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Hairy Cell Leukemia

Binimetinib will be given orally at a dose of 45mg BID continuously for 28-day cycles with no resting period between cycles.

binimetinib

Holly Eager (DiFebo), R.N.

Robert J Kreitman, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

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.

...

Background:

* Hairy cell leukemia (HCL) is an indolent B-cell leukemia comprising 2% of all leukemias, or approximately 1900 new cases per year in the US.
* BRAF V600E mutation is very common in classic HCL.
* HCL variant (HCLv) is wild type for BRAF and is more aggressive compared to classic HCL due to its lower response and shorter duration of response to standard purine analog chemotherapy. The median survival is only \~6 years compared to \>25 years for classic HCL.
* CD25+ classic-appearing HCL-cells that express unmutated IGHV4-34+ immunoglobulin rearrangement, are wild-type for BRAF, and confer a poor prognosis when treated with standard purine analog chemotherapy.
* While BRAF and MEK combination inhibition is making an impact in the treatment of BRAF V600E mutated HCL, this treatment is not applicable for patients with BRAF-WT HCL/HCLv. Furthermore, with poor survival outcomes in this patient population, lack of targeted therapy constitutes a clear unmet need.
* Recently, several BRAF WT HCL/HCLv patients have received MEK inhibitors by compassionate use and have had lifesaving partial to complete remission, however the response has not been assessed systematically in clinical trials.
* Binimetinib (also known as MEK162) is an orally bioavailable, selective and potent mitogenactivated protein (MAP) kinase kinase (MEK1 and MEK2) inhibitor, which is approved for use in combination with encorafenib for the treatment of patients with BRAF-mutant melanoma
* We have described MAP2K1 (MEK) mutations which may drive the aggressive clinical behavior of BRAF WT HCL/HCLv patients, but MEK inhibition may be clinically useful even in these patients without known MAP2K1 (MEK) mutations.

Objective:

-To determine the overall response rate (ORR) to binimetinib, in participants with BRAF WT HCL and HCLv.

Eligibility:

* BRAF WT HCL or HCLv with at least 1 prior purine analog treatment
* Need for treatment as evidenced by any one of the following: ANC \<1 x10\^3/mcL, Hgb \<10g/dL, Platelet count \<100 x10\^3/mcL, leukemia cell count \>5 x10\^3/mcL, symptomatic splenomegaly, enlarging HCL mass \> 2cm in short axis.

  -\>=18 years of age
* No uncontrolled infection, cardiopulmonary dysfunction, or secondary malignancy requiring treatment.
* No chemotherapy, immunotherapy, investigational agent or radiotherapy within 4 weeks prior to the start of study treatment.

Design:

* Single arm phase 2 trial to determine ORR in participants with relapsed/refractory BRAF WT HCL and HCLv.
* 2-phase minimax design will be used to rule out an unacceptable 10% in favor of an improved 25% ORR.
* Initially 16 evaluable participants will be enrolled. If 2 or more achieve a major response, then accrual will continue to a total of 31 evaluable participants.
* Binimetinib will be given at a dose of 45mg BID for as long as participants can continue dosing chronically without significant toxicity or a trial off therapy due to achievement of MRD negative complete remission or PR/CR in which they would like a trial off therapy. Participants may return to therapy within 2 years of stopping treatment if evidence of disease returns.

Binimetinib for People With Relapsed/Refractory BRAF Wild Type Hairy Cell Leukemia and Variant

Phase 2 Trial for Binimetinib for Patients With Relapsed/Refractory BRAF Wild Type Hairy Cell Leukemia and Variant

.All IPD recorded in the medical record will be shared with intramural investigators upon request.

Percentage of patients with the best overall response of CR or PR to therapy

the time criteria are met for CR or PR (whichever is recorded first) until the first date that patient no longer qualifies as a PR

duration of time from the start of the treatment until time of disease relapse from PR, disease progression, or death, whichever occurs first

the time from the start of the treatment until time of death from any cause

duration of time from the start of the binimetinib to next line of treatment

The fraction of patients with toxicity noted will be reported by grade and type of toxicity identified.

determine whether the response to binimetinib is different in patients with and without MAP2K1 (MEK mutations), in patients for which MEK status is known

National Cancer Institute (NCI)

Treatment with encorafenib and binimetinib

Encorafenib will be given orally at a dose of 450mg QD continuously for 28-day cycles with no resting period between cycles.

Encorafenib

Background:

Hairy cell leukemia (HCL) does not usually respond to chemotherapy. Most people with HCL have a BRAF gene mutation. This can increase the growth of cancer cells. Vemurafenib has been tested to treat these people. However, researchers think a combination of drugs might work better.

Objective:

To test if treatment with a combination of encorafenib and binimetinib in BRAF mutant

HCL is more effective than treatment with vemurafenib.

Eligibility:

People ages 18 and older with BRAF mutant HCL that did not respond to or came back after treatment

Design:

Participants will be screened with:

Medical history

Physical exam

Bone marrow biopsy: A needle will be injected through the participant s skin and into a bone to remove liquid.

Blood and urine tests

Heart and lung function tests

CT or MRI scan: Participants will lie in a machine that takes pictures of the body. They may have a contrast agent injected into a vein.

