Invest New Drugs (2015) 33:641–651 DOI 10.1007/s10637-015-0229-3
PHASE I STUDIES
Phase I and pharmacokinetics/pharmacodynamics study of the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors Shinji Nakamichi & Hiroshi Nokihara & Noboru Yamamoto & Yasuhide Yamada & Yutaka Fujiwara & Yosuke Tamura & Hiroshi Wakui & Kazunori Honda & Hidenori Mizugaki & Satoru Kitazono & Yuko Tanabe & Hajime Asahina & Naoya Yamazaki & Shigenobu Suzuki & Mieko Matsuoka & Yoshitaka Ogita & Tomohide Tamura
Received: 18 December 2014 / Accepted: 5 March 2015 / Published online: 27 March 2015 # Springer Science+Business Media New York 2015
Abstract RO4987655 is an oral and selective inhibitor of MEK, a key enzyme of the mitogen-activated protein kinase (MAPK) signaling pathway. This phase I dose-escalation study of RO4987655 in Japanese patients with advanced solid Clinical trial number: JapicCTI-111490 Electronic supplementary material The online version of this article (doi:10.1007/s10637-015-0229-3) contains supplementary material, which is available to authorized users. S. Nakamichi : H. Nokihara : N. Yamamoto : Y. Fujiwara : Y. Tamura : H. Wakui : K. Honda : H. Mizugaki : S. Kitazono : Y. Tanabe : H. Asahina : T. Tamura (*) Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan e-mail: [email protected] T. Tamura e-mail: [email protected] Y. Yamada Department of Gastrointestinal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan N. Yamazaki Department of Dermatological Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan S. Suzuki Department of Ophthalmic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan M. Matsuoka : Y. Ogita Clinical Research Planning Department, Chugai Pharmaceutical Co., Ltd., 2-1-1 Nihonbashi-muromachi, Chuo-ku, Tokyo, Japan Present Address: T. Tamura Thoracic Center, St. Luke’s International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, Japan
tumors aimed to determine maximum tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity. Patients received a single dose of RO4987655 (1, 2, 4, 5, or 6.5 mg) followed by continuous once-daily dosing (1, 2, or 4 mg QD) or twice-daily dosing (4, 5, or 6.5 mg BID) in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs). In dose-escalation, 25 patients were enrolled. After the MTD was determined, a further six patients were administered the MTD for further confirmation of safety. MTD was determined as 8 mg/day (4 mg BID) due to a total of four dose-limiting toxicities (DLTs) of grade 3 creatine phosphokinase (CPK) elevation (2 DLTs each in 10 mg/day and 13 mg/day). Most commonly related adverse events included dermatitis acneiform, CPK elevation, and eye disorders. Plasma concentration of RO4987655 appeared to increase in a dose-proportional manner with a plasma half-life of 4.32 to 21.1 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8. The inhibitory effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner. One esophageal cancer patient had confirmed partial response and seven patients showed progression-free survival for longer than 16 weeks. The MTD of RO4987655 for Japanese patients was determined as 8 mg/day (4 mg BID). RO4987655 was tolerated up to the MTD with a favorable PK/PD profile in Japanese patients with advanced solid tumors. Keywords Phase I study . Dose escalation . MAPK pathway . MEK inhibitor . Japanease
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Introduction The mitogen-activated protein kinase (MAPK) pathway, including the Ras/Raf/MEK/ERK signaling cascade, is one of the most important pathways involved in cellular proliferation and differentiation [1]. Carcinogenesis with dysregulation of the MAPK pathway has been reported in many previous studies [2–4], and constitutive activation of the MAPK pathway was reported in 36 % of various tumor cell lines, such as cell lines derived from tumors of the pancreas, colon, lung, ovary, and kidney [5]. Mutations of RAS proto-oncogenes (KRAS, HRAS, and NRAS) have been found in 50 % of colon cancers, 30 % of lung cancers, and 90 % of pancreas cancers [6], and BRAF mutations have been observed in 66 % of malignant melanomas [7]. The MAPK/ERK kinase (MEK) is the only known kinase capable of phosphorylating ERK1/2, and inhibition of MEK can potentially block the activation of downstream pathways. Therefore, several MEK inhibitors are currently under investigation [8]. RO4987655 (CH4987655), identified by Chugai Pharmaceutical Co., Ltd., is a highly specific allosteric oral MEK inhibitor that has shown anti-tumor activity in a series of human cancer xenograft models [9]. RO4987655 has a unique ring structure with high metabolic stability and slow dissociation from MEK [9], which may confer better clinical efficacy than other MEK inhibitors. In a first-in-human study of healthy volunteers, single doses of oral RO4987655 (0.5– 4 mg) were found to be safe and well tolerated [10]. A phase I dose-escalation study of RO4987655 has already been conducted in Europe [11, 12]; in that study, the maximum tolerated dose (MTD) of the study was determined as 17 mg/day (8.5 mg BID) with a favorable PK/PD profile in non-Japanese patients. The effect of ethnic factors on the tolerability and pharmacokinetics had not been elucidated. This study was conducted on Japanese patients with advanced solid tumors to evaluate adverse events (AEs) and to estimate the recommended treatment dose of RO4987655. Pharmacodynamics (PD) analysis and anti-tumor activity were also evaluated.
Materials and Methods Patients Patients with histologically or cytologically confirmed solid tumors that had progressed after standard therapies were eligible for this study. Other inclusion criteria included being 20 years old or older and having an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2, a life expectancy of 12 weeks or more, and adequate bone marrow, liver, renal, and heart function. Exclusion criteria included symptomatic brain metastasis, inflammation on the ocular surface,
Invest New Drugs (2015) 33:641–651
symptomatic gastrointestinal disorder, and breastfeeding or testing positive for pregnancy. Study design and treatment This was a phase I, open-label, single-center, dose-escalation study. The primary objectives of this study were to determine MTD based on dose-limiting toxicities (DLTs) and to evaluate safety and PK of RO4987655 in Japanese patients with advanced solid tumors. The secondary objectives were to evaluate PD and preliminary anti-tumor activity of RO4987655. This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guideline. Written informed consent was obtained from all patients before they entered the study. Patients were enrolled sequentially into escalating dosing cohorts using a standard 3+3 design. A starting dose of 1.0 mg/day was chosen based on data from a toxicity study in cynomolgus monkeys [9], clinical data from healthy volunteers [10], and patients with advanced solid tumors in the European study [11]. Patients received a single dose of RO4987655 (1, 2, 4, 5, or 6.5 mg; Cycle 0) to investigate PK/PD followed by continuous once-daily dosing (1, 2, or 4 mg QD) or twicedaily dosing (4, 5, or 6.5 mg BID; total daily dose: 8, 10, or 13 mg/day) in 28-day cycles. Drug interruption and/or dose reduction was not allowed during the first cycle unless DLT was observed. Administration was continued until unacceptable toxicity, disease progression, consent withdrawal, or any other criterion for discontinuation. Patients were fasted for 2 h pre-dose and 1 h post-dose for each administration. Safety evaluation Safety evaluation, including physical examinations, vital signs, ECOG PS, 12-lead electrocardiography, echocardiography, chest X-ray, hematologic, biochemical, and urinary laboratory evaluations, and ophthalmological examination, was performed at baseline and at specified time points throughout the study and 28 days after the final administration. Any AEs that occurred between the first single dose and 28 days after the last administration were reported. AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) ver. 3.0. All AEs in this report are Medical Dictionary for Regulatory Activities (MedDRA, ver.12.1) terms. A DLT was determined as a treatment-related AE occurring during the first cycle when the AE was either grade 3 or higher non-hematological toxicity (excluding transient electrolyte abnormalities and diarrhoea, nausea, vomiting, or skin toxicities that could be controlled by appropriate intervention), febrile neutropenia, grade 4 neutropenia continuing for 4 days or longer, grade 4 thrombocytopenia, or grade 3 thrombocytopenia requiring platelet transfusion. The MTD was determined to be the highest dose at which a DLT was seen in no more than one of six patients.
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Pharmacokinetics analysis
Results
Plasma samples for PK analysis were collected on chronologically as follows; (1) Cycle 0 Day 1: predose (0 h) and 0.5, 1, 2, 4, 8, 10 (only for 1, 2, and 4 mg QD), 12 (only for 4, 5, and 6.5 mg BID), 24, 34, 48 h postdose, (2) Cycle 1 Day 8: predose, (3) Cycle 1 Day 15: predose and 0.5, 1, 2, 4, 8, 10 (only for 1, 2, and 4 mg QD), 12 (only for 4, 5, and 6.5 mg BID), 24 (only for 1, 2, and 4 mg QD) hours postdose, and (4) Cycle 1 Day 22: predose. Plasma concentrations of RO4987655 were determined by validated liquid chromatography/tandem mass spectrometry as described in the European study [10, 11]. PK analysis was performed by a non-compartmental model using WinNonlin Ver. 5.3 (Pharsight Corporation, Cary, NC, USA).
