Download Supplementary Materials and Methods, References, Tables 1-3

Supplementary Material
Supplementary Methods
Study Design and Patients
In Part 1, an accelerated dose-titration design was used, starting at dabrafenib 12 mg
daily, and dosed continuously (21-day assessment cycle), followed by standard 3 + 3
dose escalation. Additional patients were enrolled at the recommended phase 2 dose
(RP2D) in Part 2 in 3 distinct expansion cohorts: (1) metastatic melanoma, (2)
asymptomatic untreated melanoma brain metastases, and (3) non-melanoma solid
tumors. To better define the dose-efficacy response relationship, an additional cohort of
up to 30 patients with BRAF V600E mutation-positive melanoma was included at a dose
lower than the RP2D. Treatment continued until disease progression, intolerable
toxicity, or withdrawal of consent.
Dose-escalation design
Initially, an accelerated titration design was used (1). Evaluation of at least 1 patient
who had completed 1 cycle of treatment was required prior to determining the dose for
the next cohort. At the initial occurrence of grade 2 toxicity in a patient during the first
cycle, or the first occurrence of a dose-limiting toxicity (DLT) during the first cycle,
accelerated titration was transitioned to a standard 3 + 3 dose escalation. Following
administration of a single dabrafenib dose in Cohort 1, exposure was confirmed prior to
starting repeat dosing. The starting dose was selected to provide exposure predicted to
result in minimum clinical activity based on inhibition of the target (concentration
resulting in 50% maximum inhibition [IC50] for phosphorylated extracellular signal–
regulated kinase [pERK] inhibition from xenograft mice), while keeping safe margins
relative to findings from preclinical safety assessment studies. Intra-patient dose
escalations were allowed provided that the patient had completed at least three 21-day
treatment cycles along with the first post-baseline disease assessment and up to the
highest dose level not exceeding the maximum tolerated dose.
Dose level
Toxicity in study
Accelerated dose-titration phase
Lower doses may be used if
dose level 1 exposure is
significantly higher than predicted
or if there is excessive toxicity
Starting dose: 12 mg daily (4 mg
3 times daily)
Dose level −1
Dose level 1
Subsequent dose levels
End of accelerated dosetitration phase
Increase in dose
No patients with either a grade 2
toxicity or worse or a DLT in Cycle 1
≤ 100% increase in dosea
≥ 1 patient(s) with a grade 2 toxicity
or worse or a DLT in Cycle 1
Begin 3 + 3 dose-escalation
phase (note that once 3 + 3
phase is initiated, the procedure
may revert to the accelerated
dose-titration phase)
1
3 + 3 dose-escalation phase
≥ 2 patients with a grade 2 toxicity or
Subsequent dose levels
≤ 50% increase in doseb
worse in Cycle 1
Subsequent dose levels
≥ 1 DLT
≤ 50% increase in doseb
aEarly dose escalation may use increments up to 100% if the predicted exposure (area under the curve)
is ≤ one-sixth of the ‘no observed adverse effect level’ in dogs (2.0 g•h/mL) and no grade 2 or greater
toxicity is observed.
bDose will also be limited by the predicted area under the curve, which must not exceed the toxicokinetic
limit.
Abbreviation: DLT, dose-limiting toxicity.
Definition of dose-limiting toxicity
An event was considered to be a DLT if it occurred within the first cycle of treatment
with dabrafenib and met at least 1 of the following criteria.
 Grade 4 hematologic toxicity
 Grade 3 or 4 non-hematologic toxicity (excluding alopecia). Grade 3 nausea,
vomiting, and diarrhea were considered dose limiting if uncontrolled with
standard supportive measures
 Treatment delay of > 14 consecutive days due to unresolved toxicity
 A ≥ grade 2 non-hematologic toxicity that, in the judgment of the investigator and
GSK Medical Monitor, was dose limiting
 Troponin level greater than the upper limit of normal (ULN) and > 10% coefficient
of variance (CV) level with other clinical signs, symptoms, laboratory results, or
tests consistent with cardiac toxicity
 Troponin value > ULN and > 10% CV level and increased by > 50% from
baseline for > 3 days
 Ejection fraction less than the lower limit of normal (LLN), with a relative
decrease of > 20% from baseline and a confirming assessment within 7 days
 Significant alteration in cardiac valve morphology from baseline, including any
new grade 2 or higher valvular heart disease, as defined by Common
Terminology Criteria for Adverse Events (CTCAE) v3.0 (asymptomatic moderate
regurgitation or stenosis by imaging or worse)
 Patients with clinical laboratory values that met DLT criteria were required to
have those laboratory tests repeated and verified. Patients with abnormal
troponin values were required to have appropriate work-up as clinically indicated.
