a phase i study of the safety, pharmacokinetics, and...

Refametinib and sorafenib combination in advanced cancer

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A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics

of Combination Therapy with Refametinib plus Sorafenib in Patients with

Advanced Cancer

Alex A. Adjei1*, Donald A. Richards2,3, Anthony El-Khoueiry4, Fadi Braiteh2,5, Carlos H.R.

Becerra2,6, Joe J. Stephenson, Jr.2,7, Aram F. Hezel2,8, Morris Sherman9, Lawrence Garbo2,10,

Diane P. Leffingwell11, Cory Iverson11, Jeffrey N. Miner2,11, Zancong Shen11, Li-Tain Yeh11,

Sonny Gunawan11, David M. Wilson11, Kimberly J. Manhard11, Prabhu Rajagopalan12, Heiko

Krissel13, and Neil J. Clendeninn11

1Roswell Park Cancer Institute, Buffalo, NY, USA; 2The US Oncology Network, The

Woodlands, TX, USA; 3Texas Oncology-Tyler, Houston, TX, USA; 4University of Southern

California Norris Comprehensive Cancer Center, Los Angeles, CA, USA; 5Comprehensive

Cancer Centers of Nevada, Las Vegas, NV, USA; 6Baylor Sammons Cancer Center, Houston,

TX, USA; 7Institute of Translational Oncology Research, Houston, TX, USA; 8Wilmot Cancer

Institute, University of Rochester Medical Center, Rochester, NY, USA; 9University of

Toronto and University Health Network, Toronto, Canada; 10New York Oncology

Hematology, Albany, NY, USA; 11Ardea Biosciences, Inc., San Diego, CA, USA; 12Bayer

HealthCare Pharmaceuticals, Whippany, NJ, USA; 13Bayer Pharma AG, Berlin, Germany

Keywords: refametinib, sorafenib, advanced cancer, MEK inhibitor, multikinase inhibitor

Running title: Refametinib and sorafenib combination in advanced cancer

Grant Support

This work was funded by Bayer HealthCare Pharmaceuticals and Ardea Biosciences, and by

a Conquer Cancer Foundation Drug Development Research Professorship (A.A. Adjei).

Research. on May 24, 2018. © 2015 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on December 7, 2015; DOI: 10.1158/1078-0432.CCR-15-1681

http://clincancerres.aacrjournals.org/


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*Corresponding author:

Alex A. Adjei

Roswell Park Cancer Institute

Elm & Carlton Streets

Buffalo, NY 14263, USA

Tel: +1-716-845-4101; Fax: +1-716-845-3423; E-mail: [email protected]

Disclosure of Potential Conflicts of Interest

A.A. Adjei, D.A. Richards, C.H.R. Becerra, and L. Garbo have no potential conflicts of

interest to disclose.

A. El-Khoueiry has performed a consultancy/advisory role for, and has received honoraria

from, Bristol-Myers Squibb, GlaxoSmithKline, Roche/Genentech, Celgene, and Exelixis, and

has received research funding from Astex.

F. Braiteh has: received research funding and honoraria from, and participated in speaker

bureaux for, Amgen, Bayer, Bristol-Myers Squibb, Caris Life Sciences, Celgene, Genomic

Health, Incyte, Insys, Myriad, Novartis, Pfizer, and Sanofi; received research funding and

honoraria from AstraZeneca/MedImmune, BIND Therapeutics, Dendreon, Eli Lilly,

Foundation Medicine, Gilead, Heron Therapeutics, Molecular Health, Roche/Genentech, and

Saladax Biomedical; received research funding from AbbVie, Active Biotech, BioMarin,

bioTheranostics, BN Therapeutics, Boston Biomedical, Cell Therapeutics, Daiichi Sankyo,

Endocyte, Exelis, Genomic Health, GlaxoSmithKline, Halozyme Therapeutics, ImClone,

Janssen, MEI Pharma, Merrimack, Millennium, Pharmacyclics, Plexxikon, PSMA, Seattle

Genetics, and Viamet; and stock ownership interests in Celgene and Insys.





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J.J. Stephenson, Jr. has participated in speaker bureaux for Bristol-Myers Squibb, Merck, and

Caris Life Sciences.

A.F. Hezel has performed a consultancy/advisory role for Novartis, Bayer, and

VirtualScopics, and has participated in speaker bureaux for Novartis, Bayer, and Celgene.

M. Sherman has received honoraria from, and performed a consultancy/advisory role for,

Bayer, ArQule, Lilly, Boehringer Ingelheim, Merck, Gilead, and AbbVie.

D.P. Leffingwell is an employee of Ardea Biosciences, Inc., which is a member of the

AstraZeneca Group.

C. Iverson is an employee of, has stock or other ownership interests in, and has received

travel, accommodation, and other expenses from, Ardea Biosciences, Inc., which is a member

of the AstraZeneca Group.

J. Miner and D.M. Wilson are employees of, have stock or other ownership interest in, and

have received travel, accommodation, and other expenses from Ardea Biosciences, Inc.,

which is a member of the AstraZeneca Group.

Z. Shen, S. Gunawan, and K.J. Manhard are employees of, and have stock or other ownership

interests in, Ardea Biosciences, Inc., which is a member of the AstraZeneca Group.

L.T. Yeh is an employee of Ignyta, Inc.

P. Rajagopalan is an employee of, and has stock or other ownership interests in, Bayer

HealthCare Pharmaceuticals.