Patient characteristics
Pharmacodynamics analysis Whole blood samples for PD analysis were collected on chronologically as follows; (1) Cycle 0 Day 1: predose and 1, 2, 4, 8, 10 (only for 1, 2, and 4 mg QD), 12 (only for 4, 5, and 6.5 mg BID), 24 h postdose, and (2) Cycle 1 Day 15: predose and 1, 2, 4, 8, 10 (only for 1, 2, and 4 mg QD), 12 (only for 4, 5, and 6.5 mg BID), 24 (only for 1, 2, and 4 mg QD) hours postdose. PD was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs) using validated FACS analysis as described in the European study [11] at the Kamakura Research Laboratories of Chugai Pharmaceutical, Co., Ltd., Japan. The PBMCs in each blood sample were isolated and activated by phorbol 12-myristate 13-acetate (PMA).
Tumor assessment Anti-tumor activity was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST, ver. 1.0) at baseline, and on Day 1 of Cycle 2, Cycle 3, and every other cycle thereafter. Assessment of anti-tumor activity and best overall response were reviewed by the independent committee specified by protocol.
Mutational analysis (optional) Either archival tumor tissues or biopsy samples were collected from some patients when their samples were available to analyze the mutational status of KRAS codon 12/ 13 and BRAF V600, which were assessed by the validated Scorpions-ARMS method at Mitsubishi Chemical Medience Corporation, Japan.
Thirty one patients were enrolled between November 2009 and January 2013. All patients received at least one dose of RO4987655, and all were eligible for safety/efficacy evaluation and for PK/PD analysis. Patient baseline characteristics are listed in Table 1. Safety and DLTs In dose-escalation, 25 patients were enrolled into six cohorts: 1 mg/day (n=3), 2 mg/day (n=3), 4 mg/day (n=4), 8 mg/day (n=6), 10 mg/day (n=3), and 13 mg/day (n=6). Of these, three patients withdrew during the first cycle due to disease progression. As a result of their withdrawal, 22 patients were eligible for evaluation of DLTs. The median duration of treatment for the 22 patients was 53.0 days (range: 25–237 days) with a median of 1.5 cycles (range: 1–8 cycles). Though the escalation was originally planned up to 17 mg/day i.e. the MTD in the European study [11], it was stopped due to two DLTs observed in the 13 mg/day cohort. Instead, a new cohort was given 10 mg/day. As two DLTs were reported in the 10 mg/day cohort, the 8 mg/day cohort additionally enrolled three new patients (six patients in total). All of the DLTs were grade 3 creatine phosphokinase (CPK) elevation. MTD was determined as 8 mg/day for this study as no DLTs were observed in that cohort. After the MTD was determined, six additional patients were enrolled and given the MTD to obtain additional safety data. All the patients experienced at least one AE. Most commonly occurring AEs included dermatitis acneiform, CPK elevation, and eye disorders (Table 2). Thirty patients (97 %) developed skin-related adverse events, including dermatitis acneiform (n=30), palmar–plantar erythrodysaesthesia syndrome (n=8), dry skin (n=7), skin fissures (n=2), and pruritus, photosensitivity reaction, and erythema multiforme (n=1 each). Six of 22 patients who experienced CPK elevation required drug interruption and/or dose reduction. CPK elevation was reversible with drug interruption and/or dose reduction. Out of five patients who experienced grade 3 CPK elevation, four patients developed grade 1/2 muscular weakness without clear rhabdomyolysis or cardiac disorders. Nineteen patients (61 %) experienced eye disorders, including macular oedema (n=12), visual impairment (n=10), eyelid oedema (n=3), vision blurred (n=3), and keratitis, corneal oedema, asthenopia, eye pain, eyelid ptosis, detachment of retinal pigment epithelium, and retinal exudates (n=1 each). All of the eye disorders were grade 1 except for one case of keratitis (grade 2). Most of the events resolved, but five patients (three cases of macular oedema, one case each of asthenopia and retinal exudates) remained unresolved at the final visit.
NSCLC Non-small cell lung cancer
NSCLC Pancreatic Other
[range] Height in cm, median [range] ECOG PS 0 1 Primary tumor Esophageal Colorectal Sarcoma
[44.0–61.1] 161.0 [157–163] 1 2 — 1 2 — — —
3 —
— — 2
— — 1
— 3 57.0 [28–67] 59.90
2 mg/day (N=3)
[59.5–61.8] 168.0 [159–171]
3 — 67.0 [61–72] 59.70
1 mg/day (N=3)
Patient characteristics at baseline
Sex Male Female Age in years, median [range] Weight in kg, median
Table 1
— — —
— 3 1
2 2
[46.6–69.9] 160.0 [147–173]
2 2 63.5 [46–71] 58.30
4 mg/day (N=4)
2 — —
7 1 2
5 7
[51.3–90.0] 166.0 [151–187]
9 3 60.5 [44–69] 56.25
8 mg/day (N=12)
— 1 —
1 1 —
1 2
[49.4–63.0] 155.0 [148–165]
2 1 67.0 [58–71] 50.30
10 mg/day (N=3)
2 1 1
— 2 —
3 3
[48.7–64.4] 162.0 [156–167]
4 2 63.5 [43–70] 61.20
13 mg/day (N=6)
7 (23 %) 4 (13 %) 2 (6 %) 2 (6 %)
8 (26 %) 8 (26 %)
15 (48 %) 16 (52 %)
[44.0–90.0] 163.0 [147–187]
20 (65 %) 11 (35 %) 62.0 [28–72] 59.30
Total (N=31)
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Invest New Drugs (2015) 33:641–651 Table 2
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Main adverse events (occurring in ≥10 % of patients) regardless of causality
Body system/Adverse event
All grades No. (%)
Grade 3 No. (%)
Laboratory abnormalities Blood creatine phosphokinase increased Aspartate aminotransferase increased Blood alkaline phosphatase increased Alanine aminotransferase increased Lymphocyte count decreased Haemoglobin decreased Gamma-glutamyltransferase increased Weight increased Blood glucose increased Platelet count decreased Blood urine present Skin and subcutaneous tissue disorders Dermatitis acneiform Palmar–plantar erythrodysaesthesia syndrome Dry skin Gastrointestinal disorders
30 (97) 22 (71) 20 (65) 13 (42) 10 (32) 9 (29) 7 (23) 6 (19) 6 (19) 5 (16) 3 (10) 3 (10) 30 (97) 30 (97) 8 (26) 7 (23) 23 (74)
9 (29) 5 (16) — — — 3 (10) 2 (6) — — — — — — — — — 1 (3)
Diarrhoea Stomatitis Nausea Constipation Vomiting Abdominal pain Metabolism and nutrition disorders Hypoalbuminaemia Decreased appetite Eye disorders Macular oedema Visual impairment Eyelid oedema Vision blurred General disorders and administration site conditions Oedema Face oedema Pyrexia Malaise
14 (45) 13 (42) 9 (29) 7 (23) 6 (19) 4 (13) 23 (74) 23 (74) 9 (29) 19 (61) 12 (39) 10 (32) 3 (10) 3 (10) 19 (61) 7 (23) 6 (19) 5 (16) 4 (13)
1 (3) — — — — — 1 (3) — — — — — — — — — — — —
Musculoskeletal and connective tissue disorders Muscular weakness Arthralgia Nervous system disorders Dizziness Vascular disorders Hypertension
10 (32) 4 (13) 3 (10) 8 (26) 3 (10) 3 (10) 3 (10)
— — — 1 (3) — 1 (3) 1 (3)
Thirteen incidents of treatment-related grade 3 AEs were observed in 10 patients: CPK elevation (n=5), lymphocyte count decreased (n=3), blood magnesium decreased, diarrhoea, hypertension, pulmonary haemorrhage, hyponatraemia
(n=1 each). No treatment-related grade 4 AEs were observed. A total of 11 incidents of treatment-related SAEs were reported in eight patients: one each of hypoalbuminaemia (8 mg/ day), pneumonia (8 mg/day), left ventricular dysfunction
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(8 mg/day), pulmonary haemorrhage (8 mg/day), and ileus (10 mg/day); and one case of CPK elevation and muscular weakness (10 mg/day), one case of gastrointestinal inflammation and muscular weakness (13 mg/day), and one case of CPK elevation and muscular weakness (13 mg/day). No AEs leading to death were observed except one patient died of disease progression. The primary reason for study withdrawal was disease progression (25/31, 81 %); in addition, one patient discontinued the study due to drug-related pulmonary haemorrhage (8 mg/ day) and one due to muscular weakness (13 mg/day). The primary tumor of the patient who discontinued the study due to pulmonary haemorrhage was esophageal, with lung and lymph node metastases. The patient had a history of haemoptysis and bloody sputum before study enrollment. No anti-coagulant agent was included in any concomitant treatment. The event was not associated with pneumonitis or chest infection. The event was treated with bronchial arterial embolization, and resolved without sequelae. Pharmacokinetics analysis Following the oral administration from 1 to 13 mg/day, RO4987655 was rapidly absorbed, with the time to maximum plasma concentration (Tmax) ranging from 0.833 to 1.92 h, and was eliminated from plasma with the apparent terminal halflife (t1/2) ranging from 4.32 to 21.1 h. Plasma exposure appeared to increase in a dose-proportional manner in the tested dose range (Fig. 1). RO4987655 pharmacokinetics parameters are summarized in Table 3. The observed mean accumulation index (AUCday 15/AUCday 1) was similar to the one estimated from the elimination rate constant after single dose administration (data not shown), suggesting no unexpected accumulation. After multiple dose administration, steady-state conditions were reached by Cycle 1 Day 8. Pharmacodynamics analysis The inhibitory effect of RO4987655 on pERK in PBMCs increased in a dose-dependent manner (data not shown). A simple Emax model was used to fit percentage pERK inhibition and corresponding RO4987655 concentrations (Fig. 2). In the final model, the IC50 and maximum drug effect (Imax) were estimated to be 24.8 ng/mL and 95 % respectively. Biomarkers Archival tumor tissues or biopsy samples were available from 13 patients. Three of those patients were tested positive for KRAS codon 12 mutation (colorectal cancer in the 4 mg/day cohort; pancreatic cancer in the 10 mg/day cohort; colorectal cancer in the 13 mg/day cohort). No patients were tested positive for BRAF mutation.
