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A Phase 1 Dose-Escalation Study of MEK Inhibitor MEK162 (ARRY-438162) in Patients with Advanced Solid Tumors
J. Bendell1, K. Papadopoulos2, S. Jones1, E. Barrett3, J. Christy-Bittel3, K. Guthrie3, C. Kass3, K. Litwiler3, C. Napier3, A. Patnaik2
Available at www.arraybiopharma.com
1Sarah
Cannon Research Institute (SCRI), Nashville, TN; 2START-South Texas Accelerated Research Therapeutics, San Antonio, TX; 3Array BioPharma Inc., Boulder, CO
MEK162 (ARRY-438162): A Potent MEK1/2 Inhibitor
 The RAS/RAF/MEK/ERK pathway plays a major role in cell growth and survival, and is often aberrantly
activated in many cancers.
 MEK162 is an orally bioavailable, potent, selective, ATP-uncompetitive inhibitor of MEK1/2.
 MEK162 has nanomolar activity against purified MEK enzyme (IC50 = 12 nM) and inhibits both basal and
induced levels of ERK phosphorylation in numerous cancer cell lines (IC50 values ≥ 5 nM).
 In vivo, MEK162 has demonstrated efficacy in several xenograft tumor models in mice, including those
harboring KRAS or BRAF mutations.
 In vivo, MEK162 enhances the activity of targeted therapies and standard cytotoxic agents in nonclinical
tumor models.
Methods
 The objectives of this completed Phase 1 open-label, dose-escalation study were to determine the
maximum tolerated dose (MTD) and characterize the safety profile, pharmacokinetics (PK),
pharmacodynamics (PD) and preliminary efficacy of MEK162 in patients with advanced solid tumors.
Schedule and Doses of MEK162*
In 21-day cycles:
30 mg BID
45 mg BID
60 mg BID
80 mg BID
*single QD dose on Cycle 1 Day 1 only
Safety
Safety
DLT and MTD
AEs, clinical laboratory
tests, physical exams,
ECGs, ECHO/MUGA scans,
ophthalmic exams
AEs, clinical laboratory
tests, physical exams,
ECGs, ECHO/MUGA scans,
ophthalmic exams
Efficacy
Plasma samples
(Day 1 and Day 15)
Tumor response
via RECIST v1.1
(every 6 weeks)
Biomarkers
Tumor samples (archival),
venous blood samples
(Screening and predose
on Days 1, 8, 15), skin
punch biopsy (Screening
and Day 15)
Subsequent Cycles
Cycle 1
Dose-escalation Phase (3 + 3 design)
Patient Demographics
N = 19
Median age (range), years
ECOG (0/1), n
 Dose limiting toxicities (DLTs) occurred in 2 of 3 evaluable patients in the 80 mg BID dose
cohort, thus 60 mg BID was declared the single-agent MTD.
 All DLTs resolved with interruption of dosing and upon rechallenge at a lower dose, patients
tolerated continued treatment with MEK162.
Patients
(n)
Evaluable
(n)
DLTs
(n)
30 mg BID
4
4
0
45 mg BID
4
3
0
60 mg BID
7
7
0
80 mg BID
15/4
57 (33-79)
16/3
Median lines of previous chemotherapy for advanced
disease (range), n
2 (0-8)
Race (Asian/Black/Caucasian), n
1/1/17
Tumor type, n
Colorectal
Pancreatic
Cholangiocarcinoma
Other
7
3
2
7
Mutation status *, n
Wild type on all loci tested
NRAS
KRAS
BRAF
PI3Kca
Dual KRAS/PI3Kca
Insufficient or no sample
2
2
5
1
1
1
6
* Archival tumor samples analyzed using Sequenom OncoCarta Panel and/or BEAMing digital PCR.
Pharmacokinetics
Management of MEK162 Adverse Effects
4
3
DLTs
(type and grade)
Central serous-like retinopathy (n = 1; G3)
Dermatitis acneiform (n = 1; G3 despite
maximal treatment measures)
2
Most Common Treatment-related AEs (> 2 Patients)
 Diarrhea, nausea and vomiting:
 Treated with standard antiemetic and anti-diarrheal medications; prophylactic treatment was
not required.