H. Krissel is an employee of, and has stock or other ownership interests in, Bayer Pharma

AG.





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N.J. Clendeninn is an employee of Ardea Biosciences, Inc., which is a member of the

AstraZeneca Group.

Authors’ Contributions

Conception and design: A.A. Adjei, J. Miner, K.J. Manhard, D.P. Leffingwell, J.J.

Stephenson, Jr.

Acquisition of data: L.T. Yeh, D.M. Wilson, M. Sherman, D.A. Richards, K.J. Manhard,

D.P. Leffingwell, C. Iverson, S. Gunawan, J.J. Stephenson, Jr., F. Braiteh, C.H.R. Becerra,

A.F. Hezel, L. Garbo, A. El-Khoueiry

Analysis and interpretation of data: Z. Shen, P. Rajagopalan, J. Miner, K.J. Manhard, D.P.

Leffingwell, H. Krissel, J.J. Stephenson, Jr., F. Braiteh

Writing, review, and/or revision of the manuscript: A.A. Adjei, L.T. Yeh, D.M. Wilson,

M. Sherman, Z. Shen, D.A. Richards, P. Rajagopalan, J. Miner, D.P. Leffingwell, H. Krissel,

C. Iverson, S. Gunawan, J.J. Stephenson, Jr., F. Braiteh, C.H.R. Becerra, A.F. Hezel, L.

Garbo, A. El-Khoueiry, N.J. Clendeninn, K.J. Manhard

Provision of study material or patients: A.A. Adjei, A. El-Khoueiry, M. Sherman, D.A.

Richards, C.H.R. Becerra, L. Garbo, J.J. Stephenson, Jr., F. Braiteh, A.F. Hezel





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Word count: 3806

Total number of figures and tables: 6

Clinical trial information: ClinicalTrials.gov identifier NCT00785226;

https://www.clinicaltrials.gov/ct2/show/NCT00785226?term=NCT00785226&rank=1

Previous study presentations: Preliminary data from this study have been previously

presented in poster format at the AACR-NCI-EORTC International Conference 2011:

Molecular Targets and Cancer Therapeutics:

• Adjei AA et al. Safety, pharmacokinetic, and pharmacodynamic results of BAY 86-

9766, an oral MEK inhibitor, in combination with sorafenib, an oral multikinase

inhibitor, in advanced cancer patients. Mol Cancer Ther 2011;10(11 Suppl): Abstract

A88





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Translational Relevance

This phase I dose-escalation study assessed the safety, pharmacokinetics, and efficacy of the

small-molecule MEK inhibitor refametinib combined with sorafenib, a multikinase inhibitor

with Raf inhibitory activity, in patients with advanced solid tumors. An expansion phase was

included at the maximum tolerated dose, for evaluation of pharmacodynamic parameters

associated with mitogen-activated protein kinase (MAPK) pathway activation, including

mutational analyses of KRAS, BRAF, and PI3KCA, circulating tumor cell enumeration, and

analysis of phosphorylated extracellular-related kinase (ERK). Pharmacodynamic parameters

were evaluated based on the mechanism of action and known activity of refametinib in

preclinical cancer models. Refametinib plus sorafenib was associated with a reduction in

ERK phosphorylation, tending to correlate with mutational status. This article also describes

indications of the clinical activity of refametinib plus sorafenib. These data warrant further

investigation into the activity of this combination in patients with advanced solid tumors,

including those without identified MAPK pathway mutations.





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Abstract

Purpose: To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor

refametinib combined with sorafenib, in patients with advanced solid malignancies.

Methods: This phase I dose-escalation study included an expansion phase at the maximum

tolerated dose (MTD). Patients received refametinib/sorafenib twice daily (BID) for 28 days,

from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus

sorafenib 400 mg. Plasma levels of refametinib, refametinib metabolite M17, and sorafenib

were measured for pharmacokinetic assessments. Tumors were biopsied at the MTD for

analysis of MEK pathway mutations and ERK phosphorylation.

Results: Thirty-two patients were enrolled in the dose-escalation cohort. The MTD was

refametinib 50 mg BID plus sorafenib 400 mg BID. The most common treatment-related

toxicities were diarrhea and fatigue. Refametinib was readily absorbed following oral

administration (plasma half-life of ~16 hours at the MTD), and pharmacokinetic parameters

displayed near-dose proportionality, with less than 2-fold accumulation after multiple dosing.

Another 30 patients were enrolled in the MTD cohort; 19 had hepatocellular carcinoma. The

combination was associated with significantly reduced ERK phosphorylation in 5 out of 6

patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations.

Disease was stabilized in approximately half of patients, and 1 patient with colorectal cancer

achieved a partial response at the MTD lasting approximately 1 year.

Conclusion: In this phase I study, refametinib plus sorafenib was well tolerated, with good

oral absorption, near-dose proportionality, and target inhibition in a range of tumor types.





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Introduction

The mitogen-activated protein kinase (MAPK) signaling pathway is constitutively activated

in many cancers, causing uncontrolled cellular proliferation, survival, and metastasis (1–7).

Mutations in receptor tyrosine kinases, or downstream intracellular MAPK signaling

components (e.g. RAS), are common in various tumors and present a long-studied therapeutic

target. Activation of the tyrosine/threonine kinase MEK causes activation of downstream

extracellular signal-related kinase (ERK), which subsequently activates a range of

downstream cytoplasmic and nuclear targets, promoting cell growth, differentiation, and

survival (8–10). MEK is therefore an attractive candidate for inhibition in cancer, primarily

due to its critical activating role in MAPK signaling, but also due to its structure, which

allows for the targeting of selective pharmaceutical inhibitors (11, 12). However, due to the

multifactorial nature of tumor growth and development, combined therapeutic approaches

that engage multiple targets simultaneously are often necessary to reverse or inhibit tumor

growth.