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Anti-tumor activity Anti-tumor activities by the independent assessment are listed in Table 4. Partial response (PR) was confirmed in one patient with esophageal cancer with a maximum of over 57 % regression. Stable disease (SD) was observed in eight patients. Progression-free survival (PFS) was longer than 16 weeks in seven patients including a patient with pancreatic cancer with KRAS mutation.
Discussion This is the first study to evaluate the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors. The MTD for Japanese patients with advanced solid tumors was determined as 8 mg/day (4 mg BID) which had a manageable safety profile similar to that observed in European patients [11]. Major AEs associated with the study drug were skin and subcutaneous tissue disorders (97 %), CPK elevation (71 %), and eye disorders (61 %), particularly macular oedema and visual impairment. All of these AEs were observed in the European study, although the incidence of CPK elevation and eye-related AEs were higher than those in the European study. CPK elevation has recently recognized as one of the class effects with MEK inhibitors as reported in this study, MEK162 [13], BAY 86–9766 [14], and selumetinib [15], although it was not reported as a major AE in previous studies such as trametinib [16], selumetinib [17, 18], CI-1040 [19], BAY 86–9766 [20], and AZD8330 [21]. We assumed that most episodes of CPK elevation would be asymptomatic in those studies. Although the mechanism behind the observed CPK elevation remains unknown at present, it may be relevant to CPK elevation that the MAPK signaling pathway has been suggested to play a key role in regulation of muscle cell signaling [22–24]. Another report described that the plasma CPK elevation was associated with development of skin toxicity caused by novel anticancer agents based on the retrospective analysis of 295 patients in 25 phase 1 trials [25]. Ocular toxicity is a known class effect induced by MEK inhibitors. The mechanism of MEK inhibitor-induced visual toxicity remains unclear [26]. Analysis using animal models has suggested the possibility that MEK-induced oxidative stress in the retina leads to oedema, haemorrhage, and induction of a coagulation cascade producing retinal vein occlusion (RVO) [27]. In this study, the ophthalmological examination was performed at baseline, Cycle 2 Day 1, 28 days after the final administration, and as required in the treatment period. No grade 3 or higher RVO nor eye disorder was observed, and most ocular toxicities were recovered without treatment. These ocular toxicities are potentially reversible; nevertheless,
100
1 mg QD 2 mg QD 4 mg QD 4 mg BID 5 mg BID 6.5 mg BID
1
10
a
Plasma RO4987655 conc. (ng/mL)
Fig. 1 RO4987655 plasma concentration profile of a Cycle 0 Day 1 and b Cycle 1 Day 15 (mean±standard deviation)
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1000
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0
8
16
24
32
40
48
Time (h)
10
100
1 mg QD 2 mg QD 4 mg QD 4 mg BID 5 mg BID 6.5 mg BID
1
Plasma RO4987655 conc. (ng/mL)
1000
b
0
4
8
12
16
20
24
Time (h)
careful management of patients should be carried out in further clinical trials with MEK inhibitors. The pharmacokinetics of RO4987655 was linear and no unexpected accumulation of RO4987655 in plasma was observed. This favorable pharmacokinetics profile encourages further clinical investigation of RO4987655. According to our additional analysis, plasma exposure in this study tended
to be higher in patients who experienced CPK elevation and/ or ocular toxicities such as macular oedema and visual impairment (data not shown). In particular, occurrence of grade 3 CPK elevation during Cycle 1 were clearly associated with high plasma exposure (Supplementary Fig. 1). The MTD in this study was determined to be 8 mg/day (4 mg BID). On the other hand, the European study of
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Invest New Drugs (2015) 33:641–651 Summary of RO4987655 pharmacokinetic parameters AUClast (ng*h/mL)
Cmax (ng/mL)
Tmax (h)
AUCinf (ng*h/mL)
t1/2 (h)
CL/F (L/h)
Vz/F (mL)
n Mean SD n
3 282 87.0 3
3 72.1 39.1 3
3 0.833 0.289 3
3 321 102 3
3 21.0 2.49 3
3 3300 889 3
3 98000 19600 3
Mean SD n Mean SD n Mean SD n Mean SD n Mean SD n Mean SD n
607 104 4 1550 511 12 1260 369 3 1770 161 6 2490 414 3 351 41.2 3
116 30.2 4 372 166 12 233 132 3 352 31.2 6 458 134 3 85.7 30.4 3
1.33 0.577 4 1.25 0.492 12 1.92 1.08 3 1.33 0.577 6 1.50 0.551 3 0.833 0.289 3
673 125 4 1730 483 12 1410 366 3 1880 154 6 2710 414 3 511 97.1 3
18.1 1.93 4 21.1 5.92 12 19.2 4.60 3 14.9 1.52 6 17.4 1.68 3 18.2 3.58 3
3030 508 4 2460 717 12 3030 816 3 2670 224 6 2450 355 3 2010 394 3
78300 9140 4 77500 35100 12 85400 33800 3 57700 10800 6 62000 14600 3 51300 2560 3
Mean SD n Mean SD n Mean SD n Mean SD n Mean SD
724 178 3 1820 581 11 1460 374 3 1800 59.3 5 3020 540
140 25.9 3 346 105 11 282 99.5 3 400 39.5 5 616 145
1.15 0.747 3 1.31 0.530 11 1.47 0.534 3 1.19 0.756 5 1.60 0.555
870 186 3 2190 586 11 2030 493 3 2370 113 5 3570 564
11.2 1.55 3 11.9 2.70 11 6.48 1.89 3 6.08 0.576 5 4.32 0.390
2370 488 3 1900 441 11 2070 443 3 2110 104 5 1860 305
38800 12800 3 33400 13500 11 19200 6150 3 18500 1270 5 11600 2630
Dose (mg/day) Cycle 0 Day 1
1
2
4
8
10
13
Cycle 1 Day 15
1
2
4
8
10
13
AUClast Area under the concentration—time curve from 0 to the last measurable concentration, Cmax:Maximum plasma concentration, Tmax Time to reach maximum concentration, AUCinf Area under the concentration—time curve from 0 to infinity, t1/2 Half-life, CL/F Apparent clearance, Vz/F Apparent volume of distribution, SD standard deviation
RO4987655 determined the MTD as 17 mg/day (8.5 mg BID). In the European study, mean values of AUC0–12 on Cycle 1 Day 15 in the 8, 10, and 13 mg/day cohorts were respectively 1053, 1157, and 1458 ng*h/mL [11], whereas the comparable value in our study were respectively 1460, 1800, and 3020 ng*h/mL, indicating that AUC0–12 in our
study was 1.39–2.07 times higher than that in European study. We assumed that the higher exposure resulted in the difference in MTD. Since AUClast in patients with heavy body weight tended to be lower in our study, one possible reason explaining the difference in exposure was the difference in median body weight or median body surface area (BSA)
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60 20
40
1 mg QD 2 mg QD 4 mg QD 4 mg BID 5 mg BID 6.5 mg BID
IC50= 24.8 ng/mL I max= 95 (%)
-20
0
I nhibition of pERK (%)
80
100
Fig. 2 RO4987655 concentrations and corresponding inhibitory effects on pERK (simple Emax model)
0
200
400
600
Plasma RO4987655 conc. (ng/mL)
between this study and the dose-escalation part of the European study (59.30 vs. 77.20 kg for body weight, and 1.61 vs. 1.99 m2 for BSA, respectively). There was an approximately 20 % difference between the mean dose-normalized AUClast values in the steady state at the MTD of this study and that of the European study (365 ng*h/ mL/mg vs. 303 ng*h/mL/mg, respectively), and this was well corrected by further normalization using median body weight or median BSA (The AUClast normalized by dose and median body weight were 21,645 ng*h/mL/mg*kg and 23,405 ng*h/ mL/mg*kg in this study and the European study, respectively. The AUClast normalized by dose and median BSA was Table 4
588 ng*h/mL/mg*m2 and 603 ng*h/mL/mg*m2 in this study and the European study, respectively). Although these results suggest that dose adjustment by some kind of parameter such as body weight or BSA could lead to minimizing inter-patient variability in exposure to this agent, the necessity of dose adjustment (flat dosing vs. mg/kg or mg/m2) is generally decided based on each agent’s characteristics, including variability in its absorption and metabolism, convenience, and the therapeutic window. Meanwhile, metabolizing enzymes is unlikely to be involved the cause of difference in exposures because the t1/2 of steady state in BID cohorts was similar to European study [11].