Troponin elevation caused by disease progression or an acute event, such as
sepsis or pulmonary embolism, was not considered to be a DLT. Troponin DLT
determination required central laboratory confirmation of the local laboratory
troponin changes.
Eligibility criteria
Presence of a BRAF mutation was initially optional but later mandatory due to absence
of activity in BRAF wild-type tumors.
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Inclusion criteria
A patient was eligible for inclusion in this study only if all of the following criteria applied.
 Written informed consent provided
 Aged 18 years or older
 Histologically or cytologically confirmed diagnosis of a solid tumor that is not
responsive to standard therapies or for which there is no approved or curative
therapy. Presence of a BRAF mutation was initially optional in the doseescalation cohorts but later required in both the dose-escalation and -expansion
cohorts due to absence of activity in BRAF wild-type tumors
 Performance status score of 0 or 1 according to the Eastern Cooperative
Oncology Group scale. Patients with performance status of 2 may be enrolled
with approval of the GSK Medical Monitor
 Ability to swallow and retain oral medication
 Male patients must agree to use acceptable contraception methods. This
criterion must be followed from the time of the first dose of study medication until
16 weeks after the last dose of study medication
 A female patient was eligible to participate if she was of:
– Non-childbearing potential, defined as premenopausal females with a
documented tubal ligation or hysterectomy; or postmenopausal, defined
as 12 months of spontaneous amenorrhea (in questionable cases a blood
sample with simultaneous follicle-stimulating hormone > 40 MlU/mL and
estradiol < 40 pg/mL [< 140 pmol/L] is confirmatory). Females on hormone
replacement therapy (HRT) and whose menopausal status is in doubt will
be required to use acceptable contraception methods if they wish to
continue their HRT during the study. Otherwise, they must discontinue
HRT to allow confirmation of postmenopausal status prior to study
enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse
between the cessation of therapy and the blood draw; this interval
depends on the type and dosage of HRT. Following confirmation of their
postmenopausal status, patients can resume use of HRT during the study
without use of a contraceptive method
– Childbearing potential and agrees to use acceptable contraception
methods for an appropriate period of time (as determined by the product
label or investigator) prior to the start of dosing to sufficiently minimize the
risk of pregnancy at that point. Female patients must agree to use
contraception until 4 weeks after the last dose of study medication
 Adequate organ system function, defined as:
– Absolute neutrophil count ≥ 1.2 × 109/L
– Hemoglobin ≥ 9 g/dL (patients with chronic hemolysis or similar conditions
requiring continuous red blood cell replacement will not be considered to
have met this criteria)
– Platelets ≥ 75 × 109/L
– Prothrombin time/international normalized ratio (PT/INR) and partial
thromboplastin time (PTT) ≤ 1.3 × ULN
– Total bilirubin ≤ 1.5 × ULN
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
– Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤
2.5 × ULN (if liver metastases are present, ALT and AST levels of ≤ 5 ×
ULN are allowed). Approval of the GSK Medical Monitor is required
– Creatinine ≤ ULN, or calculated creatinine clearance ≥ 50 mL/min (as
calculated by the Cockcroft–Gault formula), or 24-hour urine creatinine
clearance ≥ 50 mL/min
– Troponin ≤ ULN or ≤ 10% CV level
– Cardiac ejection fraction ≥ LLN
Additional inclusion criteria for the RP2D expansion cohorts:
– Presence of radiologically and/or clinically documented disease with ≥ 1
measurable lesion as defined by Response Evaluation Criteria In Solid
Tumors (RECIST) v1.0 (i.e., ≥ 2 cm in diameter by conventional technique
or ≥ 1 cm in diameter by computed tomography). NOTE: Patients will be
ineligible if the only measurable site of disease is located in a previously
irradiated site. A cutaneous or subcutaneous lesion identified as a target
lesion will be acceptable if ≥ 1 cm in diameter in 1 dimension.