Refametinib (BAY 86-9766/RDEA119; Bayer Pharma AG, Berlin, Germany) is a selective,

orally available, potent, allosteric (non-adenosine triphosphate competitive) inhibitor of

MEK1/2 (13) that has shown activity in multiple tumor types, including colorectal cancer

(14) and preclinical models of hepatocellular carcinoma (HCC) (15). Sorafenib (Nexavar®;

Bayer Pharma AG) is an oral multikinase inhibitor with potent activity against Raf-1 and

wild-type and mutant BRAF, and with antiangiogenic activity mediated by inhibition of

vascular endothelial growth factor receptors and platelet-derived growth factors (16).

Sorafenib is currently approved as monotherapy for advanced HCC (17), advanced renal cell

carcinoma (18), and radioactive iodine-refractory differentiated thyroid cancer (19).





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ERK1/2 signaling has been shown to be regulated by homeostatic feedback controls that

include the direct phosphorylation of inhibitory sites on Raf-1 (20), which helped to explain,

in part, the lack of efficacy of single-agent MEK inhibitors in the majority of cells. This led

to the hypothesis that combinations of a MEK inhibitor and a Raf inhibitor would be

synergistic (8), which was confirmed in a preclinical study of refametinib in combination

with sorafenib (15).

This phase I study (NCT00785226) assessed the safety and tolerability of escalating daily

oral doses of refametinib combined with sorafenib in patients with advanced solid

malignancies. Secondary objectives were to determine the pharmacokinetics (PK) and

pharmacodynamics of the combination and to describe any observed tumor response.

Additional secondary objectives were to correlate toxicity and tumor response profiles to

selected refametinib and sorafenib biomarkers, and to evaluate the safety and tolerability of

the maximum tolerated dose (MTD) of this combination in an expansion cohort of 30 patients

with advanced cancer amenable to biopsy, including 20 patients with HCC.

Materials and Methods

This study was performed in accordance with the Declaration of Helsinki, and documented

approval from the appropriate ethics committees and institutional review boards was obtained

for all participating centers prior to the study, where required.

Patients

All patients gave written, informed consent. Patients were eligible if they: were aged 18

years or over; had an Eastern Cooperative Oncology Group performance status of 0 or 1; had

cardiac function within normal range (as measured by echocardiogram or multigated

acquisition scan); and had a histologically or cytologically confirmed advanced solid





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malignancy. Patients in the MTD expansion cohort had to have an unresectable tumor, either

HCC (Child-Pugh A status) or melanoma, head and neck, colorectal, breast, or thyroid,

amenable to biopsy (optional for HCC patients). Other inclusion criteria for all cohorts were:

amylase and lipase ≤2 × upper limit of normal (ULN); hemoglobin ≥8.5 g/L; absolute

neutrophil count ≥1500/mm3; platelet count ≥75,000/mm3; total bilirubin ≤1.5 × ULN;

aspartate aminotransferase/alanine aminotransferase ≤2.5 × ULN (or ≤5 × ULN for patients

with liver involvement); pro-thrombin time international normalized ratio/partial

thromboplastin time ≤1.5 × ULN; and creatinine ≤1.5 × ULN. Exclusion criteria were: a

prior or concurrent distinct cancer in a primary site other than the one being evaluated in the

study; swallowing dysfunction or malabsorption syndrome that may impair treatment with

the study drug; cytotoxicity from chemotherapy or adverse events from administration of

other treatments 4 or more weeks prior; major surgery within 4 weeks; cardiac disease; or

HIV infection. The use of inhibitors and inducers of CYP3A4 and CYP2C19 (enzymes

known to metabolize refametinib) was to be discussed with the study sponsor.

Study Design

This open-label study comprised a dose-escalation phase to determine the MTD of

refametinib combined with sorafenib, and an MTD expansion phase to further characterize

safety and tolerability. Patients received a single dose of refametinib 3 days before

continuous treatment with refametinib and sorafenib, both twice daily (BID), for 28 days,

which constituted 1 course. Standard 3+3 design was used for the dose-escalation phase.

Dose escalation progressed if no patients experienced dose-limiting toxicities (DLTs) as

defined by the National Cancer Institute Common Terminology Criteria for Adverse Events,

version 3.0, after 28 days (Fig. 1). Protocol-defined DLTs included the following drug-

related toxicities: grade 4 neutropenia lasting more than 7 days; febrile neutropenia (grade 3





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or 4); grade 4 thrombocytopenia; grade ≥3 laboratory or non-hematologic toxicity; grade ≥3

lipase and/or amylase elevation; grade ≥3 skin toxicity (not hand-foot skin reaction); grade 4

anemia; grade ≥2 pulmonary hemorrhage/bleeding within 2 weeks of initial dose; grade ≥3

diarrhea (if persists with anti-diarrheal medication); grade ≥3 international normalized ratio

or partial thromboplastin time with associated bleeding; grade ≥3 hemorrhage/bleeding; and

missing 7 or more consecutive refametinib daily doses because of drug-related toxicity. If a

DLT was observed in 1 of 3 patients in a cohort, 3 further patients were enrolled at the same

dose. Dose escalation terminated if a DLT was observed in 2 or more patients in cohorts of 3

or 6 patients, and the dose below was declared the MTD of refametinib, combined with the

full recommended dose of sorafenib (21) (Fig. 1). Dose escalation was not to exceed

refametinib 50 mg BID, the MTD identified in a previous phase I study (NCT00610194).