Best overall response by cohort
Best overall response
1 mg/day (N=3)
2 mg/day (N=3)
4 mg/day (N=4)
8 mg/day (N=12)
10 mg/day (N=3)
13 mg/day (N=6)
Total (N=31)
CR PR SD PD NE PFS>16 weeks
0 0 1 2 0 1a
0 0 0 3 0 0
0 0 1 3 0 1b
0 0 3 7 2 2c
0 1 1 1 0 2d
0 0 2 3 1 1e
0 1 8 19 3 7
CR Complete response, PR Partial response, SD Stable disease, PD Progressive disease, NE Not evaluable, PFS Progression free survival a
114 days, sarcoma, KRAS / BRAF unknown
b
114 days, colorectal, KRAS / BRAF unknown
c
141 days, non-small cell lung cancer, KRAS / BRAF wild-type; 115 days, sarcoma, KRAS / BRAF unknown
d
224 days, esophageal, KRAS / BRAF wild-type; 122 days, pancreatic, KRAS mutant / BRAF wild-type
e
117 days, non-small cell lung cancer, KRAS / BRAF wild-type
650
We considered the MTD determined in this study was appropriate, comparing PK data such as AUC and Cmax in Japanese and European studies, although further analysis of population PK is necessary to investigate potential reasons for the difference in MTD, such as physical builds of the patients. RO4987655 showed encouraging anti-tumor activity, especially in esophageal cancer. PR was confirmed in one patient (10 mg/day cohort) with squamous cell esophageal cancer with no KRAS and BRAF mutations. The patient received 10 mg/day until the DLT was observed (grade 3 CPK elevation on Cycle 1 Day 26), and then interrupted drug administration for 18 days. The dose was reduced to 8 mg/day until cycle 6. It is the first case of esophageal patient responded to RO4987655, other than melanoma or NSCLC patients as observed in European study [12]. In addition, it was reported that gefitinib as a second-line treatment in esophageal cancer in unselected patients improved median progression-free survival, although it did not meet its primary endpoint of an overall survival benefit for gefitinib compared with placebo [28]. This observation suggested the involvement of EGFR-mediated signaling pathways in disease progression of esophageal cancer. The translational research to identify predictive biomarkers for gefitinib is underway [28]. In our study, no clear relationship was seen between response and mutational status, such as KRAS and BRAF because of the limited number of patients with mutation data. As PR was observed in an esophageal cancer patient with wild-type KRAS / BRAF, identification of biomarkers related to EGFR/MAPK pathway activation other than KRAS and BRAF will contribute to the treatment of esophageal cancer. Several MEK inhibitors are currently in clinical trials [8]. A recent phase III trial confirmed that trametinib improved progression-free and overall survival of patients with melanoma with BRAF V600 mutation as compared with chemotherapy [29]. In a phase I/II trial, dabrafenib (a B-Raf inhibitor) and trametinib were safely combined at full doses, and PFS of patients with melanoma with BRAF V600 mutations was significantly improved as compared with dabrafenib alone [30]. Furthermore, RO5126766, a dual Raf/MEK inhibitor, showed promising antitumor activity against melanoma [31, 32]. Because MEK inhibitors are expected to play a key role in future cancer treatment, further strategies to improve clinical outcomes are necessary, such as identification of biomarkers for response prediction, selection of suitable types of cancer, and combination with other molecularly targeted agents. In summary, MTD of RO4987655 for Japanese patients with advanced solid tumors was determined as 8 mg/day. RO4987655 was tolerated up to the MTD with a similar safety profile to the one observed in European patients. A favorable PK/PD profile was observed with once- or twice-daily administration. One esophageal patient with confirmed PR and seven patients with PFS of over 16 weeks were observed. These
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findings encourage the future clinical development of RO4987655. Acknowledgments The authors thank all the patients who participated in this study, their families, and staff at the National Cancer Center Hospital. This study was sponsored by Chugai Pharmaceutical Co., Ltd., Japan. Quality control of data, data analysis, and statistical analysis was performed at Chugai Pharmaceutical Co., Ltd. Writing assistance was funded by Chugai Pharmaceutical Co., Ltd. Conflicts of Interest Tomohide Tamura and Noboru Yamamoto have received honoraria and research funding from Chugai Pharmaceutical Co., Ltd. Hiroshi Nokihara has received research funding from Chugai Pharmaceutical Co., Ltd. Yasuhide Yamada, Hajime Asahina, and Naoya Yamazaki have received honoraria from Chugai Pharmaceutical Co., Ltd. Mieko Matsuoka and Yoshitaka Ogita are employees of Chugai Pharmaceutical Co., Ltd. All other authors declare that they have no conflicts of interest.
References 1. Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80:179–185 2. Fang JY, Richardson BC (2005) The MAPK signaling pathways and colorectal cancer. Lancet Oncol 6:322–327 3. Shigematsu H, Gazdar AF (2006) Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 118:257–262 4. Fecher LA, Amaravadi RK, Flaherty KT (2008) The MAPK pathway in melanoma. Curr Opin Oncol 20:183–189 5. Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O et al (1999) Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18: 813–822 6. Bos JL (1989) Ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689 7. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S et al (2002) Mutations of the BRAF gene in human cancer. Nature 417: 949–954 8. Akinleye A, Furqan M, Mukhi N, Ravella P, Liu D (2013) MEK and the inhibitors: from bench to bedside. J Hematol Oncol 6:27 9. Isshiki Y, Kohchi Y, Iikura H, Matsubara Y, Asoh K, Murata T et al (2011) Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent. Bioorg Med Chem Lett 21:1795–1801 10. Lee L, Niu H, Rueger R, Igawa Y, Deutsch J, Ishii N et al (2009) The safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of CH4987655 in healthy volunteers: target suppression using a biomarker. Clin Cancer Res 15:7368–7374 11. Leijen S, Middleton MR, Tresca P, Kraeber-Bodéré F, Dieras V, Scheulen ME et al (2012) Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. Clin Cancer Res 18:4794–4805 12. Zimmer L, Barlesi F, Martinez-Garcia M, Dieras V, Schellens JH, Spano JP et al (2014) Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with RAS-RAF mutations. Clin Cancer Res 20:4251–4261
Invest New Drugs (2015) 33:641–651 13. Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P et al (2013) MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a nonrandomised, open-label phase 2 study. Lancet Oncol 14:249–256 14. Doi T, Fuse N, Yoshino T, Shitara K, Bando H, Miyamoto H, et al (2013) A phase I study of MEK inhibitor BAY 86–9766 in Japanese patients with advanced or reflactory solid tumors [abstract]. Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; Abstract 27. 15. Carvajal RD, Sosman JA, Quevedo JF, Milhem MM, Joshua AM, Kudchadkar RR et al (2014) Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA 311:2397–2405 16. Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C et al (2012) Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol 13:773–781 17. Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, Molina JR et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol 26:2139–2146 18. Banerji U, Camidge DR, Verheul HM, Agarwal R, Sarker D, Kaye SB et al (2010) The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res 16:1613–1623 19. Lorusso PM, Adjei AA, Varterasian M, Gadgeel S, Reid J, Mitchell DYet al (2005) Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 23:5281–5293 20. Weekes CD, Von Hoff DD, Adjei AA, Leffingwell DP, Eckhardt SG, Gore L et al (2013) Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86–9766 in patients with advanced cancer. Clin Cancer Res 19:1232–1243 21. Cohen RB, Aamdal S, Nyakas M, Cavallin M, Green D, Learoyd M et al (2013) A phase I dose-finding, safety and tolerability study of AZD8330 in patients with advanced malignancies. Eur J Cancer 49: 1521–1529
651 22. Ciuffini L, Castellani L, Salvati E, Galletti S, Falcone G, Alemà S (2008) Delineating v-Src downstream effector pathways in transformed myoblasts. Oncogene 27:528–539 23. Garcia R, Grindlay J, Rath O, Fee F, Kolch W (2009) Regulation of human myoblast differentiation by PEBP4. EMBO Rep 10:278–284 24. Lawlor MA, Feng X, Everding DR, Sieger K, Stewart CE, Rotwein P (2000) Dual control of muscle cell survival by distinct growth factorregulated signaling pathways. Mol Cell Biol 20:3256–3265 25. Moreno Garcia V, Thavasu P, Blanco Codesido M, Molife LR, Vitfell Pedersen J, Puglisi M et al (2012) Association of creatine kinase and skin toxicity in phase I trials of anticancer agents. Br J Cancer 107: 1797–1800 26. Renouf DJ, Velazquez-Martin JP, Simpson R, Siu LL, Bedard PL (2012) Ocular toxicity of targeted therapies. J Clin Oncol 30:3277– 3286 27. Huang W, Yang AH, Matsumoto D, Collette W, Marroquin L, Ko M et al (2009) PD0325901, a mitogen-activated protein kinase kinase inhibitor, produces ocular toxicity in a rabbit animal model of retinal vein occlusion. J Ocul Pharmacol Ther 25:519–530 28. Dutton SJ, Ferry DR, Blazeby JM, Abbas H, Dahle-Smith A, Mansoor W et al (2014) Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol 15:894–904 29. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M et al (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367:107–114 30. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J et al (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367:1694–1703 31. Martinez-Garcia M, Banerji U, Albanell J, Bahleda R, Dolly S, Kraeber-Bodéré F et al (2012) First-in-human, phase I doseescalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res 18:4806–4819 32. Honda K, Yamamoto N, Nokihara H, Tamura Y, Asahina H, Yamada Y et al (2013) Phase I and pharmacokinetic/pharmacodynamic study of RO5126766, a first-in-class dual Raf/MEK inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 72:577–584
PHASE I STUDIES
