JJCO. Phase 1 study of ombrabulin in combination with cisplatin (CDDP) in Japanese patients with advanced solid tumors.

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1 JJCO Japanese Journal of Clinical Oncology Japanese Journal of Clinical Oncology, 2016, 46(11) doi: /jjco/hyw122 Advance Access Publication Date: 27 August 2016 Original Article Original Article Phase 1 study of ombrabulin in combination with cisplatin (CDDP) in Japanese patients with advanced solid tumors Shunji Takahashi 1, *, Kenji Nakano 1, Tomoya Yokota 2,4, Kohei Shitara 2,5, Kei Muro 2, Yoshinori Sunaga 3, Evelyne Ecstein-Fraisse 3, and Takashi Ura 2 1 Department of Medical Oncology, Cancer Chemotherapy Center and Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, 2 Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi, Japan, 3 Sanofi K.K., Tokyo, Japan, 4 Present address: Shizuoka Cancer Center, Japan, and 5 Present address: National Cancer Center Hospital East, Japan *For reprints and all correspondence: Shunji Takahashi, Department of Medical Oncology, Cancer Chemotherapy Center and Cancer Institute Hospital, Japanese Foundation for Cancer Research, Ariake, Koto-ku, Tokyo, Japan. s.takahashi-chemotherapy@jfcr.or.jp Received 12 June 2016; Accepted 6 August 2016 Abstract Objective: In clinical studies in Western countries, the recommended dose of combination ombrabulin a vascular disrupting agent, with cisplatin is 25 mg/m 2 ombrabulin with 75 mg/m 2 cisplatin every 3 weeks. Here, we report the first Phase 1 study of this treatment regimen in Japanese patients with advanced solid tumors. Methods: This was an open-label, multicenter, sequential cohort, dose-escalation Phase 1 study of ombrabulin with cisplatin administered once every 3 weeks. The study used a 3 + 3designwithout intrapatient dose escalation. The investigated dose levels of ombrabulin were 15.5 and 25 mg/m 2 combined with cisplatin 75 mg/m 2. The latter dose level was regarded as the maximum administered dose if more than one patient experienced dose-limiting toxicities. Results: Ten patients were treated, but no dose-limiting toxicity was observed at both dose levels. Ombrabulin 25 mg/m 2 with cisplatin 75 mg/m 2 was the maximum administered dose and regarded as the recommended dose in the combination regimen for Japanese patients with cancer. The most frequently reported drug-related adverse events were neutropenia, decreased appetite, constipation, nausea and fatigue. One partial response and five cases of stable disease were reported as the best overall responses. Pharmacokinetic parameters of ombrabulin and cisplatin were comparable with those in non-japanese patients. Conclusions: Ombrabulin 25 mg/m 2 with cisplatin 75 mg/m 2 once every 3 weeks was well tolerated and established as the recommended dose in Japanese patients with advanced solid tumors. The safety and pharmacokinetic profiles were comparable between Japanese and Caucasian patients. Key words: ombrabulin, cisplatin, Phase 1 trial, vascular disrupting agent, Japanese patients Introduction Ombrabulin (AVE8062 or AC7700), a tubulin-binding agent that targets the immature neovasculature of tumors (1,2), is an analog of combretastatin that depolymerizes microtubules, thereby disorganizing the cytoskeleton (3). After intravenous (IV) infusion, ombrabulin is rapidly converted to its active metabolite, RPR The Author Published by Oxford University Press. All rights reserved. For permissions, please journals.permissions@oup.com 1000

2 Jpn J Clin Oncol, 2016, Vol. 46, No Ombrabulin causes vascular blood flow shutdown by attacking endothelial cells within the tumor vasculature (4). Ombrabulin has been shown to have high antitumor efficacy in several animal models and exhibits significant synergy with other anticancer agents. The best synergistic effects associated with ombrabulin have been observed in animal studies when ombrabulin and cisplatin were administered concomitantly (5). In the clinical development of ombrabulin, three different schedules for monotherapy have been evaluated in Caucasian patients. A regimen involving intermittent IV infusion on Day 1 every 3 weeks is now recommended for ombrabulin, because this regimen