Exclusion criteria
A patient was not eligible for inclusion in this study if any of the following criteria applied.
 Currently receiving cancer therapy (chemotherapy, radiation therapy,
immunotherapy, biological therapy, hormonal therapy, surgery, and/or tumor
embolization). Use of an investigational anticancer drug within 28 days preceding
the first dose of dabrafenib
 Current use of a prohibited medication or requirement of any of these
medications during treatment with dabrafenib. Current use of therapeutic
warfarin. Low-molecular-weight heparin and prophylactic low-dose warfarin are
permitted. PT/PTT must meet the inclusion criteria. Patients taking warfarin must
have their INR followed closely
 Any major surgery, radiotherapy, or immunotherapy within the last 4 weeks.
Limited radiotherapy within the last 2 weeks
 Use of chemotherapy regimens with delayed toxicity within the last 4 weeks (6
weeks for prior nitrosourea or mitomycin C). Use of chemotherapy regimens
given continuously or on a weekly basis with limited potential for delayed toxicity
within the last 2 weeks
 Unresolved toxicity higher than grade 1 from previous anticancer therapy, except
alopecia, unless agreed to by the GSK Medical Monitor and the investigator
 Presence of active gastrointestinal disease or other condition that will interfere
significantly with the absorption, distribution, metabolism, or excretion of drugs
 A history of known HIV infection
 Primary malignancy of the central nervous system
 Symptomatic or untreated leptomeningeal or brain metastases, or spinal cord
compression. Patients previously treated for these conditions who are
asymptomatic and off corticosteroids for ≥ 1 month are permitted. Brain
metastases must be stable for ≥ 2 months, with verification by imaging (brain
magnetic resonance imaging [MRI] completed at screening). A computed
tomography scan with and without contrast may be performed if an MRI is
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contraindicated. Patients are not permitted to receive enzyme-inducing antiepileptic drugs. In the RP2D expansions, patients with asymptomatic, untreated
brain metastases who have not been stable for 2 months may be enrolled with
approval of the GSK Medical Monitor. These patients can be on a stable dose of
corticosteroids
History of alcohol or drug abuse within 6 months prior to the screening visit
Psychological, familial, sociologic, or geographic conditions that do not permit
compliance with the protocol
Concurrent condition that, in the investigator’s opinion, would jeopardize
compliance with the protocol
QTc interval ≥ 480 ms
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
functional classification system
Abnormal cardiac valve morphology (patients with minimal abnormalities can be
entered on study with approval from the GSK Medical Monitor)
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the study drug, or excipients (to date, there are no known
US Food and Drug Administration-approved drugs chemically related to
dabrafenib)
Pregnant or lactating female
Unwillingness or inability to follow the procedures outlined in the protocol
Known glucose-6-phosphate dehydrogenase deficiency
Positive test result for human papillomavirus (HPV). Entry on study allowed only
at the discretion of the patient and investigator after informed consent regarding
discussion of the risk of HPV infection. If enrolled, these patients must use
condoms for sexual activity, regardless of the use of other contraceptive
measures and childbearing status
Prior treatment with a BRAF or MEK inhibitor unless approved by the GSK
Medical Monitor.
Safety assessments
Toxicity was assessed according to CTCAE v3.0 (2) at specified intervals. Safety
evaluations were performed weekly during Cycle 1 and every 3 weeks in subsequent
cycles, and included interim medical history, physical examination, height, weight, vital
signs, complete blood count, clinical chemistry, urinalysis, CD4/CD8, troponin,
electrocardiogram (ECG), and echocardiogram. Vital sign measurements included
temperature, respiratory rate, systolic and diastolic blood pressure, and pulse rate.
Dermatologic examination was performed at baseline and as clinically indicated.
Female HPV screening and physical examination of the integument and genitalia were
performed at baseline and at the end of study. For patients who had a positive signal for
HPV at baseline (history, physical exam, or HPV screening), the decision to enroll was
at the discretion of the patient and investigator. Patients with a positive signal for HPV
who enrolled on the study underwent a genitourinary examination with every cycle.