Phase I and pharmacokinetics/pharmacodynamics study of the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors Shinji Nakamichi & Hiroshi Nokihara & Noboru Yamamoto & Yasuhide Yamada & Yutaka Fujiwara & Yosuke Tamura & Hiroshi Wakui & Kazunori Honda & Hidenori Mizugaki & Satoru Kitazono & Yuko Tanabe & Hajime Asahina & Naoya Yamazaki & Shigenobu Suzuki & Mieko Matsuoka & Yoshitaka Ogita & Tomohide Tamura
Received: 18 December 2014 / Accepted: 5 March 2015 / Published online: 27 March 2015 # Springer Science+Business Media New York 2015
Abstract RO4987655 is an oral and selective inhibitor of MEK, a key enzyme of the mitogen-activated protein kinase (MAPK) signaling pathway. This phase I dose-escalation study of RO4987655 in Japanese patients with advanced solid Clinical trial number: JapicCTI-111490 Electronic supplementary material The online version of this article (doi:10.1007/s10637-015-0229-3) contains supplementary material, which is available to authorized users. S. Nakamichi : H. Nokihara : N. Yamamoto : Y. Fujiwara : Y. Tamura : H. Wakui : K. Honda : H. Mizugaki : S. Kitazono : Y. Tanabe : H. Asahina : T. Tamura (*) Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan e-mail: [email protected] T. Tamura e-mail: [email protected] Y. Yamada Department of Gastrointestinal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan N. Yamazaki Department of Dermatological Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan S. Suzuki Department of Ophthalmic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan M. Matsuoka : Y. Ogita Clinical Research Planning Department, Chugai Pharmaceutical Co., Ltd., 2-1-1 Nihonbashi-muromachi, Chuo-ku, Tokyo, Japan Present Address: T. Tamura Thoracic Center, St. Luke’s International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, Japan
tumors aimed to determine maximum tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity. Patients received a single dose of RO4987655 (1, 2, 4, 5, or 6.5 mg) followed by continuous once-daily dosing (1, 2, or 4 mg QD) or twice-daily dosing (4, 5, or 6.5 mg BID) in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs). In dose-escalation, 25 patients were enrolled. After the MTD was determined, a further six patients were administered the MTD for further confirmation of safety. MTD was determined as 8 mg/day (4 mg BID) due to a total of four dose-limiting toxicities (DLTs) of grade 3 creatine phosphokinase (CPK) elevation (2 DLTs each in 10 mg/day and 13 mg/day). Most commonly related adverse events included dermatitis acneiform, CPK elevation, and eye disorders. Plasma concentration of RO4987655 appeared to increase in a dose-proportional manner with a plasma half-life of 4.32 to 21.1 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8. The inhibitory effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner. One esophageal cancer patient had confirmed partial response and seven patients showed progression-free survival for longer than 16 weeks. The MTD of RO4987655 for Japanese patients was determined as 8 mg/day (4 mg BID). RO4987655 was tolerated up to the MTD with a favorable PK/PD profile in Japanese patients with advanced solid tumors. Keywords Phase I study . Dose escalation . MAPK pathway . MEK inhibitor . Japanease
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Introduction The mitogen-activated protein kinase (MAPK) pathway, including the Ras/Raf/MEK/ERK signaling cascade, is one of the most important pathways involved in cellular proliferation and differentiation [1]. Carcinogenesis with dysregulation of the MAPK pathway has been reported in many previous studies [2–4], and constitutive activation of the MAPK pathway was reported in 36 % of various tumor cell lines, such as cell lines derived from tumors of the pancreas, colon, lung, ovary, and kidney [5]. Mutations of RAS proto-oncogenes (KRAS, HRAS, and NRAS) have been found in 50 % of colon cancers, 30 % of lung cancers, and 90 % of pancreas cancers [6], and BRAF mutations have been observed in 66 % of malignant melanomas [7]. The MAPK/ERK kinase (MEK) is the only known kinase capable of phosphorylating ERK1/2, and inhibition of MEK can potentially block the activation of downstream pathways. Therefore, several MEK inhibitors are currently under investigation [8]. RO4987655 (CH4987655), identified by Chugai Pharmaceutical Co., Ltd., is a highly specific allosteric oral MEK inhibitor that has shown anti-tumor activity in a series of human cancer xenograft models [9]. RO4987655 has a unique ring structure with high metabolic stability and slow dissociation from MEK [9], which may confer better clinical efficacy than other MEK inhibitors. In a first-in-human study of healthy volunteers, single doses of oral RO4987655 (0.5– 4 mg) were found to be safe and well tolerated [10]. A phase I dose-escalation study of RO4987655 has already been conducted in Europe [11, 12]; in that study, the maximum tolerated dose (MTD) of the study was determined as 17 mg/day (8.5 mg BID) with a favorable PK/PD profile in non-Japanese patients. The effect of ethnic factors on the tolerability and pharmacokinetics had not been elucidated. This study was conducted on Japanese patients with advanced solid tumors to evaluate adverse events (AEs) and to estimate the recommended treatment dose of RO4987655. Pharmacodynamics (PD) analysis and anti-tumor activity were also evaluated.
Materials and Methods Patients Patients with histologically or cytologically confirmed solid tumors that had progressed after standard therapies were eligible for this study. Other inclusion criteria included being 20 years old or older and having an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2, a life expectancy of 12 weeks or more, and adequate bone marrow, liver, renal, and heart function. Exclusion criteria included symptomatic brain metastasis, inflammation on the ocular surface,
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symptomatic gastrointestinal disorder, and breastfeeding or testing positive for pregnancy. Study design and treatment This was a phase I, open-label, single-center, dose-escalation study. The primary objectives of this study were to determine MTD based on dose-limiting toxicities (DLTs) and to evaluate safety and PK of RO4987655 in Japanese patients with advanced solid tumors. The secondary objectives were to evaluate PD and preliminary anti-tumor activity of RO4987655. This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guideline. Written informed consent was obtained from all patients before they entered the study. Patients were enrolled sequentially into escalating dosing cohorts using a standard 3+3 design. A starting dose of 1.0 mg/day was chosen based on data from a toxicity study in cynomolgus monkeys [9], clinical data from healthy volunteers [10], and patients with advanced solid tumors in the European study [11]. Patients received a single dose of RO4987655 (1, 2, 4, 5, or 6.5 mg; Cycle 0) to investigate PK/PD followed by continuous once-daily dosing (1, 2, or 4 mg QD) or twicedaily dosing (4, 5, or 6.5 mg BID; total daily dose: 8, 10, or 13 mg/day) in 28-day cycles. Drug interruption and/or dose reduction was not allowed during the first cycle unless DLT was observed. Administration was continued until unacceptable toxicity, disease progression, consent withdrawal, or any other criterion for discontinuation. Patients were fasted for 2 h pre-dose and 1 h post-dose for each administration. Safety evaluation Safety evaluation, including physical examinations, vital signs, ECOG PS, 12-lead electrocardiography, echocardiography, chest X-ray, hematologic, biochemical, and urinary laboratory evaluations, and ophthalmological examination, was performed at baseline and at specified time points throughout the study and 28 days after the final administration. Any AEs that occurred between the first single dose and 28 days after the last administration were reported. AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) ver. 3.0. All AEs in this report are Medical Dictionary for Regulatory Activities (MedDRA, ver.12.1) terms. A DLT was determined as a treatment-related AE occurring during the first cycle when the AE was either grade 3 or higher non-hematological toxicity (excluding transient electrolyte abnormalities and diarrhoea, nausea, vomiting, or skin toxicities that could be controlled by appropriate intervention), febrile neutropenia, grade 4 neutropenia continuing for 4 days or longer, grade 4 thrombocytopenia, or grade 3 thrombocytopenia requiring platelet transfusion. The MTD was determined to be the highest dose at which a DLT was seen in no more than one of six patients.
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Pharmacokinetics analysis
Results
Plasma samples for PK analysis were collected on chronologically as follows; (1) Cycle 0 Day 1: predose (0 h) and 0.5, 1, 2, 4, 8, 10 (only for 1, 2, and 4 mg QD), 12 (only for 4, 5, and 6.5 mg BID), 24, 34, 48 h postdose, (2) Cycle 1 Day 8: predose, (3) Cycle 1 Day 15: predose and 0.5, 1, 2, 4, 8, 10 (only for 1, 2, and 4 mg QD), 12 (only for 4, 5, and 6.5 mg BID), 24 (only for 1, 2, and 4 mg QD) hours postdose, and (4) Cycle 1 Day 22: predose. Plasma concentrations of RO4987655 were determined by validated liquid chromatography/tandem mass spectrometry as described in the European study [10, 11]. PK analysis was performed by a non-compartmental model using WinNonlin Ver. 5.3 (Pharsight Corporation, Cary, NC, USA).
Patient characteristics
Pharmacodynamics analysis Whole blood samples for PD analysis were collected on chronologically as follows; (1) Cycle 0 Day 1: predose and 1, 2, 4, 8, 10 (only for 1, 2, and 4 mg QD), 12 (only for 4, 5, and 6.5 mg BID), 24 h postdose, and (2) Cycle 1 Day 15: predose and 1, 2, 4, 8, 10 (only for 1, 2, and 4 mg QD), 12 (only for 4, 5, and 6.5 mg BID), 24 (only for 1, 2, and 4 mg QD) hours postdose. PD was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs) using validated FACS analysis as described in the European study [11] at the Kamakura Research Laboratories of Chugai Pharmaceutical, Co., Ltd., Japan. The PBMCs in each blood sample were isolated and activated by phorbol 12-myristate 13-acetate (PMA).