has a better safety profile than that observed with any other regimen (6). Overall, 105 patients were treated in a monotherapy study at dose levels of up to 60 mg/m 2, and the maximum tolerated dose (MTD) was established at 50 mg/m 2. In studies in non-japanese individuals, combination therapy with ombrabulin and cisplatin has been assessed in 37 patients, and the recommended dose (RD) was determined to be 25 mg/m 2 ombrabulin and 75 mg/m 2 cisplatin (7). In previous studies, no dose-limiting toxicity (DLT) had been reported with 15.5 mg/m 2 ombrabulin monotherapy or with the same dose in combination regimens. In addition, this dose showed preliminary evidence of tumor blood flow shutdown in a clinical trial (8). Accordingly, in this study, we present the first Phase 1 trial to evaluate the combination of ombrabulin and cisplatin in Japanese patients. Our data provide important insights into the establishment of an appropriate dosing regimen for this combination therapy in Japanese patients with advanced solid tumors. Patients and methods Study design This was a multicenter, open-label, nonrandomized, sequential cohort, dose escalation and pharmacokinetics (PK) Phase 1 study of ombrabulin in combination with cisplatin administered sequentially in Japanese patients with advanced solid tumors. The primary objective of the study was to determine the MTD based on the incidence of DLTs and the maximum administered dose (MAD) of ombrabulin combined with cisplatin administered every 3 weeks in patients with advanced solid tumors. The secondary objectives were as follows: (i) to assess the overall safety profile of the combination therapy; (ii) to characterize the PK profile of ombrabulin, its active metabolite RPR and cisplatin in combination and (iii) to evaluate the antitumor activity of the combination therapy. The study protocol was evaluated and approved by the institutional review board of each site, and all patients provided written informed consent for participation prior to the initiation of any study procedures. The study was performed in accordance with the Declaration of Helsinki, the International Conference on Harmonisation guidelines on Good Clinical Practice, and applicable local regulatory requirements and laws. Patient population Patients were included in the study if they met all the following inclusion criteria: ages years; Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 1; the presence of an advanced solid tumor that had become refractory to conventional treatment or for which no standard therapy exists; having advanced solid tumors that were proven based on histology or cytology, indicated for cisplatin-based therapy; adequate hematologic, renal and hepatic function; and life expectancy of at least 12 weeks. Specific criteria for exclusion were symptomatic brain metastases and carcinomatous leptomeningitis; neuropathy and ototoxicity due to previous platinum-based chemotherapy; known platinum compound hypersensitivity, medical history of myocardial infarction, angina pectoris, arrhythmia especially severe conduction disorder, such as second- or third-degree atrioventricular block, stroke or history of arterial or venous thromboembolism within the past 6 months requiring anticoagulants; a baseline QTc interval of >0.45 sec or a family history of long QT syndrome; growing vessel disease (e.g. age-related macular degeneration, diabetic retinopathy, rheumatoid arthritis) or ongoing wound healing process; and hypertension, defined as systolic blood pressure of >140 mmhg or diastolic blood pressure of >90 mmhg. Dosing and administration In studies of non-japanese individuals, the RD for combination therapy with ombrabulin and cisplatin is 25 mg/m 2 ombrabulin and 75 mg/m 2 cisplatin (7). Based on the results from previous clinical trials, a tri-weekly intermittent schedule was selected in this study. Patients were treated by IV ombrabulin administration over 30 min, immediately followed by IV cisplatin (75 mg/m 2 ) administered over 2 h every 3 weeks. All patients were adequately treated with antiemetics and hydrated according to the standard cisplatin therapeutic protocol of the study site. Study treatment was continued