Dabrafenib in Treating Patients With Solid Tumors and Kidney or Liver Dysfunction

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.

Inclusion Criteria:

- PRE-REGISTRATION ELIGIBILITY CRITERIA

- Willing to provide tissue as required per protocol for central BRAF^V600X mutation
testing

- NOTE: patients with prior BRAF^600X testing that demonstrate a mutation at V600X
will be allowed to enroll prior to central testing if the assay was performed at
a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory assay;
this includes THxID, BRAF Detection Kit, Cobas 4800 BRAF600 mutation test and
other CLIA-certified assays available at participating institutions

- 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

- 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^600X 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^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

- 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 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

- NOTE: this applies to patient in the normal and renal dysfunction cohorts (N, R3
and R4); abnormal albumin is allowed for patients in the liver dysfunction
cohorts

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
institutional upper limit of normal (ULN)

- NOTE: this applies to patient in the normal and renal dysfunction cohorts (N, R3
and R4); patients with elevated AST and/or ALT may be assigned to liver
dysfunction cohorts

- 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

- NOTE: this applies to patient in the normal and renal dysfunction cohorts (N, R3
and R4); elevated PT/INR is allowed for patients in the liver dysfunction cohorts

- Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by
echocardiogram (ECHO)

- Hepatic and renal function meeting the strata below:

- Group N: Hepatic: normal function (bilirubin =< ULN; AST =< ULN); renal: normal
function (creatinine clearance [CrCl] >= 60 mL/min as estimated by the Cockcroft
and Gault equation)

- Group R3: Hepatic: normal function (bilirubin =< ULN; AST =< ULN); renal: severe
dysfunction (CrCl >= 15 and < 30 mL/min as estimated by the Cockcroft and Gault
equation)

- 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 as estimated by the Cockcroft and Gault
equation)

- Group H2: Hepatic: moderate dysfunction (bilirubin > ULN and =< 3 x ULN; AST >
ULN); renal: acceptable function (CrCl>=≥ 60 mL/min as estimated by the Cockcroft
and Gault equation)

- Group H3: Hepatic: severe dysfunction (bilirubin > 3 x ULN and up to
investigators discretion; AST > ULN); renal: acceptable function (CrCl >= 60
mL/min as estimated by the Cockcroft and Gault equation)

- 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

- 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

- History or evidence of cardiovascular risks including any of the following:

- QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec

- History of acute coronary syndromes (including myocardial infarction or unstable
angina), coronary angioplasty, or stenting within the past 24 weeks prior to
randomization

- History or evidence of current class II, III, or IV heart failure as defined by
the New York Heart Association (NYHA) functional classification system

- Intra-cardiac defibrillators

- Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with
grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on
study); subjects with moderate valvular thickening should not be entered on study

- History or evidence of current clinically significant uncontrolled cardiac
arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30
days prior to dosing are eligible

- Treatment refractory hypertension defined as a blood pressure of systolic > 140
mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti- hypertensive
therapy

- 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