 Rash events:
 Generally G1/2, not requiring dose modification and frequently treated with oral
antihistamines and anti-inflammatory agents, topical and oral antibiotics and corticosteriods.
G3 rash events required dose modifications.
 Creatine kinase (CK) elevations:
 Elevations in CK were asymptomatic, reversible, and did not require dose modifications.
Elevations typically showed a rise beginning in Week 1 of dosing with a plateau around
3 weeks and a rapid decline when drug was held or discontinued.
 Retinal events:
 Symptomatic, reversible central serous-like retinal eye disorders were managed without
specific treatment other than dose modifications.
 Symptoms included flashing lights/floaters, altered color perception and “darkened vision”.
 Retinal findings observed on fundoscopy and confirmed by OCT included macular
edema/detachment, edema with subretinal fluid and multiple subretinal white lesions.
Reasons for Study Termination
MEK162 Dose
Pharmacokinetics
Gender (male/female), n
DLTs and MTD
30 mg BID 45 mg BID 60 mg BID 80 mg BID
Total
n=4
n=4
n=7
n=4
N = 19, (%)
Gastrointestinal disorders
Diarrhea
Nausea
Vomiting
Stomatitis/Mucositis
Abdominal pain
Dyspepsia
1
3
1
1
0
1
3
3
3
0
1
1
4
1
1
4
1
0
1
1
2
1
1
1
9 (47)
8 (42)
7 (37)
6 (32)
3 (16)
3 (16)
Skin and subcutaneous tissue
disorders
Rash*
Pruritis
Dry skin
4
2
0
3
0
1
7
3
3
1
0
0
15 (79)
5 (26)
5 (26)
General disorders and
Administrative site conditions
Peripheral edema
Fatigue
Retinal Events**
0
2
0
2
1
0
4
1
1
1
1
2
7 (37)
5 (26)
3 (16)
Other
Increased creatine kinase
Anorexia
0
1
1
1
2
0
0
1
3 (16)
3 (16)
All Grades
* “Rash” combined term includes events of rash, papular rash, macular rash, maculopapular rash,
exfoliative rash, skin exfoliation, dermatitis acneiform and acne
** “Retinal Events” include retinopathy and chorioretinopathy
Grade 3/4 Treatment-related AEs
MEK162 dose
30 mg BID
n=4
45 mg BID
n=4
60 mg BID
n=7
80 mg BID
n=4
Total
N = 19
Rash*
0
0
1
1
2
Palmar-plantar syndrome
0
0
1
0
1
Chorioretinopathy
0
0
0
1
1
Increased creatine kinase
0
0
2
0
2
* “Rash” combined term included events of rash and dermatitis acneiform
MEK162 Dose
30 mg BID 45 mg BID 60 mg BID 80 mg BID
Total
n=4
n=4
n=7
n=4
N = 19, (%)
Disease Progression
4
3
7
3
17 (90)
Discretion of Investigator*
0
1
0
0
1 ( 5)
Adverse Event
0
0
0
1
1 ( 5)
* No benefit from treatment (patient had SD at time study drug was discontinued)
Antitumor Activity
 Preliminary signs of clinical activity were observed in the 17 efficacy-evaluable patients;
15 of 17 had a (RECIST) target lesion at Baseline.
 Overall best response of PR was achieved in 1 patient (10.2 months duration).
 Stable disease was observed in 9 patients (7 in the 60 mg BID dose group) with a median
duration of 3.9 months (min, 2.1; max, 13.8).
 The median number of drug administration cycles administered was 2 in both the 30 mg and
45 mg BID dose cohorts, 4 in the 60 mg BID dose cohort and 3 in the 80 mg BID cohort.
 Plasma PK of MEK162 were assessed on Day 1 and Day 15 of Cycle 1 for each patient.
