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About
This phase I trial studies the side effects and best dose of dabrafenib in treating patients with solid tumors and kidney or liver dysfunction. Dabrafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Full description
PRIMARY OBJECTIVES:
I. To determine the toxicity profile and the maximum tolerated doses (MTDs) of dabrafenib in patients with v-raf murine sarcoma viral oncogene homolog B1 (BRAF)^V600X mutations and renal or hepatic dysfunction.
SECONDARY OBJECTIVES:
I. To assess for tumor response and various times to clinical event. II. To provide dosing recommendations for dabrafenib in patients with varying degrees of hepatic and renal dysfunction for possible inclusion in the label.
TERTIARY OBJECTIVES:
I. To assess the pharmacokinetic and pharmacogenetic profile of dabrafenib and active metabolites.
OUTLINE: This is a dose-escalation study.
Patients receive dabrafenib orally (PO) twice daily (BID) on days 1-28 (once daily [QD] on day 1 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days.
Enrollment
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Inclusion criteria
PRE-REGISTRATION ELIGIBILITY CRITERIA
Willing to provide tissue as required per protocol for central BRAF^V600X mutation testing
Patients with unknown BRAF^600X status: histologically confirmed melanoma, papillary thyroid, cholangiocarcinoma or testicular cancer that is metastatic or unresectable and for which the investigator feels a BRAF^600X targeted agent is a reasonable treatment
Ability to understand and willingness to sign written informed consent
Life expectancy of > 3 months
REGISTRATION ELIGIBILITY CRITERIA
Patients with known BRAF^V600X mutation: patients must have BRAF^V600X mutated, histologically confirmed cancer that is metastatic or unresectable and for which curative or standard therapies do not exist or are no longer effective
Any number of the following prior therapies is allowed:
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Karnofsky >= 70%)
Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
Absolute neutrophil count (ANC) >= 1.2 x 10^9/L
Hemoglobin >= 9 g/dL
Platelets >= 100 x 10^9/L
Albumin >= 2.5 g/dL
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional upper limit of normal (ULN)
Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization
Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO)
Hepatic and renal function meeting the strata below:
Women of childbearing potential must have a negative serum pregnancy test =< 7 days prior to registration
Women of child-bearing potential and men must agree to use adequate contraception (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 1 month after completion of dabrafenib administration
Ability to understand and the willingness to sign a written informed consent document
Willingness to provide blood and tissue samples as required per protocol
Patients with a history of clinical benefit from prior RAF inhibitor therapy, as judged by the investigator, will be allowed
Exclusion criteria
Patients with active biliary obstruction; NOTE: patients for which a shunt has been in place for at least 10 days prior to the first dose of dabrafenib are allowed
Reduced left ventricular ejection fraction (< 50%) or other evidence of cardiac dysfunction as determined by the investigator
Use of an investigational anti-cancer drug within 28 days preceding the first dose of dabrafenib
Patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450 family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible
Warfarin use is provisionally allowed
Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) grade 2 or higher from previous anti-cancer therapy, except alopecia
Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; Note: patients not on antiretroviral therapies are eligible for this study
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, diabetes mellitus, hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
Presence of malignancy other than the study indication under this trial within 5 years of study enrollment
History or evidence of cardiovascular risks including any of the following:
Brain metastases that are symptomatic or untreated or not stable for >= 3 months (must be documented by imaging) or requiring corticosteroids; subjects on a stable dose of corticosteroids > 1 month or who have been off corticosteroids for at least 2 weeks can be enrolled with approval of the Cancer Therapy Evaluation Program (CTEP) medical monitor; subjects must also be off enzyme-inducing anticonvulsants for > 4 weeks
History of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; or history of known cardiac arrhythmias unless it has been stably controlled
History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib or other agents used in this study
Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with dabrafenib
Any condition or medical problem in addition to the underlying malignancy and organ dysfunction which the investigator feels would pose unacceptable risk
Primary purpose
Allocation
Interventional model
Masking
8 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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