5
These patients were informed of the risk of HPV infection and were instructed to use
condoms for sexual activity, regardless of the use of other contraceptive measures and
childbearing status.
Definition of adverse events
An adverse event (AE) is any untoward medical occurrence in a patient or clinical
investigation participant that is temporally associated with the use of a medicinal
product, whether or not it is considered related to the medicinal product. An AE can
therefore be any unfavorable and unintended sign (including an abnormal laboratory
finding), symptom, or disease (new or exacerbated) temporally associated with the use
of a medicinal product.
Events meeting the definition of an AE include:
 Any abnormal laboratory test results (hematology, clinical chemistry, or
urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital
signs measurements), including those that worsen from baseline, and thought to
be clinically significant in the medical and scientific judgment of the investigator
 Exacerbation of a chronic or intermittent pre-existing condition, including either
an increase in frequency and/or intensity of the condition
 A new condition detected or diagnosed after administration of the investigational
product, even though it may have been present prior to the start of the study
 Signs, symptoms, or the clinical sequelae of a suspected interaction
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either the
investigational product or a concomitant medication (the overdose per se will not
be reported as an AE/serious AE [SAE]).
Events that do not meet the definition of an AE include:
 Any clinically significant abnormal laboratory findings or other abnormal safety
assessments that are associated with the underlying disease, unless judged by
the investigator to be more severe than expected for the patient’s condition
 The disease/disorder being studied, or expected progression, signs, or
symptoms of the disease/disorder being studied, unless more severe than
expected for the patient’s condition
 Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition
that leads to the procedure is an AE
 Situations where an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital)
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s)
present or detected at the start of the study that do not worsen
Definition of serious adverse events
If an event is not an AE per the protocol definition, then it cannot be an SAE even if
serious conditions are met (e.g., hospitalization for signs/symptoms of the disease
under study, death due to progression of disease, etc).
An SAE is any untoward medical occurrence that, at any dose:
6
a. Results in death
b. Is life threatening
NOTE: The term “life threatening” in the definition of “serious” refers to an event in
which the patient was at risk of death at the time of the event. It does not refer to an
event, that hypothetically might have caused death, if it were more severe.
c. Requires hospitalization or prolongation of existing hospitalization
NOTE: In general, hospitalization signifies that the patient has been detained (usually
involving at least an overnight stay) at the hospital or emergency ward for observation
and/or treatment that would not have been appropriate in the physician's office or an
outpatient setting. Complications that occur during hospitalization are AEs. If a
complication prolongs hospitalization or fulfills any other serious criteria, the event is
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the
AE should be considered serious. Hospitalization for elective treatment of a pre-existing
condition that did not worsen from baseline is not considered an AE.
d. Results in disability/incapacity
NOTE: The term “disability” means a substantial disruption of a person’s ability to
conduct normal life functions. This definition is not intended to include experiences of
relatively minor medical significance, such as uncomplicated headache, nausea,
vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle), that may
interfere or prevent everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect
f. Medical or scientific judgment should be exercised in deciding whether reporting
is appropriate in other situations, such as important medical events that may not
be immediately life-threatening or result in death or hospitalization but may
jeopardize the patient or may require medical or surgical intervention to prevent
one of the other outcomes listed in the aforementioned definition. These should
also be considered serious. Examples of such events are invasive or malignant
cancers, intensive treatment in an emergency room or at home for allergic
bronchospasm, blood dyscrasias or convulsions that do not result in
hospitalization, or development of drug dependency or drug abuse. ALT > 3 ×
ULN and total bilirubin > 2 × ULN (> 35% direct bilirubin; bilirubin fractionation
required) or INR > 1.5 without evidence of biliary obstruction or progressive
disease would be considered an untoward medical occurrence, and therefore an
SAE. Other hepatic events should be documented as an AE or SAE as
appropriate.
Disease-related events or outcomes not qualifying as SAEs
An event that is part of the natural course of the disease under study (i.e., disease
progression) should not be reported as an SAE. Progression of the patient’s neoplasia
will be recorded in the clinical assessments in the electronic case report form (eCRF).