PK parameter estimates for MEK162:
Cycle 1, Day 15
Parameter (Units)
30 mg
(n = 4)
45 mg
(n = 3)
60 mg
(n = 6)
Tmax (hr)
1.5 (1.5 - 3.83)
2 (1.07 - 2.87)
3 (0.533 - 7.12)
Cmax (ng/mL)
417 (39.9%)
273 (64.7%)
493 (31.8%)
AUCtau (ng*hr/mL)
1560 (70.6%)
1740 (35.6%)
2280 (16.6%)
CL/F (L/hr)
19.3 (70.6%)
25.8 (35.6%)
26.3 (16.6%)
Vz/F (L)
83.9 (67.7%)
152 (17.4%)
140 (35.5%)
Accumulation
1.48 (25.9%)
1.51 (0.485%)
1.14 (7.54%)
Values are geometric mean (%CV) for all parameters except Tmax which is median (min-max). Day 15 values for 80 mg BID
dose group were not calculable due to low n.
 Exposure of MEK162 increased in a dose-proportional manner.
 MEK162 was absorbed quickly, on average reaching maximum concentrations in plasma within
~2 hours of dosing.
 The between-patient reproducibility of exposure was similar on Day 1 (31% CV) to that on
Day 15 of dosing (40% CV).
 No indication of nonlinear PK; modest accumulation on repeat dosing (32% increase, 20% CV).
 Mean plasma concentrations of MEK162 were maintained above the in vitro IC50 for cell
proliferation continuously at all dose levels studied with twice-daily dosing.
 These PK results, the first reported for MEK162 in an oncology setting, are equivalent to those
observed in healthy subjects, suggesting minimal effect on PK due to disease state.
MEK162 Day 15
Dose Proportionality
MEK162 Day 15
Concentrations versus Time
60 mg
30 mg
45 mg
In vitro IC50
Time (hr)
MEK162 AUCinf (hr*ng/mL)
AACR-NCI-EORTC, Nov 12-16, 2011, San Francisco, CA
MEK162 Geometric Mean Plasma
Concentration (ng/mL)
Abstract # B243
MEK162 BID dose
Case Study: Partial Response, Cholangiocarcinoma
Pharmacodynamics
 Case history:
 57-year-old male (ECOG 0) with metastatic intrahepatic cholangiocarcinoma, diagnosed in
Jun 2005.
 Prior treatment included initial surgical resection then followed by partial hepatic resection
with radiofrequency ablation in Dec 2006, treated with 4 previous lines of chemotherapy for
metastatic disease (gemcitabine + cisplatin, capecitabine + radiation therapy, paclitaxel +
lapatinib+ pazopanib, capecitabine + LBH 589).
 Baseline tumor sites in pancreas (target) and liver (non-target).
 MEK162 was initiated at 80 mg BID. Main AEs included: G3 facial and body rash events that
required both dose interruptions and dose reductions within the first 3 months of study drug
treatment. Total duration of treatment was 16.6 months.
 RECIST v1.1: PR, duration 10.2 months.
 Molecular profile:
 NRAS (Q61R) mutation (archival sample).
 Overall long-term sustained reductions in both TNFα and IL6 relative to baseline.
 Circulating TNFα levels sensitive to dosing interruptions.
 Preliminary data:
 Circulating cytokines:
 TNFα showed a consistent, roughly dose-responsive decrease with treatment.
 Skin biopsy markers:
 Substantial, but not dose-responsive, decreases in Ki67 were seen, consistent with inhibition
of cell proliferation.
 A dose-responsive decrease in pERK was observed.
Summary
 MEK162 had an acceptable safety profile at doses up to the MTD of 60 mg BID and showed
preliminary signs of clinical activity.
 MEK162 displayed desirable PK properties with dose-dependent exposures and preliminary
evidence of MEK-related PD marker changes.
 An expansion phase of the study is ongoing in order to further explore toxicity and PK in patients
with biliary cancer and in patients with KRAS- or BRAF-mutant metastatic colorectal cancer.
We Thank the Patients and Their Families