Tumor assessment Anti-tumor activity was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST, ver. 1.0) at baseline, and on Day 1 of Cycle 2, Cycle 3, and every other cycle thereafter. Assessment of anti-tumor activity and best overall response were reviewed by the independent committee specified by protocol.
Mutational analysis (optional) Either archival tumor tissues or biopsy samples were collected from some patients when their samples were available to analyze the mutational status of KRAS codon 12/ 13 and BRAF V600, which were assessed by the validated Scorpions-ARMS method at Mitsubishi Chemical Medience Corporation, Japan.
Thirty one patients were enrolled between November 2009 and January 2013. All patients received at least one dose of RO4987655, and all were eligible for safety/efficacy evaluation and for PK/PD analysis. Patient baseline characteristics are listed in Table 1. Safety and DLTs In dose-escalation, 25 patients were enrolled into six cohorts: 1 mg/day (n=3), 2 mg/day (n=3), 4 mg/day (n=4), 8 mg/day (n=6), 10 mg/day (n=3), and 13 mg/day (n=6). Of these, three patients withdrew during the first cycle due to disease progression. As a result of their withdrawal, 22 patients were eligible for evaluation of DLTs. The median duration of treatment for the 22 patients was 53.0 days (range: 25–237 days) with a median of 1.5 cycles (range: 1–8 cycles). Though the escalation was originally planned up to 17 mg/day i.e. the MTD in the European study [11], it was stopped due to two DLTs observed in the 13 mg/day cohort. Instead, a new cohort was given 10 mg/day. As two DLTs were reported in the 10 mg/day cohort, the 8 mg/day cohort additionally enrolled three new patients (six patients in total). All of the DLTs were grade 3 creatine phosphokinase (CPK) elevation. MTD was determined as 8 mg/day for this study as no DLTs were observed in that cohort. After the MTD was determined, six additional patients were enrolled and given the MTD to obtain additional safety data. All the patients experienced at least one AE. Most commonly occurring AEs included dermatitis acneiform, CPK elevation, and eye disorders (Table 2). Thirty patients (97 %) developed skin-related adverse events, including dermatitis acneiform (n=30), palmar–plantar erythrodysaesthesia syndrome (n=8), dry skin (n=7), skin fissures (n=2), and pruritus, photosensitivity reaction, and erythema multiforme (n=1 each). Six of 22 patients who experienced CPK elevation required drug interruption and/or dose reduction. CPK elevation was reversible with drug interruption and/or dose reduction. Out of five patients who experienced grade 3 CPK elevation, four patients developed grade 1/2 muscular weakness without clear rhabdomyolysis or cardiac disorders. Nineteen patients (61 %) experienced eye disorders, including macular oedema (n=12), visual impairment (n=10), eyelid oedema (n=3), vision blurred (n=3), and keratitis, corneal oedema, asthenopia, eye pain, eyelid ptosis, detachment of retinal pigment epithelium, and retinal exudates (n=1 each). All of the eye disorders were grade 1 except for one case of keratitis (grade 2). Most of the events resolved, but five patients (three cases of macular oedema, one case each of asthenopia and retinal exudates) remained unresolved at the final visit.
NSCLC Non-small cell lung cancer
NSCLC Pancreatic Other
[range] Height in cm, median [range] ECOG PS 0 1 Primary tumor Esophageal Colorectal Sarcoma
[44.0–61.1] 161.0 [157–163] 1 2 — 1 2 — — —
3 —
— — 2
— — 1
— 3 57.0 [28–67] 59.90
2 mg/day (N=3)
[59.5–61.8] 168.0 [159–171]
3 — 67.0 [61–72] 59.70
1 mg/day (N=3)
Patient characteristics at baseline
Sex Male Female Age in years, median [range] Weight in kg, median
Table 1
— — —
— 3 1
2 2
[46.6–69.9] 160.0 [147–173]
2 2 63.5 [46–71] 58.30
4 mg/day (N=4)
2 — —
7 1 2
5 7
[51.3–90.0] 166.0 [151–187]
9 3 60.5 [44–69] 56.25
8 mg/day (N=12)
— 1 —
1 1 —
1 2
[49.4–63.0] 155.0 [148–165]
2 1 67.0 [58–71] 50.30
10 mg/day (N=3)
2 1 1
— 2 —
3 3
[48.7–64.4] 162.0 [156–167]
4 2 63.5 [43–70] 61.20
13 mg/day (N=6)
7 (23 %) 4 (13 %) 2 (6 %) 2 (6 %)
8 (26 %) 8 (26 %)
15 (48 %) 16 (52 %)
[44.0–90.0] 163.0 [147–187]
20 (65 %) 11 (35 %) 62.0 [28–72] 59.30
Total (N=31)
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Invest New Drugs (2015) 33:641–651 Table 2
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Main adverse events (occurring in ≥10 % of patients) regardless of causality
Body system/Adverse event
All grades No. (%)
Grade 3 No. (%)
Laboratory abnormalities Blood creatine phosphokinase increased Aspartate aminotransferase increased Blood alkaline phosphatase increased Alanine aminotransferase increased Lymphocyte count decreased Haemoglobin decreased Gamma-glutamyltransferase increased Weight increased Blood glucose increased Platelet count decreased Blood urine present Skin and subcutaneous tissue disorders Dermatitis acneiform Palmar–plantar erythrodysaesthesia syndrome Dry skin Gastrointestinal disorders
30 (97) 22 (71) 20 (65) 13 (42) 10 (32) 9 (29) 7 (23) 6 (19) 6 (19) 5 (16) 3 (10) 3 (10) 30 (97) 30 (97) 8 (26) 7 (23) 23 (74)
9 (29) 5 (16) — — — 3 (10) 2 (6) — — — — — — — — — 1 (3)
Diarrhoea Stomatitis Nausea Constipation Vomiting Abdominal pain Metabolism and nutrition disorders Hypoalbuminaemia Decreased appetite Eye disorders Macular oedema Visual impairment Eyelid oedema Vision blurred General disorders and administration site conditions Oedema Face oedema Pyrexia Malaise
14 (45) 13 (42) 9 (29) 7 (23) 6 (19) 4 (13) 23 (74) 23 (74) 9 (29) 19 (61) 12 (39) 10 (32) 3 (10) 3 (10) 19 (61) 7 (23) 6 (19) 5 (16) 4 (13)
1 (3) — — — — — 1 (3) — — — — — — — — — — — —
Musculoskeletal and connective tissue disorders Muscular weakness Arthralgia Nervous system disorders Dizziness Vascular disorders Hypertension
10 (32) 4 (13) 3 (10) 8 (26) 3 (10) 3 (10) 3 (10)
— — — 1 (3) — 1 (3) 1 (3)
Thirteen incidents of treatment-related grade 3 AEs were observed in 10 patients: CPK elevation (n=5), lymphocyte count decreased (n=3), blood magnesium decreased, diarrhoea, hypertension, pulmonary haemorrhage, hyponatraemia
(n=1 each). No treatment-related grade 4 AEs were observed. A total of 11 incidents of treatment-related SAEs were reported in eight patients: one each of hypoalbuminaemia (8 mg/ day), pneumonia (8 mg/day), left ventricular dysfunction
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(8 mg/day), pulmonary haemorrhage (8 mg/day), and ileus (10 mg/day); and one case of CPK elevation and muscular weakness (10 mg/day), one case of gastrointestinal inflammation and muscular weakness (13 mg/day), and one case of CPK elevation and muscular weakness (13 mg/day). No AEs leading to death were observed except one patient died of disease progression. The primary reason for study withdrawal was disease progression (25/31, 81 %); in addition, one patient discontinued the study due to drug-related pulmonary haemorrhage (8 mg/ day) and one due to muscular weakness (13 mg/day). The primary tumor of the patient who discontinued the study due to pulmonary haemorrhage was esophageal, with lung and lymph node metastases. The patient had a history of haemoptysis and bloody sputum before study enrollment. No anti-coagulant agent was included in any concomitant treatment. The event was not associated with pneumonitis or chest infection. The event was treated with bronchial arterial embolization, and resolved without sequelae. Pharmacokinetics analysis Following the oral administration from 1 to 13 mg/day, RO4987655 was rapidly absorbed, with the time to maximum plasma concentration (Tmax) ranging from 0.833 to 1.92 h, and was eliminated from plasma with the apparent terminal halflife (t1/2) ranging from 4.32 to 21.1 h. Plasma exposure appeared to increase in a dose-proportional manner in the tested dose range (Fig. 1). RO4987655 pharmacokinetics parameters are summarized in Table 3. The observed mean accumulation index (AUCday 15/AUCday 1) was similar to the one estimated from the elimination rate constant after single dose administration (data not shown), suggesting no unexpected accumulation. After multiple dose administration, steady-state conditions were reached by Cycle 1 Day 8. Pharmacodynamics analysis The inhibitory effect of RO4987655 on pERK in PBMCs increased in a dose-dependent manner (data not shown). A simple Emax model was used to fit percentage pERK inhibition and corresponding RO4987655 concentrations (Fig. 2). In the final model, the IC50 and maximum drug effect (Imax) were estimated to be 24.8 ng/mL and 95 % respectively. Biomarkers Archival tumor tissues or biopsy samples were available from 13 patients. Three of those patients were tested positive for KRAS codon 12 mutation (colorectal cancer in the 4 mg/day cohort; pancreatic cancer in the 10 mg/day cohort; colorectal cancer in the 13 mg/day cohort). No patients were tested positive for BRAF mutation.