until development of disease progression or unacceptable toxicity. Patient safety profiles and tolerability were individually assessed in Cycle 1. Dose escalation was decided based on results of the incidence of DLTs in Cycle 1. A cycle for a combined administration of ombrabulin and cisplatin was defined as a 21-day period. The presence and severity of DLTs were determined in Cycle 1. DLTs included any drug-related clinical adverse events (AEs) or laboratory abnormalities. Nonvascular hematologic DLTs were defined as follows: hematologic toxicity, including Grade 4 neutropenia lasting >5 days, Grade 4 thrombocytopenia and Grade 4 anemia; Grade 4 febrile neutropenia with fever of 38.0 C or more and Grade 3 febrile neutropenia with fever of 38.5 C or more; and calculated creatinine clearance of <40 ml/min; and any Grade 3 4 nonhematologic toxicity (other than nausea, vomiting, transaminases increase lasting <8 days and hypersensitivity). Vascular DLTs were defined as follows: documented angina pectoris and documented arterial thromboembolism; systolic blood pressure of 180 mmhg or higher and/or diastolic blood pressure of 120 mmhg or higher (for at least two successive measurements taken at a 30-min interval), acute impairment of the target organ (brain, heart and kidney), National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) hypotension of Grade 2 or higher or systolic blood pressure of <90 mmhg (for at least two successive measurements taken at a 30-min interval); troponin-i value above myocardial necrosis limits; ST- and T-wave changes suggesting ischemia; resting ejection fraction <50% with at least a 20% decline in the resting ejection fraction from baseline value; and other Grade 3 4 vascular events not listed (except some AEs at the tumor site, such as intratumor hemorrhage or tumor hemorrhagic necrosis, which are not life-threatening). The study was based on a standard escalation strategy using a design without intrapatient dose escalation. The planned dose levels of ombrabulin were 15.5 and 25 mg/m 2 combined with a fixed dose of 75 mg/m 2 cisplatin. Sequential cohorts of three or six Japanese patients with malignant solid tumors were treated with successively higher doses of ombrabulin. Initially, three patients were

3 1002 Phase 1 study of ombrabulin with CDDP enrolled at the dose level of 15.5 mg/m 2 ombrabulin combined with 75 mg/m 2 cisplatin (Level 1) and assessed for DLTs during Cycle 1. If none of the three patients experienced a drug-related DLT, the dose was escalated to Level 2a (ombrabulin 25 mg/m 2 combined with cisplatin 75 mg/m 2 ). However, if one patient out of the initial three patients experienced a DLT in the first cycle, then an additional three patients were to be enrolled to Level 1. If more than one patient experienced a DLT, this dose level was to be regarded as the MAD. If only one out of these six patients experienced a DLT, patient enrollment to Level 2a was to be started. Level 2a was evaluated in the same manner as Level 1. If more than one patient experienced a DLT at Level 2a, Level 2a was to be considered as the MAD and up to six additional patients were to be allocated to Level 2b (ombrabulin 20 mg/m 2 combined with cisplatin 75 mg/m 2 ). Even if up to one DLT (out of three or six patients) was observed at Level 2a (i.e. MAD not achieved), a higher dose was not to be evaluated, and Level 2a was to be presumed as the MTD. Safety, efficacy and PK assessments The safety population comprised all patients who had received at least one dose of study drug. The primary endpoint in this study was the incidence of drug-related DLTs during Cycle 1. The details of DLTs are described above. The safety profile was evaluated based on the incidence and severity (as graded by the NCI CTCAE v. 3.0) of AEs or laboratory abnormalities. Tumor response was assessed in patients with a measurable lesion at baseline according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria. The number of patients with tumor response was determined by pooling patients with complete response (CR) and partial response (PR). Tumor assessment of all target or nontarget lesions (measurable and nonmeasurable) and magnetic