Following determination of the MTD, an expansion cohort was opened.

DLTs were managed with dose interruptions until recovery, or until discontinuation if

interruptions lasted more than 4 weeks. Dermatologic toxicities were expected, and patients

were instructed to moisturize BID with alcohol-free emollient and to minimize exposure to

sunlight.

Assessments

Screening included baseline demographics and characteristics, laboratory tests, blood

samples for circulating tumor cell (CTC) enumeration, and tumor biopsy for consenting non-

HCC patients in the MTD expansion cohort (if tissue blocks were unavailable). Blood

samples for PK analysis of refametinib and metabolite M17 were collected on days 1–4 of

course 1, and day 1 of course 2, pre-dose and at 0.5, 1, 3, 6, 8, and 24 hours post-dose for all

cohorts, and on days 1–4 of course 1 at 48 and 72 hours for cohorts 4 and 5 and the MTD

expansion cohort. Additional PK samples were collected on day 15 of courses 1–3. Blood





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samples for CTC analysis and tumor biopsies were collected in the fourth week of course 1 or

the first week of course 2. Tumor biopsies were assessed for mutational status of KRAS,

BRAF, and PIK3CA, and for immunohistochemical labeling of phosphorylated ERK (pERK),

along with CTC samples, and Ki67 and phosphorylated Akt. Tumors were assessed by

computed tomography and magnetic resonance imaging scans at screening, every 8 weeks,

and at study termination (Response Evaluation Criteria in Solid Tumors version 1.0).

Confirmatory scans were performed 4–6 weeks after the documentation of an objective

response. Brow or scalp hair follicles were collected for pERK analysis on day 1 of course 1

pre-dose and at 2, 4, 24, and 26 hours post-dose, and during courses 2 and 3.

Statistical Analysis

The sample size for the dose-escalation phase was not based on formal power calculations

because the study objectives were focused on initial safety and tolerability assessments.

Thirty patients were planned to be enrolled in the MTD expansion cohort. Descriptive

statistics were used for safety analyses for all patients who received at least 1 dose of

refametinib. Efficacy analyses included all patients who completed at least 2 courses of

treatment. Phosphorylated ERK was analyzed using a 1-way analysis of variance with

Dunnett’s multiple comparison to compare pre- and post-drug treatment values. Matched

biopsy samples were analyzed using paired t-tests.





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Results

Patient Demographics and Disposition

Sixty-two patients were enrolled overall, with 32 in the dose-escalation phase: 3 in cohort 1,

8 in cohort 2A, 3 in cohort 2B, 4 in cohort 3, 6 in cohort 4, and 8 in cohort 5 (Table 1).

Enrollment and dose escalation proceeded according to design with the following exceptions:

in cohort 2A, 1 patient experienced 2 DLTs (rash and pruritus), leading to an expansion of the

cohort to 6 patients, 2 of whom required replacement, and no additional DLTs were observed;

in cohort 4, 1 patient experienced 1 DLT (rash), leading to the enrollment of 3 additional

patients; and in cohort 5, 2 patients had to be replaced, and 1 patient experienced a DLT

(hyperuricemia), leading to enrollment of 3 additional patients. Treatment was tolerated in

cohort 5 (refametinib 50 mg BID plus sorafenib 400 mg BID), and as refametinib dosing

above the monotherapy MTD of 50 mg BID was not planned, this was declared the MTD,

prompting enrollment of 11 non-HCC and 19 HCC patients into the MTD expansion cohort.

The mean age was similar between non-HCC and HCC patients, and most patients were male

and white (Table 1). Frequent non-HCC malignancies included colorectal cancer (53.5%)

and melanoma (14.0%). More HCC patients had an Eastern Cooperative Oncology Group

performance status of 1 compared with non-HCC patients (63.2% vs. 32.6%).

Non-HCC patients received a mean of 156.2 doses (range, 1–868) of refametinib and 134.8

doses (range, 0–416) of sorafenib. Mean treatment duration was 99.5 days (range, 12–477)

with a mean of 3.6 courses (range, 1–17). HCC patients received a mean of 125.9 doses

(range, 11–403) of refametinib and 92.6 doses (range, 10–215) of sorafenib. Mean treatment

duration was 87.9 days (range, 15–265) with a mean of 3.2 courses (range, 1–9).





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Safety

Forty-three non-HCC patients and 19 HCC patients were eligible for safety analysis. Primary

reasons for study discontinuation included disease progression and adverse events (AEs)

(Table 2). All patients experienced at least 1 AE, and most experienced at least 1 AE

considered possibly related to refametinib or sorafenib (Table 2). Serious AEs were more

frequent in non-HCC patients (41.9% vs. 21.1%); 10 non-HCC patients had serious AEs

considered possibly related to refametinib. Six non-HCC patients and 1 HCC patient had

grade 5 AEs, although none was considered treatment-related.

