Ignite Creation Date:
2024-05-06 @ 2:27 PM
Last Modification Date:
2024-10-26 @ 1:31 PM
Study NCT ID:
NCT04324112
Status:
RECRUITING
Last Update Posted:
2024-06-05
First Post:
2020-03-26
Brief Title:
Encorafenib Plus Binimetinib for People With BRAF V600 Mutated RelapsedRefractory HCL
Sponsor:
National Cancer Institute NCI
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Phase 2 Trial of Encorafenib Plus Binimetinib for Patients With BRAF V600 Mutated RelapsedRefractory HCL
Status:
RECRUITING
Status Verified Date:
2024-09-26
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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
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
Detailed Description:
Background
Hairy cell leukemia HCL is an indolent B-cell leukemia comprising 2 of all leukemias or approximately 1900 new casesyear 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 x103mcL Hgb 10gdL Platelet count 100 x103mcL leukemia cell count 5 x103mcL 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 PRCR 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
Hairy cell leukemia HCL is an indolent B-cell leukemia comprising 2 of all leukemias or approximately 1900 new casesyear 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 x103mcL Hgb 10gdL Platelet count 100 x103mcL leukemia cell count 5 x103mcL 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 PRCR 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 20-C-0076 | None | None | None |