resonance imaging and/or computed tomography were performed within 28 days of the first administration of study drug. Tumor response assessments were repeated every second cycle until disease progression or treatment discontinuation. The main objectives of PK assessment were to determine the concentration of ombrabulin, its metabolite RPR and cisplatin (free and total) in plasma and to investigate the PK interactions between each of the analytes with cisplatin. Blood samples for pharmacokinetic analysis of ombrabulin and its metabolite RPR were obtained from all patients on Day 1 to Day 3 at Cycle 1 and Cycles 2 4. At Cycle 1, blood samples for ombrabulin and RPR were collected before infusion, immediately prior to the end of infusion, and 5, 10, 25, 45, 60 min, and 2, 4, 6, 10, 24 and 48 h post infusion. At Cycles 2 4, blood samples were collected immediately prior to the end of infusion and 10 min post infusion. Blood samples for pharmacokinetic analysis of cisplatin were obtained from all patients on Day 1 to Day 4 at Cycle 1. Blood samples for cisplatin were collected before infusion, immediately prior to the end of infusion, and 15, 30, 60 min, and 2, 4, 8, 22, 46 and 70 h post infusion. Plasma concentrations of ombrabulin and its active metabolite (RPR258063) were determined by validated liquid chromatography tandem mass spectrometry (LC MS-MS) methods, with a lower limit of quantitation (LLOQ) of 2 ng/ml. Plasma concentrations of total (plasma protein bound and unbound) and free (plasma protein unbound) cisplatin were determined by LC MS-MS with LLOQs of 100 and 1 ng/ml, respectively. The PK parameters were calculated by noncompartmental analysis with validated software (PKDMS version 2.1 with WinNonlin Professional, version 5.2.1; Pharsight, St. Louis, MO, USA), except for C max and t max, which were obtained directly from actual observations. Results This multicenter, open-label, nonrandomized, dose-escalation Phase 1 study was conducted from March 2010 to May 2011 at two institutions in Japan. A total of 10 patients were treated in the study, including 4 patients treated with 15.5 mg/m 2 ombrabulin plus 75 mg/m 2 cisplatin (Level 1) and 6 patients treated with 25 mg/m 2 ombrabulin plus 75 mg/m 2 cisplatin (Level 2a). None of the patients received the 20 mg/m 2 dose of ombrabulin (Level 2b). Demographics and other baseline characteristics Demographics and other baseline characteristics are summarized in Table 1. All 10 patients were Japanese and had a PS (ECOG) of 0 or 1 at baseline. The enrolled patients included five women and five men, with a median age of 49.5 years (range: years). Primary tumors were located in the breast (three patients, 30.0%), esophagus (two patients, 20.0%), parotid (two patients, 20.0%) and an unknown site (three patients, 30.0%). Histologically, the tumors were adenocarcinomas (four patients, 40.0% ), squamous cell carcinoma (two patients, 20.0%) or others (four patients, 40.0%). The median number of previous chemotherapy regimens, excluding neoadjuvant and adjuvant therapy, was 1.0 (range: 0 4). All patients had metastatic tumors, with most patients exhibiting involvement of at least two organs. Extent of exposure to study drugs When the next study drug administration was carried out >24 days after the previous administration, a cycle was regarded as delayed. Eight patients had delayed cycles due to AEs. One of these patients also had the dose of cisplatin reduced at Cycle 3 to 60 mg/m 2. Every patient was treated at a predetermined dose level of ombrabulin (Table 2). Three patients experienced the following AEs or post-treatment AEs that led to treatment discontinuation: Grade 2 fatigue at Cycle 4 in a patient treated with 25 mg/m 2 ombrabulin, Grade 2 cerebral infarction and Grade 2 renal infarction in a patient treated with 25 mg/m 2 ombrabulin and Grade 1 creatinine clearance decreased at Cycle 1 in a patient treated with 15.5 mg/m 2 ombrabulin. Safety evaluation All 10 patients were treated and were included in the treated/safety population. However, one patient was excluded from the DLT evaluable population, because the exact profile of neutropenia could not be measured due to premedication with granulocyte-colony stimulating factor. This patient was replaced with a different patient. The primary safety endpoint was the incidence of DLTs at Cycle 1; this endpoint was assessed in nine evaluable patients. Since no DLTs were reported at Cycle 1 in patients treated with 25 mg/m 2 ombrabulin combined with 75 mg/m 2 cisplatin (Level 2a), Level 2a was the MAD and regarded as the RD in the combination regimen for Japanese patients. All 10 patients experienced at least one AE that was considered related to study treatment (Table 3). Three patients at the 25 mg/m 2