Common AEs (≥20% incidence) in non-HCC patients included diarrhea, fatigue, nausea,

dermatitis acneiform, and vomiting (Supplementary Table 1); no dose-related trends in AE

incidence were observed. AE findings were generally similar in HCC patients, with the

addition of increased aspartate aminotransferase and peripheral edema. Frequent treatment-

related grade 3 or 4 AEs included diarrhea, rash, and increased blood alkaline phosphatase in

non-HCC patients, and diarrhea, dermatitis acneiform, and increased aspartate

aminotransferase in HCC patients (Supplementary Table 2).

Of the 4 DLTs reported in 3 non-HCC patients, 3 (pruritus and rash in 1 patient, and rash in

another) were considered possibly treatment-related; grade 4 hyperuricemia in 1 patient was

considered unlikely to be treatment-related (Supplementary Table 3). During dose escalation,

5 non-HCC patients experienced AEs leading to study discontinuation; grade 3 left

ventricular dysfunction (1 patient) and grade 4 subarachnoid hemorrhage (1 patient) were

deemed possibly treatment-related, whereas all others (grade 2 nausea, grade 2 vomiting,

grade 3 gastrointestinal hemorrhage, grade 4 fall, and grade 5 convulsion) were either not or

not likely to be treatment-related. Most AEs leading to study discontinuation in HCC

patients (hyperbilirubinemia, increased aspartate aminotransferase, diarrhea, dermatitis





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acneiform, ascites, thrombocytopenia, and left ventricular dysfunction) were grade 2 or 3 and

were considered possibly treatment-related, except for delirium (grade 2) in 1 patient.

Pharmacokinetics

All patients participated in the single-dose PK assessment of refametinib. Refametinib was

readily absorbed, with maximum plasma concentrations typically observed approximately

3 hours after administration (Fig. 2A; Supplementary Table 4). At the MTD, plasma

concentration declined, with a geometric mean half-life of 16.7 hours, with comparable

values for HCC and non-HCC patients (17.6 and 15.7 hours, respectively). In the dose range

studied, PK parameters appeared to increase in a manner broadly consistent with dose

proportionality, with moderate variability.

Multiple-dose plasma refametinib concentrations on day 1 of course 2 increased with dose

(Fig. 2B; Supplementary Table 5). At the MTD, refametinib multiple-dose exposure was

comparable in HCC and non-HCC patients; geometric mean maximum drug concentration

(Cmax) values were 708 ng/mL and 674 ng/mL, and area under the curve (AUC)0–12 values

were 6528 ng×h/mL and 5631 ng×h/mL, respectively. Multiple-dose AUC0–12 values were

higher than single-dose AUC0–12 values by an average of approximately 40%.

Plasma concentrations of the inactive refametinib metabolite M17 generally increased with

dose and were lower compared with refametinib, with higher variability. After single and

multiple dosing, metabolite M17 AUC0–12 accounted for approximately 12–31% of

refametinib exposure without relationship to the refametinib dose administered or disease

type. At the MTD, metabolite M17 geometric mean Cmax values were 176 ng/mL and

188 ng/mL, and AUC0–12 values were 1505 ng×h/mL and 1315 ng×h/mL, in HCC and non-

HCC patients, respectively. Geometric mean half-life of metabolite M17 was approximately

20 hours, and up to 2-fold accumulation was observed after BID dosing.





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Plasma sorafenib concentrations at 200 mg BID and 400 mg BID dose levels showed

moderate to high variability, and exposure decreased with increasing doses of refametinib up

to 30 mg BID (Supplementary Table 6). At the MTD, sorafenib exposure was lower in HCC

patients (Cmax 2076 ng/mL) compared with non-HCC patients (Cmax 3866 ng/mL).

Pharmacodynamics

Mutational analysis was performed on tumor biopsies collected from 10 patients in the MTD

expansion cohort, for 6 of whom pERK analysis was performed in matched biopsies

(Table 3). Two patients had KRAS-activating mutations (G12V and G13D), 1 had a BRAF-

activating mutation (V600E), and 1 had a PIK3CA mutation. Two further patients (1 with

colorectal cancer and 1 with head-and-neck cancer) were wild type for all mutations tested.

There was a significant reduction (average 62%) in pERK levels post-dose with refametinib

and sorafenib compared with baseline, with a 113-point reduction in H-score (Table 3).

Matched biopsies from the 3 patients with MAPK-activating mutations showed the largest

reduction (average 80%); 1 patient with colorectal cancer (wild-type status) showed no

reduction. The level of pERK reduction did not correlate with clinical outcome (data not

shown). There was no significant reduction in the percentage of cells stained positively for

Ki67, or in phosphorylated Akt H-score (data not shown).

Total and pERK values were measured in 307 hair follicle samples from 62 patients over 2 to

3 courses of treatment. There was a trend towards reduced pERK levels in hair follicles post-

dose in cohorts 1–5, although this was not significantly different from baseline

(Supplementary Fig. 1). In the MTD expansion cohort in course 1, there was a significant

reduction of pERK of 54% and 65% at 2 and 4 hours post-dose, respectively (P < 0.001).

CTC enumeration with simultaneous pERK analysis was performed in 7 samples from

11 patients in the MTD expansion cohort. There was a significant reduction (35%) in CTC





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pERK after day 28 of course 1 compared with baseline (P < 0.05), although there was no

significant change in CTC number (Supplementary Fig. 2).

