Nilotinib Plus Dabrafenib/Trametinib or Encorafenib/Binimetinib in Metastatic Melanoma
Nilotinib Plus Dabrafenib/Trametinib or Encorafenib/Binimetinib in Metastatic Melanoma
This is a phase 1 dose-escalation study of nilotinib in combination with fixed-dose dabrafenib and trametinib regimen for patients with metastatic or unresectable melanoma carrying a BRAF V600 mutation and have relapsed on a BRAF/MEK inhibitor therapy. The goal is to assess the toxicity and tolerability and determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of the combination of nilotinib with dabrafenib and trametinib or with encorafenib and binimetinib. Additionally, this study will assess pharmacokinetic parameters of dabrafenib and nilotinib when used in combination.
Melanoma,
Phase I
Phase I
Adults
Chemotherapy - cytotoxic,
Mol. targeted/Immunotherapy/Biologics
AMN107,
Binimetinib,
Dabrafenib,
Encorafenib,
Nilotinib,
Trametinib
Johnson, Douglas
International
Vanderbilt University
12-07-2023
Eligibility
18 Years and older
ALL
false
Inclusion Criteria:
Patients must have histologically confirmed metastatic or unresectable melanoma. Radiological evaluation should occur within 28 days prior to enrollment initiation.
Patients must have histologically confirmed metastatic or unresectable melanoma. Radiological evaluation should occur within 28 days prior to enrollment initiation.
Patients must have a BRAF V600 mutation. Any CLIA-certified mutation testing is acceptable to document mutation status.
Patients must have a BRAF V600 mutation. Any CLIA-certified mutation testing is acceptable to document mutation status.
Patients must have stable disease on dabrafenib and trametinib or on encorafenib and binimetinib for a duration of greater than or equal to 3 months OR have failed any BRAFi/MEKi regimen to qualify for the trial, including the dabrafenib/trametinib combination and/or the encorafenib/ binimetinib combination.
Patients must have stable disease on dabrafenib and trametinib or on encorafenib and binimetinib for a duration of greater than or equal to 3 months OR have failed any BRAFi/MEKi regimen to qualify for the trial, including the dabrafenib/trametinib combination and/or the encorafenib/ binimetinib combination.
Patient may have had prior immunotherapy for metastatic disease or prior cellular therapy (although NOT mandatory). NOTE: Other prior therapies are not allowed, with the exception of radiation.
Patient may have had prior immunotherapy for metastatic disease or prior cellular therapy (although NOT mandatory). NOTE: Other prior therapies are not allowed, with the exception of radiation.
Age 18 years.
Age 18 years.
ECOG performance status 1.
ECOG performance status 1.
Patients must have adequate organ and marrow function as defined below:
Patients must have adequate organ and marrow function as defined below:
absolute neutrophil count 1,500/mcL
absolute neutrophil count 1,500/mcL
platelets 100,000/mcL
platelets 100,000/mcL
total bilirubin institutional upper limit of normal (ULN)
total bilirubin institutional upper limit of normal (ULN)
AST(SGOT)/ALT(SGPT) 3 institutional ULN
AST(SGOT)/ALT(SGPT) 3 institutional ULN
creatinine institutional ULN OR
creatinine institutional ULN OR
glomerular filtration rate (GFR) 60 mL/min/1.73 m2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m2.
glomerular filtration rate (GFR) 60 mL/min/1.73 m2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m2.
Patients with known human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
Patients with known human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
For patients with known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
For patients with known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with known HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with known HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
Patients with treated brain metastases are eligible if follow-up brain imaging 4 weeks or longer after central nervous system (CNS)-directed therapy shows no evidence of progression.
Patients with treated brain metastases are eligible if follow-up brain imaging 4 weeks or longer after central nervous system (CNS)-directed therapy shows no evidence of progression.
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
Measurable (target) disease by Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria. Target lesions selected for tumor measurements should be those where additional (e.g., palliative) treatments are not indicated or anticipated. Measurable disease per RECIST 1.1 requirements: defined as longest diameter to be recorded for non-nodal lesions > 10mm and short axis for nodal lesions >15 mm using conventional techniques
Measurable (target) disease by Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria. Target lesions selected for tumor measurements should be those where additional (e.g., palliative) treatments are not indicated or anticipated. Measurable disease per RECIST 1.1 requirements: defined as longest diameter to be recorded for non-nodal lesions > 10mm and short axis for nodal lesions >15 mm using conventional techniques
The effects of nilotinib, encorafenib, dabrafenib, binimetinib and trametinib on the developing human fetus are unknown, women of childbearing potential and men must agree to use adequate contraception (non-hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of nilotinib, dabrafenib, and trametinib administration.