Death due to disease progression is to be recorded on the Record of Death eCRF page
and not as an SAE. However, if the progression of the underlying disease is greater
than that which would normally be expected for the patient or if the investigator
considers that there was a causal relationship between treatment with dabrafenib or
protocol design/procedures and the disease progression, then it must be reported as an
SAE. Any new primary cancer must be reported as an SAE.
7
BRAF testing
Tumor tissue genotyping for BRAF was performed with accredited assays using allelespecific polymerase chain reaction (PCR). The main methods of tumor tissue
genotyping for BRAF varied slightly at each site and at Response Genetics (RGI), as
follows.
 The University of Texas MD Anderson Cancer Center: the analysis was limited to
codons 468–474 of exon 11 and codons 595–600 of exon 15 of the BRAF gene
 Westmead Hospital: each sample was amplified and sequenced for the whole of
exon 15 or subjected to high-resolution melt analysis and, if abnormal,
sequenced between codons 597 and 607
 RGI: an allele-specific PCR was used to detect the specific mutations Val600Glu:
1799T>A and Val600Lys: 1798_99GT>AA in exon 15 of the BRAF gene
Pharmacokinetics testing
In the dose-escalation cohorts in Part 1, blood samples (2 mL) for determination of
plasma concentrations of dabrafenib and its metabolites, including hydroxy-, carboxy-,
and desmethyl-dabrafenib, were collected after a single dose on day 1, after repeat
dosing on day 8 and/or 15 predose, and at 0.5, 1, 2, 3, 4, 6, 8, and 10 to 12 hours postdose during Cycle 1. A 24-hour sample was obtained after the single dose on day 1,
and repeat dosing started thereafter on day 2. A single trough PK sample was collected
predose on either day 8 or 15, whichever day did not include the serial PK sampling. In
the pharmacokinetics (PK)/pharmacodynamics (PD) expansion cohort of Part 1, a
reduced PK schedule, with PK assessment only after repeat dosing (day 8 or 15), was
used.
In the RP2D dose-expansion cohorts in Part 2, blood samples for analysis of plasma
dabrafenib concentration and its metabolites were collected using a sparse sampling
strategy, with samples collected > 1 hour after administration of the first dose on day 1,
predose on days 8 and 15 of Cycle 1, and at the start of Cycles 2, 3, and 4.[Ouellet et
al, 2014]
Tumor response assessments
The first tumor restaging in Part 1 of the study was obtained at week 9. Tumor size was
measured as the longest plane diameter in a number of target lesions, based on
RECIST 1.0 criteria. Following the assessment, patients were allowed to dose escalate
if tolerance in higher dosing cohorts had been established. Cohorts 1 to 5, with doses
up to 100 mg twice daily (BID), were dose-escalated after week 9. Dose response
assessment was based on investigator-reported week 9 tumor size measurement.
Statistical analysis
8
The effect of dabrafenib on tumor pERK inhibition, fluorodeoxyglucose positron
emission tomography (FDG-PET) and tumor size was evaluated with a PK/PD model
using a nonlinear mixed-effects analysis. Different exposure-response models were
evaluated, including an inhibitory Emax model as described below:
RESP  BSL  (1 
Emax  CONC
IC50  CONC
)
where RESP is the response variable (H score, maximum standardized uptake value, or
lesion diameter), BSL is the baseline value, Emax is the maximum possible inhibition
(may be fixed to 1), IC50 is the inhibitory concentration resulting in 50% of Emax, and
CONC represents the concentration exposure. Exposure was tested as either predose
dabrafenib concentration or effective concentration (EFF), which was calculated as
follows based on the relative potency of dabrafenib and its metabolites:
EFF = [dabrafenib] + 2* [hydroxy-dabrafenib] + [desmethyl-dabrafenib]/8
9
Supplementary Results
Data for AEs were based on a data cutoff of March 2011. The most common ≥ grade 2
treatment-related AEs observed at all doses included cutaneous squamous cell
carcinoma or keratoacanthoma, fatigue, and pyrexia (Table S1). Dose reductions were
necessary in 13 (7%) patients because of a total of 21 AEs, of which the most common
were pyrexia (5 patients [3%]), fatigue (3 patients [2%]), and neutropenia (2 patients
[1%]). No deaths or discontinuations of treatment resulted from AEs, and 140 patients
(76%) experienced no drug-related AEs higher than grade 2.