Eye exam

Participants will take the study drugs by mouth in 28-day cycles. They will take encorafenib daily. They will take binimetinib twice daily. They will keep a pill diary.

Participants will take their temperature daily.

Participants will have at least 1 visit before each cycle. Visits will include repeats of some screening tests. They will also include abdominal ultrasounds, exercise stress tests, and skin evaluations.

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. Then they will have annual follow-ups....

Background:

* Hairy cell leukemia (HCL) is an indolent B-cell leukemia comprising 2% of all leukemias, or approximately 1900 new cases/year in the US. The nucleoside analogs cladribine and pentostatin are highly active as monotherapy with complete remission (CR) rates of 80 to 90%. However, there is no cure from chemotherapy and patients eventually relapse with worse efficacy and cumulative toxicity (stem cell damage and neuropathy) with each repeated chemotherapy course.
* About 90% of classic HCL patients have the BRAF V600E mutation, which leads to Ras-independent activation of the MAPK pathway, causing increased phosphorylation (hyper-activation) of MEK, followed by ERK, therefore promoting the proliferation and survival of HCL cells.
* The BRAF inhibitor, vemurafenib, when used as a single agent for the treatment of HCL achieved high response rate with CR rate of 38% in 50 patients reported from 2 trials, however, treatment was limited to several months and responses lacked durability, with median CR duration of 19 months in 1 trial. In this trial, 100% of the CRs were positive for minimal residual disease (MRD) by immunohistochemistry (IHC), and failure to eradicate MRD after several months of vemurafenib likely lead to the lack of CR durability.
* In a recent trial of combined inhibition of BRAF and MEK using dabrafenib and trametinib treatment, 49% of 41 evaluable patients achieved CR, and MRD was eradicated in 15% of patients on this trial. At NIH, we enrolled a total of 28 HCL patients on this trial and achieved a CR rate of 68% amongst our patients by managing toxicity and allowing patients to remain on treatment.
* A major challenge in the long-term treatment of HCL patients with dabrafenib and trametinib is managing fever, which has necessitated long-term or intermittent steroids use for most patients.
* In the COLOMBUS trial, the combination of the BRAF inhibitor, encorafenib and the MEK inhibitor, binimetinib was found to be superior to vemurafenib for BRAF V600E+ melanoma with respect to PFS and OS and was well tolerated with low rates of toxicities including pyrexia.
* To our knowledge, neither encorafenib nor binimetinib has been tested in HCL, but the low rate of pyrexia with encorafenib plus binimetinib in melanoma suggests that this combination may be well tolerated in HCL.

Objective:

- To determine if treatment with combination encorafenib and binimetinib in BRAF V600 mutant + HCL is associated with a CR rate which exceeds that of vemurafenib.

Eligibility:

* BRAF V600 mutant HCL with at least 1 prior purine analog treatment
* Need for treatment, as evidenced by any one of the following: ANC \<1 x10\^3/mcL, Hgb \<10g/dL, Platelet count \<100 x10\^3/mcL, leukemia cell count \>5 x10\^3/mcL, symptomatic splenomegaly, enlarging HCL mass \> 2cm in short axis
* Greater than or equal to 18 years of age
* No uncontrolled infection, cardiopulmonary dysfunction, or secondary malignancy requiring treatment.
* No chemotherapy, immunotherapy, investigational agent or radiotherapy within 4 weeks prior to the start of study treatment.

Design:

* Phase 2 trial, single arm, non-randomized trial to determine if the combination of encorafenib and binimetinib achieves a CR rate in HCL which is historically higher than that of vemurafenib.
* Simon optimal 2-phase design will be used to rule out an unacceptable CR rate of 35% in favor of an improved 55% CR rate.
* Initially 12 evaluable participants will be enrolled. If 5 or more achieve CR, then accrual will continue to a total of 32 evaluable participants
* Encorafenib will be given at a dose of 450mg QD and binimetinib at a dose of 45mg BID for as long as participants can continue dosing chronically without significant toxicity or a trial off therapy due to achievement of MRD negative complete remission or PR/CR in which they would like a trial off therapy. Participants may return to therapy within 2 years of stopping treatment if evidence of disease returns.

Encorafenib Plus Binimetinib for People With BRAF V600 Mutated Relapsed/Refractory HCL

Phase 2 Trial of Encorafenib Plus Binimetinib for Patients With BRAF V600 Mutated Relapsed/Refractory HCL

determine if treatment with combination encorafenib and binimetinib in BRAF V600 mutant + HCL is associated with a CR rate which exceeds that of vemurafenib

Fraction of patients who achieve MRD negative CR after treatment with encorafenib and binimetinib

duration of time from the start of the study drugs to next line of treatment

the time from study enrollment to the first occurrence of progression, relapse after response, or death from any cause

fraction of patients that have pyrexia at any time while on study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Binimetinib for People With Relapsed/Refractory BRAF Wild Type Hairy Cell Leukemia and Variant	NCT04322383	Hairy Cell Leuk...	binimetinib	18 Years -	National Institutes of Health Clinical Center (CC)
Encorafenib Plus Binimetinib for People With BRAF V600 Mutated Relapsed/Refractory HCL	NCT04324112	Hairy Cell Leuk...	binimetinib Encorafenib	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for mek1

Every month we try and update this database with for mek1 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for mek1

Every month we try and update this database with for mek1 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for mek1 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.