The effects of nilotinib, encorafenib, dabrafenib, binimetinib and trametinib on the developing human fetus are unknown, women of childbearing potential and men must agree to use adequate contraception (non-hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of nilotinib, dabrafenib, and trametinib administration.
Patients must have the ability to understand and the willingness to sign a written informed consent document.
Patients must have the ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
Patients with chronic hypokalemia or chronic hypomagnesemia. Patients can be eligible with a repeat screening, if results show repletion.
Patients with chronic hypokalemia or chronic hypomagnesemia. Patients can be eligible with a repeat screening, if results show repletion.
Patients with long QT syndrome or baseline QTc (Fridericia) >470 msec in males and >480 msec in females (ULN for each respectively).
Patients with long QT syndrome or baseline QTc (Fridericia) >470 msec in males and >480 msec in females (ULN for each respectively).
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1 or greater than baseline) with the exception of alopecia, grade 2 fatigue, vitiligo or endocrinopathies on stable replacement therapy).
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1 or greater than baseline) with the exception of alopecia, grade 2 fatigue, vitiligo or endocrinopathies on stable replacement therapy).
Patients who are receiving any other investigational therapies that could affect the primary or secondary outcomes of this study.
Patients who are receiving any other investigational therapies that could affect the primary or secondary outcomes of this study.
Untreated brain metastases are not allowed.
Untreated brain metastases are not allowed.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to nilotinib, dabrafenib, encorafenib, binimetinib and trametinib.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to nilotinib, dabrafenib, encorafenib, binimetinib and trametinib.
Patients receiving any medications or substances that are strong CYP3A inhibitors are ineligible for this trial. Patients receiving any medications or substances that are strong CYP3A inducers are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
Patients receiving any medications or substances that are strong CYP3A inhibitors are ineligible for this trial. Patients receiving any medications or substances that are strong CYP3A inducers are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
Patients receiving any medications or substances that are strong CYP2C8 inhibitors are ineligible for the dabrafenib+ trametinib. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
Patients receiving any medications or substances that are strong CYP2C8 inhibitors are ineligible for the dabrafenib+ trametinib. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
Use of proton pump inhibitors concurrent with nilotinib is prohibited. Use of short-acting antacids or H2 blockers as an alternative to proton pump inhibitors is allowable.
Use of proton pump inhibitors concurrent with nilotinib is prohibited. Use of short-acting antacids or H2 blockers as an alternative to proton pump inhibitors is allowable.
Use of drugs or substances known to prolong QT interval is prohibited with Nilotinib
Use of drugs or substances known to prolong QT interval is prohibited with Nilotinib
Patients with uncontrolled intercurrent illness.
Patients with uncontrolled intercurrent illness.
Patients with psychiatric illness/social situations that would limit compliance with study requirements.
Patients with psychiatric illness/social situations that would limit compliance with study requirements.
Pregnant or lactating women
Pregnant or lactating women
Inclusion of Women and Minorities
Inclusion of Women and Minorities
-There are no exclusions for trial participation based on gender nor race.
-There are no exclusions for trial participation based on gender nor race.
Patients must have histologically confirmed metastatic or unresectable melanoma. Radiological evaluation should occur within 28 days prior to enrollment initiation.
Patients must have histologically confirmed metastatic or unresectable melanoma. Radiological evaluation should occur within 28 days prior to enrollment initiation.
Patients must have a BRAF V600 mutation. Any CLIA-certified mutation testing is acceptable to document mutation status.
Patients must have a BRAF V600 mutation. Any CLIA-certified mutation testing is acceptable to document mutation status.
Patients must have stable disease on dabrafenib and trametinib or on encorafenib and binimetinib for a duration of greater than or equal to 3 months OR have failed any BRAFi/MEKi regimen to qualify for the trial, including the dabrafenib/trametinib combination and/or the encorafenib/ binimetinib combination.
Patients must have stable disease on dabrafenib and trametinib or on encorafenib and binimetinib for a duration of greater than or equal to 3 months OR have failed any BRAFi/MEKi regimen to qualify for the trial, including the dabrafenib/trametinib combination and/or the encorafenib/ binimetinib combination.
Patient may have had prior immunotherapy for metastatic disease or prior cellular therapy (although NOT mandatory). NOTE: Other prior therapies are not allowed, with the exception of radiation.
Patient may have had prior immunotherapy for metastatic disease or prior cellular therapy (although NOT mandatory). NOTE: Other prior therapies are not allowed, with the exception of radiation.
Age 18 years.
Age 18 years.
ECOG performance status 1.
ECOG performance status 1.