4 Jpn J Clin Oncol, 2016, Vol. 46, No Table 1. Summary of demographics and other characteristics of patients at baseline Dose level (mg/m 2 ) All (N = 10) A15.5/C75 (N = 4) A25/C75 (N = 6) Sex [n (%)]: Male 1 (25.0) 4 (66.7) 5 (50.0) Race [n (%)]: Japanese 4 (100.0) 6 (100.0) 10 (100.0) Age (years) Mean ± SD 50.5 ± ± ± 11.6 Median (min, max) 52.0 (31, 67) 49.5 (39, 64) 49.5 (31, 67) Performance status (ECOG) [n (%)] 0 3 (75.0) 5 (83.3) 8 (80.0) 1 1 (25.0) 1 (16.7) 2 (20.0) Primary tumor site [n (%)] Breast 2 (50.0) 1 (16.7) 3 (30.0) Esophagus 1 (25.0) 1 (16.7) 2 (20.0) Parotid 0 2 (33.3) 2 (20.0) Unknown primary 1 (25.0) 2 (33.3) 3 (30.0) Histology type [n (%)] Adenocarcinoma 2 (50.0) 2 (33.3) 4 (40.0) Squamous cell carcinoma 1 (25.0) 1 (16.7) 2 (20.0) Others a 1 (25.0) 3 (50.0) 4 (40.0) No. of prior chemotherapy regimens b Median (min, max) 1.0 (1, 4) 0.5 (0, 4) 1.0 (0, 4) Extent of disease at baseline [n (%)] Metastatic 4 (100.0) 6 (100.0) 10 (100.0) Locally advanced No. of organs involved [n (%)] 1 1 (25.0) 2 (33.3) 3 (30.0) 2 2 (50.0) 3 (50.0) 5 (50.0) (25.0) 1 (16.7) 2 (20.0) A: Corresponds to AVE8062 (ombrabulin). C: Corresponds to cisplatin; SD, standard deviation; ECOG, Eastern Cooperative Oncology Group. Notes: Regardless of target or nontarget lesion, the organs subjected to baseline tumor evaluation were included in this summary. The bilateral organs were regarded as single organs in tumor evaluation, e.g. left and right lungs were counted only once. a Malignant fibrous histiocytoma, epithelial myoepithelial carcinoma, neuroendocrine carcinoma, malignant phyllodes tumor. b Excluding neoadjuvant and adjuvant therapy. Table 2. Extent of exposure to the study drugs Dose level (mg/m 2 ) A15.5/C75 (N = 4) A25/C75 (N = 6) Number of cycles administered 2.0 (1, 4) 4.0 (2, 6) [median (min, max)] Patients with 1 delayed cycle 3 (75.0%) 5 (83.3%) Patients with 1 dose reduction 0 1 (16.7%) Cumulative dose of ombrabulin ± ± (mg/m 2 ) [mean ± SD] Relative dose intensity of ombrabulin ± ± [mean ± SD] Reason for treatment discontinuation Adverse event(s) 1 (25.0%) 2 (33.3%) Disease progression 3 (75.0%) 3 (50.0%) Others 0 1 (16.7%) ombrabulin dose level and one patient at the 15.5 mg/m 2 ombrabulin dose level experienced AEs of Grades 3 or 4 that were assessed as being related to the study drug. There were no AEs leading to death or SAEs in this study. Two patients receiving 25 mg/m 2 ombrabulin experienced AEs that led to treatment discontinuation, and a third patient receiving 15.5 mg/m 2 ombrabulin had a posttreatment AE that also led to treatment discontinuation. The most frequently reported study drug related AEs at both ombrabulin dose levels were neutropenia, decreased appetite, constipation, nausea and fatigue (75.0% and 83.3% at the 15.5 and 25 mg/m 2 dose levels, respectively). Hiccups were frequently reported in patients receiving 25 mg/m 2 ombrabulin (83.3%). There were no Grade 3 or 4 AEs, except neutropenia. Four patients experienced study drug-related Grade 3 neutropenia, including three patients receiving 25 mg/m 2 ombrabulin and one patient receiving 15.5 mg/m 2 ombrabulin. A total of eight patients experienced AEs that led to a delayed cycle; specifically, eight patients experienced neutropenia, two patients experienced thrombocytopenia, one patient experienced fatigue and lung abscess and one patient experienced decreased creatinine renal clearance. There were no patients who experienced Grade 4 hematological abnormalities. Six patients (60.0%) experienced Grade 3 neutropenia (two patients receiving 15.5 mg/m 2 ombrabulin and four patients receiving 25 mg/m 2 ombrabulin), two patients (20.0%) experienced Grade 3 lymphopenia (one each receiving 15.5 or 25 mg/m 2 ombrabulin) and one patient (10.0%) experienced Grade 3 leukopenia (receiving 25 mg/m 2 ombrabulin). There were no patients who experienced Grade 3 or 4 liver, renal or metabolic function abnormalities. No cumulative or new toxicities were observed. Most of

