacious and safe in the treatment of refractory LCH; however, the timing of its commencement and duration of therapy is yet to be established. Larger prospective collaborative trials are needed to answer the appropriate treatment duration and effective maintenance therapy approach.
Progressive nodular histiocytosis in a 9-year-old boy treated with cobimetinib. [2023]Progressive nodular histiocytosis is a rare variant of non-Langerhans cell histiocytosis that affects the skin and mucous membranes and displays a progressive clinical course and poor response to treatment. We describe a case of severe progressive nodular histiocytosis harboring a KRAS p.G12S mutation in a 9-year-old boy, refractory to chemotherapy, who was successfully treated with the MEK inhibitor cobimetinib. This is the first report of the use of MEK inhibition for this histiocytosis subtype in a pediatric patient.