Binimetinib for Hairy Cell Leukemia
Recruiting in Palo Alto (17 mi)
Overseen byRobert J Kreitman, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Chemotherapy, Immunotherapy, Radiotherapy, others
Disqualifiers: Pregnancy, Active infection, Cardiovascular disease, others
No Placebo Group
Prior Safety Data
Approved in 4 Jurisdictions
Trial Summary
What is the purpose of this trial?Background:
Most people with hairy cell leukemia have a BRAF gene mutation. They can be treated with BRAF inhibitors, drugs that target this mutation. For people who do not have this mutation, BRAF inhibitors are not a treatment option. We found that in hairy cell leukemia, when BRAF is not mutated, the MEK gene frequently is. Binimetinib is a MEK inhibitor which targets MEK. It is important to determine if this drug can be a good treatment option in those who cannot benefit treatment with BRAF inhibitors.
Objective:
To see if binimetinib is an effective treatment for hairy cell leukemia that does not have a BRAF mutation.
Eligibility:
People ages 18 and older with hairy cell leukemia without a mutation in the BRAF gene and whose disease either did not respond to treatment or came back after treatment
Design:
Participants will be screened with:
* Medical history
* Physical exam
* Blood and urine tests
* Lung and heart tests
* Eye exam
* Bone marrow biopsy: A needle will be injected through the participant s skin into the bone to remove a sample of marrow.
* CT or MRI scan: Participants will lie in a machine that takes pictures of the body. They might receive a contrast agent by vein.
Before they start treatment, participants will have an abdominal ultrasound, pulmonary function tests, and exercise stress tests.
Participants will take binimetinib by mouth twice daily in 28-day cycles. They will keep a medication diary.
Participants will have at least one visit before every cycle. Visits will include repeats of some screening tests.
Participants may continue treatment as long as their disease does not get worse and they do not have bad side effects.
About a month after their last dose of treatment, participants will have a follow-up visit. They will then have visits once a year.
...
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you have had chemotherapy, immunotherapy, or radiotherapy within 4 weeks before starting the study treatment, or if you are currently taking other investigational agents.
Is Binimetinib (Mektovi) generally safe for humans?
The safety of Binimetinib (Mektovi) has been evaluated in other conditions, and it is known to cause some side effects, such as skin issues, when used as part of BRAF inhibitor therapy. However, specific safety data for its use in hairy cell leukemia is not provided in the available research.
12345How is the drug Binimetinib unique for treating Hairy Cell Leukemia?
Binimetinib is unique for treating Hairy Cell Leukemia because it is a MEK inhibitor, which targets a specific pathway in cancer cells, potentially offering a new approach compared to traditional chemotherapy or other treatments that do not specifically target this pathway.
678910Eligibility Criteria
Adults over 18 with hairy cell leukemia that doesn't have the BRAF gene mutation, who've had their disease return or not respond to treatment. They must have certain blood count levels and organ function, agree to use contraception, and be willing to sign consent. Excluded if recently treated with other therapies, pregnant/breastfeeding, uncontrolled illnesses, active infections like HBV/HCV or HIV without proper control.Inclusion Criteria
My liver, kidney, and blood functions meet the required levels for the trial.
My disease did not improve or worsened within a year after treatment, or it came back after treatment.
I cannot or do not want to participate in the Moxetumomab Pasudotox trial.
+6 more
Exclusion Criteria
I cannot swallow or keep down the medication.
I have heart problems or significant heart disease.
Is pregnant or breastfeeding or expecting to conceive within the projected duration of the study treatment
+15 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants take binimetinib by mouth twice daily in 28-day cycles. They will have at least one visit before every cycle, including repeats of some screening tests.
Ongoing 28-day cycles
1 visit per cycle (in-person)
Follow-up
About a month after their last dose of treatment, participants will have a follow-up visit. They will then have visits once a year.
1 month after treatment, then annually
1 visit (in-person) after treatment, annual visits
Participant Groups
The trial is testing binimetinib—a MEK inhibitor—on participants taking it orally twice daily in cycles of 28 days. It's for those whose leukemia lacks a BRAF mutation and aims to see if this drug can effectively treat their condition when other treatments haven't worked.