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Anti-tumor activity Anti-tumor activities by the independent assessment are listed in Table 4. Partial response (PR) was confirmed in one patient with esophageal cancer with a maximum of over 57 % regression. Stable disease (SD) was observed in eight patients. Progression-free survival (PFS) was longer than 16 weeks in seven patients including a patient with pancreatic cancer with KRAS mutation.
Discussion This is the first study to evaluate the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors. The MTD for Japanese patients with advanced solid tumors was determined as 8 mg/day (4 mg BID) which had a manageable safety profile similar to that observed in European patients [11]. Major AEs associated with the study drug were skin and subcutaneous tissue disorders (97 %), CPK elevation (71 %), and eye disorders (61 %), particularly macular oedema and visual impairment. All of these AEs were observed in the European study, although the incidence of CPK elevation and eye-related AEs were higher than those in the European study. CPK elevation has recently recognized as one of the class effects with MEK inhibitors as reported in this study, MEK162 [13], BAY 86–9766 [14], and selumetinib [15], although it was not reported as a major AE in previous studies such as trametinib [16], selumetinib [17, 18], CI-1040 [19], BAY 86–9766 [20], and AZD8330 [21]. We assumed that most episodes of CPK elevation would be asymptomatic in those studies. Although the mechanism behind the observed CPK elevation remains unknown at present, it may be relevant to CPK elevation that the MAPK signaling pathway has been suggested to play a key role in regulation of muscle cell signaling [22–24]. Another report described that the plasma CPK elevation was associated with development of skin toxicity caused by novel anticancer agents based on the retrospective analysis of 295 patients in 25 phase 1 trials [25]. Ocular toxicity is a known class effect induced by MEK inhibitors. The mechanism of MEK inhibitor-induced visual toxicity remains unclear [26]. Analysis using animal models has suggested the possibility that MEK-induced oxidative stress in the retina leads to oedema, haemorrhage, and induction of a coagulation cascade producing retinal vein occlusion (RVO) [27]. In this study, the ophthalmological examination was performed at baseline, Cycle 2 Day 1, 28 days after the final administration, and as required in the treatment period. No grade 3 or higher RVO nor eye disorder was observed, and most ocular toxicities were recovered without treatment. These ocular toxicities are potentially reversible; nevertheless,
100
1 mg QD 2 mg QD 4 mg QD 4 mg BID 5 mg BID 6.5 mg BID
1
10
a
Plasma RO4987655 conc. (ng/mL)
Fig. 1 RO4987655 plasma concentration profile of a Cycle 0 Day 1 and b Cycle 1 Day 15 (mean±standard deviation)
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1000
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0
8
16
24
32
40
48
Time (h)
10
100
1 mg QD 2 mg QD 4 mg QD 4 mg BID 5 mg BID 6.5 mg BID
1
Plasma RO4987655 conc. (ng/mL)
1000
b
0
4
8
12
16
20
24
Time (h)
careful management of patients should be carried out in further clinical trials with MEK inhibitors. The pharmacokinetics of RO4987655 was linear and no unexpected accumulation of RO4987655 in plasma was observed. This favorable pharmacokinetics profile encourages further clinical investigation of RO4987655. According to our additional analysis, plasma exposure in this study tended
to be higher in patients who experienced CPK elevation and/ or ocular toxicities such as macular oedema and visual impairment (data not shown). In particular, occurrence of grade 3 CPK elevation during Cycle 1 were clearly associated with high plasma exposure (Supplementary Fig. 1). The MTD in this study was determined to be 8 mg/day (4 mg BID). On the other hand, the European study of
648 Table 3
Invest New Drugs (2015) 33:641–651 Summary of RO4987655 pharmacokinetic parameters AUClast (ng*h/mL)
Cmax (ng/mL)
Tmax (h)
AUCinf (ng*h/mL)
t1/2 (h)
CL/F (L/h)
Vz/F (mL)
n Mean SD n
3 282 87.0 3
3 72.1 39.1 3
3 0.833 0.289 3
3 321 102 3
3 21.0 2.49 3
3 3300 889 3
3 98000 19600 3
Mean SD n Mean SD n Mean SD n Mean SD n Mean SD n Mean SD n
607 104 4 1550 511 12 1260 369 3 1770 161 6 2490 414 3 351 41.2 3
116 30.2 4 372 166 12 233 132 3 352 31.2 6 458 134 3 85.7 30.4 3
1.33 0.577 4 1.25 0.492 12 1.92 1.08 3 1.33 0.577 6 1.50 0.551 3 0.833 0.289 3
673 125 4 1730 483 12 1410 366 3 1880 154 6 2710 414 3 511 97.1 3
18.1 1.93 4 21.1 5.92 12 19.2 4.60 3 14.9 1.52 6 17.4 1.68 3 18.2 3.58 3
3030 508 4 2460 717 12 3030 816 3 2670 224 6 2450 355 3 2010 394 3
78300 9140 4 77500 35100 12 85400 33800 3 57700 10800 6 62000 14600 3 51300 2560 3
Mean SD n Mean SD n Mean SD n Mean SD n Mean SD
724 178 3 1820 581 11 1460 374 3 1800 59.3 5 3020 540
140 25.9 3 346 105 11 282 99.5 3 400 39.5 5 616 145
1.15 0.747 3 1.31 0.530 11 1.47 0.534 3 1.19 0.756 5 1.60 0.555
870 186 3 2190 586 11 2030 493 3 2370 113 5 3570 564
11.2 1.55 3 11.9 2.70 11 6.48 1.89 3 6.08 0.576 5 4.32 0.390
2370 488 3 1900 441 11 2070 443 3 2110 104 5 1860 305
38800 12800 3 33400 13500 11 19200 6150 3 18500 1270 5 11600 2630
Dose (mg/day) Cycle 0 Day 1
1
2
4
8
10
13
Cycle 1 Day 15
1
2
4
8
10
13
AUClast Area under the concentration—time curve from 0 to the last measurable concentration, Cmax:Maximum plasma concentration, Tmax Time to reach maximum concentration, AUCinf Area under the concentration—time curve from 0 to infinity, t1/2 Half-life, CL/F Apparent clearance, Vz/F Apparent volume of distribution, SD standard deviation
RO4987655 determined the MTD as 17 mg/day (8.5 mg BID). In the European study, mean values of AUC0–12 on Cycle 1 Day 15 in the 8, 10, and 13 mg/day cohorts were respectively 1053, 1157, and 1458 ng*h/mL [11], whereas the comparable value in our study were respectively 1460, 1800, and 3020 ng*h/mL, indicating that AUC0–12 in our
study was 1.39–2.07 times higher than that in European study. We assumed that the higher exposure resulted in the difference in MTD. Since AUClast in patients with heavy body weight tended to be lower in our study, one possible reason explaining the difference in exposure was the difference in median body weight or median body surface area (BSA)
Invest New Drugs (2015) 33:641–651
649
60 20
40
1 mg QD 2 mg QD 4 mg QD 4 mg BID 5 mg BID 6.5 mg BID
IC50= 24.8 ng/mL I max= 95 (%)
-20
0
I nhibition of pERK (%)
80
100
Fig. 2 RO4987655 concentrations and corresponding inhibitory effects on pERK (simple Emax model)
0
200
400
600
Plasma RO4987655 conc. (ng/mL)
between this study and the dose-escalation part of the European study (59.30 vs. 77.20 kg for body weight, and 1.61 vs. 1.99 m2 for BSA, respectively). There was an approximately 20 % difference between the mean dose-normalized AUClast values in the steady state at the MTD of this study and that of the European study (365 ng*h/ mL/mg vs. 303 ng*h/mL/mg, respectively), and this was well corrected by further normalization using median body weight or median BSA (The AUClast normalized by dose and median body weight were 21,645 ng*h/mL/mg*kg and 23,405 ng*h/ mL/mg*kg in this study and the European study, respectively. The AUClast normalized by dose and median BSA was Table 4
588 ng*h/mL/mg*m2 and 603 ng*h/mL/mg*m2 in this study and the European study, respectively). Although these results suggest that dose adjustment by some kind of parameter such as body weight or BSA could lead to minimizing inter-patient variability in exposure to this agent, the necessity of dose adjustment (flat dosing vs. mg/kg or mg/m2) is generally decided based on each agent’s characteristics, including variability in its absorption and metabolism, convenience, and the therapeutic window. Meanwhile, metabolizing enzymes is unlikely to be involved the cause of difference in exposures because the t1/2 of steady state in BID cohorts was similar to European study [11].