A lower-dose cohort (50 mg BID) was included in Part 2 of this study to better define the
dose-efficacy relationship. Among the first 15 patients with BRAF V600E mutations
treated at 50 mg BID, only 3 (20%) had a confirmed partial response (PR) at the time of
the interim analysis, which was less than the number of confirmed responses (n = 4)
required to continue enrollment on this cohort.
10
Table S1. Treatment-related adverse events of ≥ grade 2 reported in at least 5% of
patients by dose (3)
Dabrafenib Dabrafenib Dabrafenib
≤ 75 mg
100 mg
100 mg
BID
BID
TID
(n = 54)
(n = 10)
(n = 20)
Cutaneous squamous cell carcinoma, n (%)
Grade 2
0
0
0
Grade 3
4 (7)
0
5 (25)
Total
4 (7)
0
5 (25)
Fatigue, n (%)
Grade 2
4 (7)
1 (10)
0
Grade 3
0
1 (10)
0
Total
4 (7)
2 (20)
0
Pyrexia, n (%)
Grade 2
2 (4)
2 (20)
1 (5)
Grade 3
0
0
0
Total
2 (4)
2 (20)
1 (5)
Dabrafenib
150 mg
BID
(n = 70)
Dabrafenib
200 mg
BID
(n = 20)
Dabrafenib
300 mg
BID
(n = 10)
Total
(N = 184)
0
5 (7)
5 (7)
0
4 (20)
4 (20)
0
2 (20)
2 (20)
0
20 (11)
20 (11)a
3 (4)
0
3 (4)
3 (15)
0
3 (15)
1 (10)
1 (10)
2 (20)
12 (7)
2 (1)
14 (8)
3 (4)
1 (1)
4 (6)
1 (5)
0
1 (5)
1 (10)
0
1 (10)
10 (5)
1 (< 1)
11 (6)
a
Keratoacanthoma was observed in 3 patients, of whom 2 also developed cutaneous
squamous cell carcinoma; 21 patients (11%) had squamous cell carcinoma or
keratoacanthoma.
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Table S2. Summary of plasma dabrafenib pharmacokinetic parameters after singledose administration of dabrafenib gelatin capsules under fasted conditions (dose
escalation: Part 1)
Cmax,a
tmax,b
AUC0-,a
ng/mL
h
h•ng/mL
37.5
4.00
NA
349 (7.13)
2.00
1681 (1.94)c
2
35 mg QD
3
[293–417]
(1.00–3.02)
[NA]
254 (51.8)
2.00
1247 (27.7)
3
35 mg BID
4
[117–551]
(1.03–3.00)
[809–1922]
611 (28.9)
1.00
2736 (23.2)
4
70 mg BID
4
[389–958]
(1.00–3.00)
[1900–3940]
484 (106)
1.55
4668 (43.5)d
5
100 mg BID
6
[195–1200]
(0.50–8.00)
[1659–13,138]
900 (38.2)
2.04
4462 (39.2)
6
100 mg TID
6
[611–1326]
(1.92–6.00)
[3002–6633]
986 (73.2)
2.00
4943 (36.7)e
7
150 mg BID
11
[635–1531]
(1.00–10.0)
[3558–6866]
1508 (71.6)
2.00
8164 (51.7)f
8
200 mg BID
7
[832–2734]
(1.00–2.05)
[4462–14,934]
1456 (121)
2.00
9980 (47.0)f
9
300 mg BID
10
[737–2877]
(1.00–8.02)
[6869–14,499]
665 (56.7)
2.50
3821 (55.2)c
10
75 mg BID
6
[382–1158]
(1.00–4.00)
[2015–7246]
a Data reported as geometric mean (CV%) and [95% CI]; 95% CIs were reported only for n > 2.
b Tmax reported as median (range).
c PK parameter could not be calculated in 1 patient.
d PK parameter could not be calculated in 3 patients.
e PK parameter could not be calculated in 4 patients.
f PK parameter could not be calculated in 2 patients.
