A Phase 1 and Pharmacokinetic Study of Dabrafenib (GSK2118436B) in Patients With BRAFV600X Mutations and Renal or Hepatic Dysfunction
Trial status: Open for Enrollment
Why is this study being done?
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.
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.
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.
Who is eligible to participate?
- PRE-REGISTRATION ELIGIBILITY CRITERIA
- Willing to provide tissue as required per protocol for central BRAF-V600 mutation testing
- NOTE: Patients with prior BRAF testing that demonstrate a mutation at V600 will be allowed to enroll prior to central testing if the assay was performed at a Clinical Laboratory Improvement Amendments (CLIA)-certified lab using the COBAS, Pyromark BRAF, Karmonos Detroit Medical Center-University Laboratories (DMC)-UL BRAF, THxID BRAF or Response Genetics BRAF assays; if the assay was based on other methodology other than COBAS, Pyromark BRAF, Karmonos DMC-UL BRAF, THxID BRAF or Response Genetics BRAF assays, the results should be confirmed by central lab testing prior to patient enrollment; should central testing prove to be discordant with initial result (wild-type, non-mutated BRAF), patient will be allowed to continue on study at the discretion of the investigator
- Patients with unknown BRAF status: histologically confirmed melanoma, papillary thyroid, cholangiocarcinoma or testicular cancer that is metastatic or unresectable and for which the investigator feels a BRAF targeted agent is a reasonable treatment
- NOTE: patient must be screened by central BRAF testing and must demonstrate a V600 mutation prior to start of study agent
- Note: other tumor types without known BRAF mutations will not be eligible for central testing
- Ability to understand and willingness to sign written informed consent
- Life expectancy of > 3 months
- REGISTRATION ELIGIBILITY CRITERIA
- Patients with known BRAF-V600 mutation: patients must have BRAF-V600 mutated, histologically confirmed cancer that is metastatic or unresectable and for which curative or standard therapies do not exist or are no longer effective
- NOTE: Colorectal cancers with BRAF mutations ARE NOT allowed
- NOTE: Any mutation at the V600 position that results in a change from V (valine) is allowed; this includes E, D, K, R or other mutations not noted here at the V600 position
- Any number of the following prior therapies is allowed:
- Chemotherapy >= 28 days prior to registration
- Mitomycin C/nitrosoureas >= 42 days prior to registration
- Immunotherapy >= 28 days prior to registration
- Biologic therapy >= 28 days prior to registration
- Radiation therapy >= 28 days prior to registration
- Radiation to < 25% of bone marrow
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Karnofsky >= 70%)
- Able to swallow and retain oral medication
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
- Hemoglobin >= 9 g/dL
- Platelets >= 75 x 10^9/L
- Hepatic and renal function meeting one of the strata below:
- Group N: Hepatic: normal function (bilirubin =< upper limit of normal [ULN]; aspartate aminotransferase [AST] =< ULN); Renal: normal function (creatinine clearance [CrCl] >= 60 mL/min)
- Group R3: Hepatic: normal function (bilirubin =< ULN; AST =< ULN); Renal: severe dysfunction (CrCl >= 15 and < 30 mL/min)
- Group R4: Hepatic: normal function (bilirubin =< ULN; AST =< ULN; Renal: renal failure (hemodialysis)
- Group H1: Hepatic: mild dysfunction (bilirubin =< ULN; AST > ULN); Renal: acceptable function (CrCl >= 60 mL/min)
- Group H2: Hepatic: moderate dysfunction (bilirubin > ULN and =< 3 x ULN; AST > ULN); Renal: acceptable function (CrCl>=≥ 60 mL/min)
- Group H3: Hepatic: severe dysfunction (bilirubin > 3 x ULN and up to investigators discretion; AST > ULN); Renal: acceptable function (CrCl >= 60 mL/min)
- 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 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
- 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
- For patients on intermediate inducers or inhibitors, attempts should be made to switch to an alternative agent or delay enrollment until treatment course with concomitant agent completed; if not possible, patient may be enrolled if it is felt to be in the patients best interest as decided by the investigator
- Weak inhibitors of CYP3A or CYP2C8 should be used with caution and attempts made to limit their use or find alternative agents, if possible
- 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
- 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