Best overall response by cohort
Best overall response
1 mg/day (N=3)
2 mg/day (N=3)
4 mg/day (N=4)
8 mg/day (N=12)
10 mg/day (N=3)
13 mg/day (N=6)
Total (N=31)
CR PR SD PD NE PFS>16 weeks
0 0 1 2 0 1a
0 0 0 3 0 0
0 0 1 3 0 1b
0 0 3 7 2 2c
0 1 1 1 0 2d
0 0 2 3 1 1e
0 1 8 19 3 7
CR Complete response, PR Partial response, SD Stable disease, PD Progressive disease, NE Not evaluable, PFS Progression free survival a
114 days, sarcoma, KRAS / BRAF unknown
b
114 days, colorectal, KRAS / BRAF unknown
c
141 days, non-small cell lung cancer, KRAS / BRAF wild-type; 115 days, sarcoma, KRAS / BRAF unknown
d
224 days, esophageal, KRAS / BRAF wild-type; 122 days, pancreatic, KRAS mutant / BRAF wild-type
e
117 days, non-small cell lung cancer, KRAS / BRAF wild-type
650
We considered the MTD determined in this study was appropriate, comparing PK data such as AUC and Cmax in Japanese and European studies, although further analysis of population PK is necessary to investigate potential reasons for the difference in MTD, such as physical builds of the patients. RO4987655 showed encouraging anti-tumor activity, especially in esophageal cancer. PR was confirmed in one patient (10 mg/day cohort) with squamous cell esophageal cancer with no KRAS and BRAF mutations. The patient received 10 mg/day until the DLT was observed (grade 3 CPK elevation on Cycle 1 Day 26), and then interrupted drug administration for 18 days. The dose was reduced to 8 mg/day until cycle 6. It is the first case of esophageal patient responded to RO4987655, other than melanoma or NSCLC patients as observed in European study [12]. In addition, it was reported that gefitinib as a second-line treatment in esophageal cancer in unselected patients improved median progression-free survival, although it did not meet its primary endpoint of an overall survival benefit for gefitinib compared with placebo [28]. This observation suggested the involvement of EGFR-mediated signaling pathways in disease progression of esophageal cancer. The translational research to identify predictive biomarkers for gefitinib is underway [28]. In our study, no clear relationship was seen between response and mutational status, such as KRAS and BRAF because of the limited number of patients with mutation data. As PR was observed in an esophageal cancer patient with wild-type KRAS / BRAF, identification of biomarkers related to EGFR/MAPK pathway activation other than KRAS and BRAF will contribute to the treatment of esophageal cancer. Several MEK inhibitors are currently in clinical trials [8]. A recent phase III trial confirmed that trametinib improved progression-free and overall survival of patients with melanoma with BRAF V600 mutation as compared with chemotherapy [29]. In a phase I/II trial, dabrafenib (a B-Raf inhibitor) and trametinib were safely combined at full doses, and PFS of patients with melanoma with BRAF V600 mutations was significantly improved as compared with dabrafenib alone [30]. Furthermore, RO5126766, a dual Raf/MEK inhibitor, showed promising antitumor activity against melanoma [31, 32]. Because MEK inhibitors are expected to play a key role in future cancer treatment, further strategies to improve clinical outcomes are necessary, such as identification of biomarkers for response prediction, selection of suitable types of cancer, and combination with other molecularly targeted agents. In summary, MTD of RO4987655 for Japanese patients with advanced solid tumors was determined as 8 mg/day. RO4987655 was tolerated up to the MTD with a similar safety profile to the one observed in European patients. A favorable PK/PD profile was observed with once- or twice-daily administration. One esophageal patient with confirmed PR and seven patients with PFS of over 16 weeks were observed. These
Invest New Drugs (2015) 33:641–651
findings encourage the future clinical development of RO4987655. Acknowledgments The authors thank all the patients who participated in this study, their families, and staff at the National Cancer Center Hospital. This study was sponsored by Chugai Pharmaceutical Co., Ltd., Japan. Quality control of data, data analysis, and statistical analysis was performed at Chugai Pharmaceutical Co., Ltd. Writing assistance was funded by Chugai Pharmaceutical Co., Ltd. Conflicts of Interest Tomohide Tamura and Noboru Yamamoto have received honoraria and research funding from Chugai Pharmaceutical Co., Ltd. Hiroshi Nokihara has received research funding from Chugai Pharmaceutical Co., Ltd. Yasuhide Yamada, Hajime Asahina, and Naoya Yamazaki have received honoraria from Chugai Pharmaceutical Co., Ltd. Mieko Matsuoka and Yoshitaka Ogita are employees of Chugai Pharmaceutical Co., Ltd. All other authors declare that they have no conflicts of interest.
References 1. Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80:179–185 2. Fang JY, Richardson BC (2005) The MAPK signaling pathways and colorectal cancer. Lancet Oncol 6:322–327 3. Shigematsu H, Gazdar AF (2006) Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 118:257–262 4. Fecher LA, Amaravadi RK, Flaherty KT (2008) The MAPK pathway in melanoma. Curr Opin Oncol 20:183–189 5. Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O et al (1999) Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18: 813–822 6. Bos JL (1989) Ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689 7. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S et al (2002) Mutations of the BRAF gene in human cancer. Nature 417: 949–954 8. Akinleye A, Furqan M, Mukhi N, Ravella P, Liu D (2013) MEK and the inhibitors: from bench to bedside. J Hematol Oncol 6:27 9. Isshiki Y, Kohchi Y, Iikura H, Matsubara Y, Asoh K, Murata T et al (2011) Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent. Bioorg Med Chem Lett 21:1795–1801 10. Lee L, Niu H, Rueger R, Igawa Y, Deutsch J, Ishii N et al (2009) The safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of CH4987655 in healthy volunteers: target suppression using a biomarker. Clin Cancer Res 15:7368–7374 11. Leijen S, Middleton MR, Tresca P, Kraeber-Bodéré F, Dieras V, Scheulen ME et al (2012) Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. Clin Cancer Res 18:4794–4805 12. Zimmer L, Barlesi F, Martinez-Garcia M, Dieras V, Schellens JH, Spano JP et al (2014) Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with RAS-RAF mutations. Clin Cancer Res 20:4251–4261
Invest New Drugs (2015) 33:641–651 13. Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P et al (2013) MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a nonrandomised, open-label phase 2 study. Lancet Oncol 14:249–256 14. Doi T, Fuse N, Yoshino T, Shitara K, Bando H, Miyamoto H, et al (2013) A phase I study of MEK inhibitor BAY 86–9766 in Japanese patients with advanced or reflactory solid tumors [abstract]. Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; Abstract 27. 15. Carvajal RD, Sosman JA, Quevedo JF, Milhem MM, Joshua AM, Kudchadkar RR et al (2014) Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA 311:2397–2405 16. Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C et al (2012) Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol 13:773–781 17. Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, Molina JR et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol 26:2139–2146 18. Banerji U, Camidge DR, Verheul HM, Agarwal R, Sarker D, Kaye SB et al (2010) The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res 16:1613–1623 19. Lorusso PM, Adjei AA, Varterasian M, Gadgeel S, Reid J, Mitchell DYet al (2005) Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 23:5281–5293 20. Weekes CD, Von Hoff DD, Adjei AA, Leffingwell DP, Eckhardt SG, Gore L et al (2013) Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86–9766 in patients with advanced cancer. Clin Cancer Res 19:1232–1243 21. Cohen RB, Aamdal S, Nyakas M, Cavallin M, Green D, Learoyd M et al (2013) A phase I dose-finding, safety and tolerability study of AZD8330 in patients with advanced malignancies. Eur J Cancer 49: 1521–1529
651 22. Ciuffini L, Castellani L, Salvati E, Galletti S, Falcone G, Alemà S (2008) Delineating v-Src downstream effector pathways in transformed myoblasts. Oncogene 27:528–539 23. Garcia R, Grindlay J, Rath O, Fee F, Kolch W (2009) Regulation of human myoblast differentiation by PEBP4. EMBO Rep 10:278–284 24. Lawlor MA, Feng X, Everding DR, Sieger K, Stewart CE, Rotwein P (2000) Dual control of muscle cell survival by distinct growth factorregulated signaling pathways. Mol Cell Biol 20:3256–3265 25. Moreno Garcia V, Thavasu P, Blanco Codesido M, Molife LR, Vitfell Pedersen J, Puglisi M et al (2012) Association of creatine kinase and skin toxicity in phase I trials of anticancer agents. Br J Cancer 107: 1797–1800 26. Renouf DJ, Velazquez-Martin JP, Simpson R, Siu LL, Bedard PL (2012) Ocular toxicity of targeted therapies. J Clin Oncol 30:3277– 3286 27. Huang W, Yang AH, Matsumoto D, Collette W, Marroquin L, Ko M et al (2009) PD0325901, a mitogen-activated protein kinase kinase inhibitor, produces ocular toxicity in a rabbit animal model of retinal vein occlusion. J Ocul Pharmacol Ther 25:519–530 28. Dutton SJ, Ferry DR, Blazeby JM, Abbas H, Dahle-Smith A, Mansoor W et al (2014) Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol 15:894–904 29. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M et al (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367:107–114 30. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J et al (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367:1694–1703 31. Martinez-Garcia M, Banerji U, Albanell J, Bahleda R, Dolly S, Kraeber-Bodéré F et al (2012) First-in-human, phase I doseescalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res 18:4806–4819 32. Honda K, Yamamoto N, Nokihara H, Tamura Y, Asahina H, Yamada Y et al (2013) Phase I and pharmacokinetic/pharmacodynamic study of RO5126766, a first-in-class dual Raf/MEK inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 72:577–584