1Treatment groups
Experimental Treatment
Group I: Arm 1/Experimental therapyExperimental Treatment1 Intervention
Treatment with binimetinib
Binimetinib is already approved in United States, European Union, Canada, Japan for the following indications:
🇺🇸 Approved in United States as Mektovi for:
- Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation
🇪🇺 Approved in European Union as Mektovi for:
- Unresectable or metastatic melanoma with a BRAF V600 mutation
🇨🇦 Approved in Canada as Mektovi for:
- Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation
🇯🇵 Approved in Japan as Mektovi for:
- Unresectable or metastatic melanoma with a BRAF V600 mutation
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
BRAF in the cross-hairs. [2020]Hairy cell leukemia (HCL) is a rare, chronic B-cell lymphoproliferative disorder characterized by distinctive morphologic features and an indolent clinical course. The discovery of a recurrent activating mutation in BRAF (BRAF V600E) as a disease-defining genetic event in HCL has substantial diagnostic and therapeutic implications. Areas covered: Herein the authors review the role of BRAF V600E and RAF-MEK-ERK signaling in the pathogenesis of HCL, anecdotal clinical reports of BRAF inhibitor monotherapy in management of relapsed or refractory HCL, larger phase 2 trials investigating efficacy of BRAF inhibitor therapy for HCL, adverse effects commonly associated with BRAF inhibitor therapy, including cutaneous toxicity, and mechanisms of therapeutic resistance. Expert opinion: Ongoing and planned studies will help to optimize the use of BRAF inhibitor therapy for HCL by determining the efficacy of BRAF inhibition in combination with other antigen targeted or molecularly targeted therapies, and more broadly, to determine how hematologists can best utilize and sequence emerging diagnostic and therapeutic modalities in the care of patients with newly diagnosed and relapsed or refractory HCL.
Bendamustine and rituximab in relapsed and refractory hairy cell leukemia. [2022]To determine tolerability and for the first time explore efficacy of bendamustine-rituximab (BR) in multiply relapsed/refractory hairy cell leukemia (HCL), using two different dose levels of bendamustine.
A population-based study of hairy cell leukemia over a period of 20 years. [2021]There are limited population-based studies of hairy cell leukemia (HCL), a rare chronic lymphoproliferative disorder of B-cells. We conducted a population-based study that included all patients diagnosed with HCL between 1996 and 2016 in Western Normandy. Recorded data focused on medical history, clinical presentation, biological results, treatment modalities in the first line and in relapsed/refractory patients and the occurrence of secondary malignancies. One hundred and twenty-three HCL patients were registered in the database. HCL represented 0.7% of all malignant hematological disorders and 3.0% of all leukemia. The overall age-standardized incidence ratio (SIR) was 0.39/100,000 inhabitants in men and 0.09/100,000 in women, and it remained stable over the 20-year period analyzed. One hundred and seven patients (88%) received first-line treatment, 33 patients (27%) received at least 2 lines of treatment and 14 patients (11%) received more than 2 lines. Cladribine used as first-line treatment induced a high hematological complete response (HCR) rate of 92%. The median overall survival (OS) was over 15 years, with 5-year and 10-year survival rates of 84% and 70.5%. No significant differences in OS were observed between men and women, between the calendar periods studied or between patients who received a single line treatment with IFN-α or PNA. The risk of relapse was higher with IFN-α treatment, requiring subsequent treatments in that patients. The time to next treatment (TTN) tends to be longer for PNAs compared to IFN-α even if difference is not significant. Secondary cancers were observed in 9/123 patients (7.3%) with solid tumors in 8 patients and hematological malignancy in one patient. Our data confirm in real life that single courses of cladribine administered to patients with HCL induce high response rates, the majority of which are HCR. Relapses seem less frequent than with IFN-α and the administration schedule is less restrictive for the patients. The emergence of chemo-immunotherapy and the development of effective new drugs such as recombinant immunotoxins and BRAF targeting will offer new possibilities in the management of HCL patients.
Acute myeloid leukemia following treatment with cladribine for hairy cell leukemia: a case report and review of the literature. [2019]The overall survival of patients with hairy cell leukemia (HCL) has significantly increased in recent years because of the development of effective treatments such as interferon alpha and purine analogs. Several reports have described an increased risk of secondary cancers, particularly solid tumors, in patients with HCL. We describe a case of a patient with HCL, who had prolonged pancytopenia after a single course of cladribine. Fifteen months after the diagnosis of HCL the patient developed acute myeloid leukemia (AML) and died shortly afterwards. Review of the literature shows few reports of acute leukemia in HCL patients. All of the 11 reported cases of leukemia in patients with HCL have been in patients who have been treated with either interferon alpha or purine analogs, and developed several years (mean 4.3 years; range 1.6-6.4 years) after the diagnosis of HCL. Our case is unusual in that the patient developed AML shortly (1.2 years) after the diagnosis and treatment of HCL. Further studies are needed to clarify whether leukemias seen in patients following the treatment of their HCL are incidental findings or related to HCL and its treatments.
BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity. [2022]Hairy cell leukemia (HCL) shows unique clinicopathological and biological features. HCL responds well to purine analogs but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (vemurafenib; dabrafenib) or MEK (trametinib) inhibitors. Results were validated in vivo in samples from vemurafenib-treated HCL patients within a phase 2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, tartrate-resistant acid phosphatase, and cyclin D1, smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by coculture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and MEK inhibitors in HCL.
Therapeutic strategies for chronic myeloid leukemia in the chronic (stable) phase. [2015]During the last four decades, the optimal first-line treatment for chronic myeloid leukemia (CML) in chronic (stable) phase has progressed from alkylating agents, to hydroxyurea (HU), and then to interferon-alfa (IFN-alpha). Treatment for younger patients with suitable donors also includes allogeneic stem cell transplantation, which offers the chance of prolonged leukemia-free survival to about 20% of all CML patients and is the only certain approach to cure. Recently, three phase II studies of imatinib mesylate (STI571), a new inhibitor specific for tyrosine kinase of the Bcr-Abl oncoprotein, have been reported. They led the Food and Drug Administration (FDA) to approve use of this agent to treat CML patients following failure of or withdrawal from IFN-alpha. The advent of imatinib also led to a reassessment of the role of allogeneic transplantation. This article reviews evidence for the safety and efficacy of imatinib and allogeneic stem cell transplantation and suggests strategic approaches to treatment in the new era of tyrosine kinase inhibition.
Imatinib mesylate in chronic myeloid leukemia: frontline treatment and long-term outcomes. [2016]The tyrosine kinase inhibitor Imatinib Mesylate has dramatically improved the clinical outcome of chronic myeloid leukemia (CML) patients in the chronic phase of the disease, generating unprecedented rates of complete hematologic and cytogenetic responses and sustained reductions in BCR-ABL transcripts. Here, we present an overview on the efficacy and safety of Imatinib and describe the most important clinical studies employing this drug for the frontline treatment of chronic phase CML. We also discuss recent reports describing the long-term outcome of patients receiving Imatinib for their disease. The imminent availability of generic forms of Imatinib coupled with the approval of expensive second-generation tyrosine kinase inhibitors underlines an unmet need for early molecular parameters that may distinguish CML patients likely to benefit from the drug from those that should receive alternative forms of treatment.
Dasatinib for chronic myelogenous leukemia improves skin symptoms of systemic sclerosis. [2020]A 64-year-old man was diagnosed with limited cutaneous systemic sclerosis 5 years prior to this report. His sclerotic skin symptoms did not respond to oral low-dose prednisone (5-10 mg/day). Five years after the diagnosis, the patient presented with leukocytosis 3.8 × 109/L in a routine blood test, and was finally diagnosed with chronic-phase chronic myelogenous leukemia (CML). The leukemia responded optimally to initial dasatinib, and a complete cytogenetic response was achieved after 6 months of therapy. His skin symptoms dramatically improved in parallel with dasatinib therapy, as indicated by a decrease in the modified Rodnan skin score, from 12 points at diagnosis to 2 after 9 months. It has been reported that imatinib, a first-generation tyrosine kinase inhibitor, improves skin sclerosis in some patients with systemic sclerosis. To the best of our knowledge, this is the first report of simultaneous improvement of CML and limited cutaneous systemic sclerosis in response to dasatinib. Further study of the mechanism of action of dasatinib is crucial.
Ponatinib in the therapy of chronic myeloid leukemia. [2017]Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder that has become the neoplastic poster child for understanding the disease biology of a malignant disease and targeting effective therapy. The targeted therapy of BCR-ABL inhibition by tyrosine kinase inhibitors (TKI) has provided the epitome for "Ehlrich's magic bullet" postulated decades ago.
Chronic myeloid leukemia: a model for oncology. [2007]Leukemias have traditionally served as model systems for research on neoplasia because of the easy availability of cell material from blood and marrow for diagnosis, monitoring and studies on pathophysiology. Beyond these more technical aspects, chronic myeloid leukemia (CML) became the first neoplasia in which the elucidation of the genotype led to a rationally designed therapy of the phenotype. Targeting of the pathogenetically relevant BCR-ABL tyrosine kinase with the selective kinase inhibitor imatinib has induced remissions with almost complete disappearance of any signs and symptoms of CML. This therapeutic success has triggered an intensive search for target structures in other cancers and has led to the development of numerous inhibitors of potential targets, which are being studied in preclinical and clinical trials worldwide. This review deals with some of the recent developments that have evolved since our last review in this journal in 2000 (Hehlmann R, Hochhaus A, Berger U, Reiter A (2000) Current trends in the management of chronic myelogenous leukemia.