Efficacy

Thirty-eight (88.4%) non-HCC patients and 16 (84.2%) HCC patients were evaluable for

response assessment. For non-HCC patients, the disease control rate (complete response,

partial response, and stable disease) for refametinib plus sorafenib was 65.8% (25 out of

38 patients); no patients achieved a complete response, 1 (2.6%) patient achieved a partial

response, 24 (63.2%) patients achieved stable disease, of whom 16 (42.1%) had stable

disease for 15 or more weeks, and 12 (31.6%) had progressive disease (Fig. 3A). One patient

was not evaluable for response. The patient with a confirmed partial response had colorectal

cancer, was in the MTD expansion cohort, was wild type for all mutations tested, and had a

durable response of 358 days. The disease control rate in HCC patients was 43.8%; no

patients had a complete response or partial response, 7 (43.8%) had stable disease, of whom

6 (37.5%) had stable disease for 15 or more weeks, and 7 (43.8%) had progressive disease

(Fig. 3B). Two were not evaluable for response.

Discussion

This phase I trial evaluated the safety and efficacy of the combination therapy of refametinib

with sorafenib in patients with advanced malignancies.

The baseline demographics and disease characteristics of the non-HCC population were

broadly consistent with a previous phase I study of refametinib monotherapy (14), although

the HCC population comprised slightly more males. Only HCC patients with Child-Pugh A

status were enrolled to ensure patients had stable liver function, similar to previous sorafenib

trials (22, 23).





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Although sorafenib dosing had been established elsewhere as 400 mg BID, because of safety

concerns the initial dose-escalation cohorts approached this level cautiously. Lack of toxicity

in cohort 2A (refametinib 5 mg BID plus sorafenib 400 mg BID) led to escalation with

sorafenib 400 mg BID as the backbone. The MTD was determined to be refametinib 50 mg

BID in combination with sorafenib 400 mg BID, consistent with the phase I refametinib

monotherapy study (14). Overall, daily oral dosing of refametinib plus sorafenib was well

tolerated, up to and including at the MTD, with indications of clinical activity, consistent

with the phase I study (14). Common treatment-emergent AEs included gastrointestinal

toxicity, fatigue, dermatologic toxicities, and anorexia, as reported in the phase I study and in

a study of patients with unresectable HCC (14, 24). Dermatologic toxicities were expected

based on previous trials of other MEK inhibitors (25–28). Most AEs were managed by

temporary dose interruptions or modifications, concomitant treatments, and supportive care.

Serious AEs were reported by both non-HCC patients and HCC patients, although most were

either not or not likely to be treatment-related. The higher incidence of serious AEs in non-

HCC patients may, in part, be explained by the slightly longer duration of treatment

compared with HCC patients.

Overall, refametinib displayed a dose-related increase in exposure that was similar between

non-HCC and HCC patients at the MTD (refametinib 50 mg BID). Refametinib PK

characteristics and single-dose exposure were generally consistent with those reported in the

phase I trial of refametinib monotherapy (14), although multiple-dose exposure was slightly

lower in the current study. Refametinib PK were not affected by co-administration of

sorafenib, although at increased doses of refametinib, sorafenib exposure appeared to be

lower than historical monotherapy data (14) and was lower in HCC patients compared with

non-HCC patients. Conclusive interpretations of PK results are difficult due to the small

sample sizes, particularly at the lower dose levels (2–5 patients per cohort), and observed





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variability in PK parameters. In a phase II study of refametinib and sorafenib (24), multiple-

dose PK results were consistent with historical data, without any apparent decrease in

exposure.

Preliminary antitumor activity was observed with the combination therapy; biopsies from

patients with colorectal and head-and-neck cancers showed significant reductions in pERK

levels compared with baseline levels. MAPK pathway-activating mutations were identified

in 4 out of 6 patients and, although the sample size was small, those with activating mutations

tended to show greater increases in the magnitude of pERK reduction. These preliminary

data suggest that the combination of refametinib plus sorafenib was effective in inhibiting

ERK phosphorylation in advanced tumors to a similar level as seen in the phase I

monotherapy study (14). However, in contrast to the monotherapy study, 1 patient with

head-and-neck cancer with no identified mutations showed a 50% reduction in pERK levels

following treatment. Further, there was no significant correlation between pERK reduction

and clinical benefit in this small data set. Indeed, the patient with colorectal cancer who did

not have MAPK pathway-activating mutations had a durable partial response lasting for

358 days.

Hair follicle and CTC pERK levels were examined as a potentially less invasive surrogate

pharmacodynamic marker of the refametinib plus sorafenib combination. A significant

reduction in pERK levels in hair follicles was identified in the MTD expansion cohort in

course 1, further suggesting that refametinib was effective in inhibiting ERK

phosphorylation, although the sample size was small (at least 3 patients per time point). A

statistically significant, yet modest, reduction in CTC pERK level during course 1 was also

identified, although total CTC levels were not decreased. High levels of variation in CTC

number and pERK level were expected based on previous reports of CTCs in mixed tumor





20

types (29). No changes in phosphorylated Akt levels or in Ki67 labeling were observed post-

dosing, suggesting that refametinib does not cause wide-reaching inhibitory effects in MAPK

signaling pathways. Thus, although there is a trend for reduction in pERK with the

refametinib plus sorafenib combination in hair follicles or CTCs, the applicability of this

approach for use as a surrogate pharmacodynamic marker for this drug combination remains

questionable.