5 1004 Phase 1 study of ombrabulin with CDDP the electrocardiograms, cardiovascular assessments, echocardiograms and chest X-rays were within the normal range. None of the abnormalities were considered medically important by principal investigators and medical experts. Efficacy evaluation The primary efficacy endpoint was the objective tumor response as defined by the RECIST and was measured in all 10 patients. Patients with objective response were defined by pooling patients who achieved CR or PR. The best overall responses are summarized in Table 4. One patient with neuroendocrine carcinoma achieved PR, and five patients achieved stable disease (SD). All five patients with SD had four cycles of study treatment and exhibited SD at Cycle 2. The patient with PR had six cycles of study treatment and exhibited PR at Cycle 2. PK evaluation Blood samples were collected from all 10 patients for PK evaluations of ombrabulin, RPR and total and free cisplatin within ±15% of the predefined sampling times. Semi-log time profiles of the mean plasma ombrabulin and RPR concentrations in Cycle 1 are presented in Fig. 1. Semi-log time profiles of the mean plasma total and free cisplatin concentrations in Cycle 1 are presented in Fig. 2. Descriptive statistics for ombrabulin and RPR PK parameters by dose level in Cycle 1 are presented in Table 5. When administered with 15.5 and 25 mg/m 2 ombrabulin, the terminal half-life of the active metabolite, RPR258063, was much longer than that of ombrabulin, with geometric mean value ranging from 5.10 to 6.57 h and from to h, respectively. In each cycle of study treatment, no significant changes in plasma concentrations of ombrabulin or RPR were observed. For a 1.61-fold increase in ombrabulin dose (30 min IV infusion) from 15.5 to 25 mg/m 2 in Cycle 1, ombrabulin (1.44-fold for AUC) and RPR (1.81-fold for AUC) exposure increased in a nearly dose-proportional manner. Table 3. Ombrabulin safety profile Preferred term, n (%) Dose level (mg/m 2 ) A15.5/C75 (N = 4) A25/C75 (N = 6) All grades Grade 3 or 4 All grades Grade 3 or 4 Any class 4 (100.0) 1 (25.0) 6 (100.0) 3 (50.0) Neutropenia 3 (75.0) 1 (25.0) 5 (83.3) 3 (50.0) Decreased appetite 3 (75.0) 0 5 (83.3) 0 Constipation 3 (75.0) 0 5 (83.3) 0 Nausea 3 (75.0) 0 5 (83.3) 0 Fatigue 3 (75.0) 0 5 (83.3) 0 Face edema 1 (25.0) 0 4 (66.7) 0 Hiccups (83.3) 0 Headache 2 (50.0) 0 2 (33.3) 0 Hypertension 2 (50.0) 0 2 (33.3) 0 Dysgeusia 1 (25.0) 0 3 (50.0) 0 Tumor pain 2 (50.0) 0 1 (16.7) 0 Edema peripheral (50.0) 0 Note: Most frequent treatment emergent adverse events reported in >2 patients are listed. Discussion In this study, we describe the first Phase 1 study of Japanese patients with advanced solid tumors treated with ombrabulin in combination Table 4. The best tumor response Best overall response [n (%)] Dose level (mg/m 2 ) A15.5/C75 (N = 4) A25/C75 (N = 6) All (N = 10) PR 0 1 (16.7) 1 (10.0) a SD 1 (25.0) 4 (66.7) 5 (50.0) b PD 2 (50.0) 1 (16.7) 3 (30.0) c Non-CR / Non-PD 1 (25.0) 0 1 (10.0) d PR, partial response; SD, stable disease; PD, progressive disease; CR, complete response. a Carcinoma of unknown primary (histology type: neuroendocrine carcinoma). b Carcinoma of the breast (two patients), parotid (two patients), and esophagus (one patient). c Carcinoma of the breast (one patient) and unknown origin (two patients). d Esophageal cancer; the patient had no measurable lesion at the baseline. (a) (b) 1000 Mean AVE8062 Concentration (ng/ml) mg/m 2 ombrabulin + 75 mg/m 2 cisplatin (n = 4) 25 mg/m 2 ombrabulin + 75 mg/m 2 cisplatin (n = 6) LLOQ = 2 (ng/ml) Mean RPR Concentration (ng/ml) mg/m 2 ombrabulin + 75 mg/m 2 cisplatin (n = 4) 25 mg/m 2 ombrabulin + 75 mg/m 2 cisplatin (n = 6) LLOQ = 2 (ng/ml) Nominal Time (h) Nominal Time (h) Figure 1. Mean plasma ombrabulin (a) and RPR (b) concentrations in Cycle 1.