Cohort
1
Dose regimen
12 mg QD
n
1
t1/2,a
h
NA
6.55 (8.00)c
[NA]
5.23 (30.2)
[3.27–8.37]
6.16 (32.7)
[3.71–10.2]
3.99 (23.1)d
[2.27–7.03]
6.13 (26.3)
[4.68–8.04]
4.99 (28.1)e
[3.86–6.43]
6.46 (33.2)f
[4.33–9.65]
5.07 (33.1)f
[3.88–6.64]
6.76 (31.8)c
[4.60–9.93]
Abbreviations: AUC0–∞, area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time; BID,
twice daily; Cmax, maximum observed concentration;NA, not applicable; PK, pharmacokinetics; QD, once daily; t1/2, terminal
phase half-life; tmax, time of occurrence of Cmax;TID, 3 times daily.
12
Table S3. Summary of plasma dabrafenib pharmacokinetic parameters after repeated
dose administration of dabrafenib gelatin capsules under fasting conditions on day 8 or
day 15 (dose escalation: Part 1)
Cmax,a
tmax,b
ng/mL
h
34.7
4.00
339 (54.5)
3.00
2
35 mg QD
Day 8
3
[95.5–1206]
(1.00–3.00)
280 (55.4)
2.00
Day 8
7
[174–452]
(1.02–6.00)
3
35 mg BID
Day 15
1
182
2.07
528 (53.7)
1.82
Day 8
12
[384–727]
(0–3.03)
4
70 mg BID
Day 15
1
404
3.03
763 (44.8)
2.04
5
100 mg BID
Day 8
10
[562–1037]
(0.50–4.00)
854 (58.9)
2.00
Day 8
12
[604–1208]
(0.50–2.12)
6
100 mg TID
413 (2.57)
1.98
Day 15
2
[NA]
(1.95–2.00)
1353 (57.1)
2.00
Day 8
11
[947–1932]
(1.00–2.17)
7
150 mg BID
806 (95.1)
1.83
Day 15
7
[383–1693]
(1.00–3.00)
2109 (20.8)
2.46
Day 8
2
[NA]
(2.00–2.92)
8
200 mg BID
850 (54.2)
2.00
Day 15
15
[641–1126]
(0.93–4.00)
1126 (81.1)
1.53
9
300 mg BID
Day 15
6
[534–2374]
(1.03–3.00)
583 (39.9)
2.00
10
75 mg BID
Day 15
6
[389–873]
(1.00–3.00)
a Data reported as geometric mean (CV%) and [95% CI]; 95% CIs were reported only for n > 2.
b tmax reported as median (range).
c PK parameter could not be calculated in 1 patient.
Cohort
1
Dose regimen
12 mg QD
Visit
Day 8
n
1
AUC0-,a
h•ng/mL
429
1515 (18.3)
[966–2375]
1038 (45.7)c
[657–1640]
492
2045 (31.7)c
[1662–2517]
1669
2646 (37.8)
[2037–3437]
2568 (45.9)
[1944–3391]
1779 (59.8)
[NA]
4189 (47.2)
[3099–5661]
2619 (76.7)
[1396–4911]
5739 (9.43)
[NA]
2994 (51.1)
[2294–3909]
3744 (56.9)
[2148–6526]
2062 (29.7)
[1520–2798]
C,a
ng/mL
5.83
7.37 (115)
[0.750–72.4]
34.1 (179)
[11.3–103]
9.97
63.0 (103)
[36.7–108]
81.2
55.3 (118)
[28.3–108]
87.8 (75.5)
[57.3–135]
141 (65.1)
[NA]
80.2 (65.8)
[53.6–120]
96.1 (98.9)
[44.8–206]
66.1 (35.9)
[NA]
94.6 (118)
[56.4–159]
58.4 (84.8)
[26.9–126]
59.0 (162)
[18.0–194]
Abbreviations: AUC0-, area under the concentration-time curve over the dosing interval; BID, twice daily; Cmax, maximum
observed concentration; C, pre-dose concentrations; NA, not applicable; PK, pharmacokinetics; QD, once daily; TID, 3 times
daily; tmax, time of occurrence of Cmax.
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References
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2. Common terminology criteria for adverse events (CTCAE) v3.0 [homepage on the
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http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf.
3. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, et al.
Dabrafenib in patients with melanoma, untreated brain metastases, and other solid
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