The low overall response rate (1.9%; 1 out of 54) was not unlike the activity of sorafenib

monotherapy (response rate of 2%, and 71% of patients achieved stable disease) in a phase III

trial in HCC (SHARP) (23). However, in the present study, patients tended to have received

a greater number of prior therapies than in SHARP. The disease control rate was 65.8%

(25 out of 38) in non-HCC patients, indicating the ability of refametinib combined with

sorafenib to achieve increased disease control in a range of solid tumor types. The disease

control rate of 43.8% (7 out of 19) observed in HCC patients was similar to that of 44.8%

reported in a study of Asian patients with HCC (24). Of note in this study, 4 patients had

RAS mutations, of whom 3 had confirmed partial responses ranging from 128 to 382 days. In

contrast, in the present study, the lone partial response was in a patient with colorectal cancer

whose tumor was wild type for KRAS and BRAF, whereas 3 colorectal cancer patients with

activating mutations failed to respond to the refametinib plus sorafenib combination.

However, direct comparisons with the study in Asian patients with HCC are difficult due to

differences in patient demographics and the small sample size. Furthermore, the mutational

status of the HCC patients in the present study was not determined.

Overall, refametinib plus sorafenib combination therapy is well tolerated in 28-day courses

up to the MTD in non-HCC and HCC patients, with a dose-proportional PK profile. The

clinical benefit observed indicates that the combination therapy may be favorable for use in a





21

variety of advanced solid-tumor types, including those where no MAPK-pathway mutations

are identified. Further investigation into the safety and efficacy of refametinib plus sorafenib

combination therapy is therefore warranted, and phase II studies of refametinib as

monotherapy and in combination with sorafenib in HCC patients prospectively identified to

have RAS activating mutations are ongoing (NCT01915589 and NCT01915602,

respectively).

Acknowledgments

We thank Tanja Torbica, PhD, at Complete HealthVizion for assistance in the preparation

and revision of the draft manuscript, based on detailed discussion and feedback from all the

authors. Editorial assistance was funded by Bayer HealthCare Pharmaceuticals.





22

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Table 1. Patient demographics and baseline disease characteristics

Non-HCC patients HCC patients

Dose-escalation cohort

(n = 32)

MTD expansion cohort

(n = 11)

Total

(N = 43)


(n = 19)

Mean age, years (range) 59.7 (33–78) 63.6 (45–87) 60.8 (33–87) 63.7 (53–79)

Males, n (%) 18 (56.3) 7 (63.6) 25 (58.1) 15 (78.9)

Race, n (%)

White 28 (87.5) 10 (90.9) 38 (88.4) 18 (94.7)

Black 3 (9.4) 1 (9.1) 4 (9.3) 1 (5.3)

Asian 1 (3.1) 0 1 (2.3) 0

Tumor typea, n (%)

Colorectal 15 (46.9) 8 (72.7) 23 (53.5) N/A

Esophageal 2 (6.3) 0 2 (4.7) N/A

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Head and neck 1 (3.1) 2 (18.2) 3 (7.0) N/A

Lung 1 (3.1) 0 1 (2.3) N/A

Melanoma 5 (15.6) 1 (9.1) 6 (14.0) N/A

Ovarian 2 (6.3) 0 2 (4.7) N/A

Pancreatic 4 (12.5) 0 4 (9.3) N/A

Prostate 1 (3.1) 0 1 (2.3) N/A

Small-bowel adenocarcinoma 1 (3.1) 0 1 (2.3) N/A

Hepatocellular carcinoma N/A N/A N/A 19 (100)

Years since initial diagnosis

Mean (range) 4.0 (0.6–22.2) 4.3 (1.6–10.4) 4.4 (0.6–22.2) 1.4 (0–4.1)b

ECOG performance status, n (%)

0 24 (75.0) 5 (45.5) 29 (67.4) 7 (36.8)

1 8 (25.0) 6 (54.5) 14 (32.6) 12 (63.2)

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Prior cancer therapy, n (%)

Surgery 32 (100) 11 (100) 43 (100) 15 (78.9)

Chemotherapy 29 (90.6) 11 (100) 40 (93.0) 12 (63.2)

Radiation therapy 9 (28.1) 3 (27.3) 12 (27.9) 2 (10.5)

Immunotherapy 1 (3.1) 3 (27.3) 4 (9.3) 0

Hormone therapy 1 (3.1) 0 1 (2.3) 0

Other therapy 3 (9.4) 1 (9.1) 4 (9.3) 10 (52.6)

aAppendiceal adenocarcinoma, colon, colon adenocarcinoma, colorectal adenocarcinoma, rectal adenocarcinoma, and appendiceal were

categorized as colorectal; esophageal carcinoma and esophageal squamous-cell carcinoma were categorized as esophageal; adenocarcinoma

pancreatic cancer was categorized as pancreatic; and adenocystic was categorized as head and neck.

bThe minimum value of 0 years was due to rounding down values for 2 patients (0.01 years and 0.02 years).

Abbreviations: ECOG, Eastern Cooperative Oncology Group; N/A, not applicable.