Patients must have adequate organ and marrow function as defined below:
Patients must have adequate organ and marrow function as defined below:
absolute neutrophil count 1,500/mcL
absolute neutrophil count 1,500/mcL
platelets 100,000/mcL
platelets 100,000/mcL
total bilirubin institutional upper limit of normal (ULN)
total bilirubin institutional upper limit of normal (ULN)
AST(SGOT)/ALT(SGPT) 3 institutional ULN
AST(SGOT)/ALT(SGPT) 3 institutional ULN
creatinine institutional ULN OR
creatinine institutional ULN OR
glomerular filtration rate (GFR) 60 mL/min/1.73 m2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m2.
glomerular filtration rate (GFR) 60 mL/min/1.73 m2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m2.
Patients with known human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
Patients with known human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
For patients with known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
For patients with known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with known HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with known HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
Patients with treated brain metastases are eligible if follow-up brain imaging 4 weeks or longer after central nervous system (CNS)-directed therapy shows no evidence of progression.
Patients with treated brain metastases are eligible if follow-up brain imaging 4 weeks or longer after central nervous system (CNS)-directed therapy shows no evidence of progression.
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
Measurable (target) disease by Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria. Target lesions selected for tumor measurements should be those where additional (e.g., palliative) treatments are not indicated or anticipated. Measurable disease per RECIST 1.1 requirements: defined as longest diameter to be recorded for non-nodal lesions > 10mm and short axis for nodal lesions >15 mm using conventional techniques
Measurable (target) disease by Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria. Target lesions selected for tumor measurements should be those where additional (e.g., palliative) treatments are not indicated or anticipated. Measurable disease per RECIST 1.1 requirements: defined as longest diameter to be recorded for non-nodal lesions > 10mm and short axis for nodal lesions >15 mm using conventional techniques
The effects of nilotinib, encorafenib, dabrafenib, binimetinib and trametinib on the developing human fetus are unknown, women of childbearing potential and men must agree to use adequate contraception (non-hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of nilotinib, dabrafenib, and trametinib administration.
The effects of nilotinib, encorafenib, dabrafenib, binimetinib and trametinib on the developing human fetus are unknown, women of childbearing potential and men must agree to use adequate contraception (non-hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of nilotinib, dabrafenib, and trametinib administration.
Patients must have the ability to understand and the willingness to sign a written informed consent document.
Patients must have the ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
Patients with chronic hypokalemia or chronic hypomagnesemia. Patients can be eligible with a repeat screening, if results show repletion.
Patients with chronic hypokalemia or chronic hypomagnesemia. Patients can be eligible with a repeat screening, if results show repletion.
Patients with long QT syndrome or baseline QTc (Fridericia) >470 msec in males and >480 msec in females (ULN for each respectively).
Patients with long QT syndrome or baseline QTc (Fridericia) >470 msec in males and >480 msec in females (ULN for each respectively).
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1 or greater than baseline) with the exception of alopecia, grade 2 fatigue, vitiligo or endocrinopathies on stable replacement therapy).
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1 or greater than baseline) with the exception of alopecia, grade 2 fatigue, vitiligo or endocrinopathies on stable replacement therapy).
Patients who are receiving any other investigational therapies that could affect the primary or secondary outcomes of this study.
Patients who are receiving any other investigational therapies that could affect the primary or secondary outcomes of this study.
Untreated brain metastases are not allowed.
Untreated brain metastases are not allowed.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to nilotinib, dabrafenib, encorafenib, binimetinib and trametinib.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to nilotinib, dabrafenib, encorafenib, binimetinib and trametinib.
Patients receiving any medications or substances that are strong CYP3A inhibitors are ineligible for this trial. Patients receiving any medications or substances that are strong CYP3A inducers are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
Patients receiving any medications or substances that are strong CYP3A inhibitors are ineligible for this trial. Patients receiving any medications or substances that are strong CYP3A inducers are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
Patients receiving any medications or substances that are strong CYP2C8 inhibitors are ineligible for the dabrafenib+ trametinib. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
Patients receiving any medications or substances that are strong CYP2C8 inhibitors are ineligible for the dabrafenib+ trametinib. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
Use of proton pump inhibitors concurrent with nilotinib is prohibited. Use of short-acting antacids or H2 blockers as an alternative to proton pump inhibitors is allowable.
Use of proton pump inhibitors concurrent with nilotinib is prohibited. Use of short-acting antacids or H2 blockers as an alternative to proton pump inhibitors is allowable.
Use of drugs or substances known to prolong QT interval is prohibited with Nilotinib
Use of drugs or substances known to prolong QT interval is prohibited with Nilotinib
Patients with uncontrolled intercurrent illness.
Patients with uncontrolled intercurrent illness.
Patients with psychiatric illness/social situations that would limit compliance with study requirements.
Patients with psychiatric illness/social situations that would limit compliance with study requirements.
Pregnant or lactating women
Pregnant or lactating women
Inclusion of Women and Minorities
Inclusion of Women and Minorities
-There are no exclusions for trial participation based on gender nor race.
-There are no exclusions for trial participation based on gender nor race.