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Table 2. Reasons for discontinuation and summary of treatment-emergent adverse events

Non-HCC patients HCC patients

Dose-escalation cohort

(n = 32)


(n = 11)

Total

(N = 43)


(n = 19)

Reasons for discontinuation, n (%)

Disease progression 19 (59.4) 9 (81.8) 28 (65.1) 9 (47.4)

AEa 4 (12.5) 1 (9.1) 5 (11.6) 5 (26.3)

Symptomatic deterioration 5 (15.6) 0 5 (11.6) 3 (15.8)

Withdrawn consent 4 (12.5) 1 (9.1) 5 (11.6) 2 (10.5)

Any AEa, n (%) 32 (100) 11 (100) 43 (100) 19 (100)

Any drug-related AEa (refametinib), n (%) 30 (93.8) 9 (81.8) 39 (90.7) 19 (100)

Any drug-related AEa (sorafenib), n (%) 30 (93.8) 10 (90.9) 40 (93.0) 19 (100)

Maximum severity of AEsa by CTCAE,

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version 3.0 grade, n (%)

Grade 1 (mild) 3 (9.4) 0 3 (7.0) 0

Grade 2 (moderate) 7 (21.9) 2 (18.2) 9 (20.9) 3 (15.8)

Grade 3 (severe) 16 (50.0) 7 (63.6) 23 (53.5) 12 (63.2)

Grade 4 (life-threatening) 2 (6.3) 0 2 (4.7) 3 (15.8)

Grade 5 (fatal) 4 (12.5) 2 (18.2) 6 (14.0) 1 (5.3)

Any SAE, n (%) 12 (37.5) 6 (54.5) 18 (41.9) 4 (21.1)

Total number of SAEs 26 10 36 10

Any drug-related SAE (refametinib), n (%) 5 (15.6) 0 5 (11.6) 0

Any drug-related SAE (sorafenib), n (%) 5 (15.6) 1 (9.1) 6 (14.0) 0

aAEs assessed by National Cancer Institute CTCAE, version 3.0.

Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; SAE, serious adverse event.

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Table 3. Molecular analysis of matched tumor biopsy samples from 6 non-HCC patients in the MTD expansion cohort

Mutational status pERK H-score

Disease KRAS BRAF PIK3CA Pre / post Percent change (%)

Time post-dose (hours)a

Colorectal cancer WT WT WT 0 / 40 >100 4.3

Colorectal cancer G12V WT WT 230 / 60 −74 4.5

Colorectal cancer G13D WT WT 90 / 20 −78 0.4

Colorectal cancerb WT V600E WT 260 / 30 −88 >12

Head and neck WT WT W1051C 280 / 150 −46 3.2

Head and neckb WT WT WT 240 / 120 −50 >24

Mean 183 / 70 −62

aEstimated based on biopsy timing.

bDosing interruption on day of biopsy.

Abbreviation: WT, wild type.

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Figure 1. Dose-escalation protocol.

Abbreviation: BID, twice daily.

Figure 2. Single-dose (A) and multiple-dose (B) geometric mean plasma concentration–time

profiles for refametinib on day 1 of course 1 and on day 1 of course 2, respectively.

Abbreviations: R, refametinib; S, sorafenib.

Figure 3. Waterfall plot of best response in target lesions by dose level in each cohort, in

non-HCC patients (A) and HCC patients (B).

Dashed lines indicate stable disease between 20% increase and 30% decrease from baseline.

One patient was excluded from each plot as there was no calculable change in the sum of

longest diameters of target lesions.

aMaximum percentage decrease (or minimum increase if no decrease) in the sum of the

longest diameters of target lesions at a given visit relative to baseline.

bPartial response; 1 patient with melanoma had a >30% reduction in the sum of the longest

diameter for target lesions, but did not achieve a partial response because of the appearance

of a new lesion.

Table 1. Patient demographics and baseline disease characteristics

Table 2. Reasons for discontinuation and summary of treatment-emergent adverse events

Table 3. Molecular analysis of matched tumor biopsy samples from 6 non-HCC patients in

the MTD expansion cohort

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Cohort 1:refametinib 5 mg BID

+ sorafenib 200 mg BID

Cohort 2A:refametinib 5 mg BID

+ sorafenib 400 mg BID

Cohort 2B:refametinib 10 mg BID + sorafenib 200 mg BID

Cohort 3:refametinib 10 mg BID + sorafenib 400 mg BID



MTD expansion cohort (non-HCC):

refametinib 50 mg BID + sorafenib 400 mg BID

MTD expansion cohort:refametinib 50 mg BID + sorafenib 400 mg BID

Alternate enrollment between 2A and 2B

Declare refametinib 50 mg BID + sorafenib 400 mg BID as MTD

Dose-escalation

cohorts

MTD expansion

cohortExcluding

HCC patients HCC patients

Expand at MTDEnroll patients with speci�c non-HCC solid tumors and patients with HCC

Fig. 1




800

600

400

200

0

0 24 48 72

Refa

met

inib

con

cent

ratio

n (n

g/m

L)

Time (hours)

A

800

600

400

200

0

0 2 4 8

Refa

met

inib

con

cent

ratio

n (n

g/m

L)

Time (hours)

B

6

5 mg (R) + 200 mg (S)5 mg (R) + 400 mg (S)10 mg (R) + 200 mg (S)10 mg (R) + 400 mg (S)30 mg (R) + 400 mg (S)50 mg (R) + 400 mg (S) non-HCC50 mg (R) + 400 mg (S) HCC

Fig. 2




1009080706050403020100

–10–20–30–40–50–60–70–80–90

–100

100908070605040302010

0–10–20–30–40–50–60–70–80–90

–100

Cohort

12A2B3455 + MTD

5 + MTD

CohortC

hang

e fro

m b

asel

ine

(%)a

Cha

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Fig. 3




Published OnlineFirst December 7, 2015.Clin Cancer Res Alex A Adjei, Donald Richards, Anthony B. El-Khoueiry, et al. plus Sorafenib in Patients with Advanced CancerPharmacodynamics of Combination Therapy with Refametinib A Phase I Study of the Safety, Pharmacokinetics, and

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