6 Jpn J Clin Oncol, 2016, Vol. 46, No (a) mg/m 2 ombrabulin + 75 mg/m 2 cisplatin (n = 4) 25 mg/m 2 ombrabulin + 75 mg/m 2 cisplatin (n = 6) LLOQ = 100 (ng/ml) (b) Mean Total Cisplatin Concentration (ng/ml) Mean Free Cisplatin Concentration (ng/ml) mg/m 2 ombrabulin + 75 mg/m 2 cisplatin (n = 4) 25 mg/m 2 ombrabulin + 75 mg/m 2 cisplatin (n = 6) LLOQ = 1 (ng/ml) Nominal Time (h) Nominal Time (h) Figure 2. Mean plasma total cisplatin (a) and free cisplatin (b) concentrations in Cycle 1. Table 5. Mean ± SD (geometric mean) [percentage of coefficient of variation] of ombrabulin and RPR PK parameters in Cycle 1 PK parameter Dose level (mg/m 2 ) A15.5/C75 (N = 4) A25/C75 (N = 6) Ombrabulin RPR Ombrabulin RPR C max (ng/ml) 685 ± ± ± ± 25.0 (684) [6.2] (100) [8.8] (952) [38.2] (182) [13.6] Metabolic ratio a (C max ) ± ± (0.147) [8.10] (0.191) [26.5] AUC (ng h/ml) 304 ± ± ± ± 131 (303) [10.3] (233) [18.9] (438) [41.4] (423) [29.8] Metabolic ratio a (AUC) ± ± (0.769) [14.6] (0.964) [28.8] t 1/2z (h) ± ± ± ± 2.94 (0.197) [9.0] (5.10) [65.8] (0.211) [40.5] (6.57) [41.2] CL (ml/h) ± ± (67800) [16.2] (85900) [36.8] V ss (ml) ± ± (21800) [18.3] (51700) [136.4] a Metabolic ratio = C max (or AUC) of RPR / C max (or AUC) of ombrabulin. AUC, area under the curve; CL, clearance. with cisplatin. The objectives of the study were to assess the safety, PK parameters and tumor response of a combination of ombrabulin given at two dose levels (15.5 and 25 mg/m 2 )withcisplatin75mg/m 2.The MAD has already been determined as 25 mg/m 2 ombrabulin and 75 mg/m 2 cisplatin in Caucasians, and this combination regimen was recommended as the RD. Our results showed that this same regimen was the MAD in Japanese patients, and no DLTs were reported in Cycle 1. The protocol specified that no higher dose levels were to be investigated when Level 2a was tolerable in Japanese patients; therefore, the study was completed at the end of Level 2a. Thus, our data suggested that the RD for Japanese patients was Level 2a, the same as that for Caucasians. No AEs leading to death, SAEs or Grade 3 or 4 AEs were reported, except for Grade 3 neutropenia experienced by four patients. The most frequently observed AEs were nausea, neutropenia, decreased appetite, constipation, fatigue, hiccups, face edema, dysgeusia, hypertension and headache. In a study of ombrabulin monotherapy conducted in Western countries, the most common drug-related AEs at the RD of 50 mg/m 2 were headache (31%), asthenia (28%), abdominal pain (26%), nausea (26%), diarrhea (23%) and hypertension (23%); these were mainly mild to moderate (9). In a previous Japanese Phase 1 study of ombrabulin monotherapy (10), no DLTs were observed up to 35 mg/m 2. Only one of six patients treated at 50 mg/m 2 experienced DLTs, including transient Grade 2 hypertension and Grade 3 diarrhea. The safety profiles of the combination regimen in this study were similar to those in previous monotherapy studies with higher doses of ombrabulin; no unknown AEs were observed at 25 mg/m 2 ombrabulin combined with 75 mg/m 2 cisplatin (Level 2a) in this study. Additionally, the safety profile observed in this study was comparable with that in a Phase 3 trial conducted mainly in the USA and Europe in patients with advanced soft-tissue sarcomas (11), except for a slightly higher incidence of Grade 3 4 neutropenia in Japanese patients. In this Phase 3 study, in which cisplatin was used as a standard medicine to compare ombrabulin and placebo, neutropenia and thrombocytopenia were observed more frequently with ombrabulin plus cisplatin than with placebo plus cisplatin. However, these are known AEs for ombrabulin, and no clear ethnic

7 1006 Phase 1 study of ombrabulin with CDDP differences were noted in the safety of ombrabulin between Japanese and non-japanese patients. Tumor response was assessed according to RECIST 1.1. One patient with neuroendocrine carcinoma of unknown primary origin (10.0%) showed PR, whereas five patients (50.0%) showed SD, including four of six patients at the 25 mg/m 2 ombrabulin dose level (with parotid cancer, esophageal cancer and sarcoma) and one of four patients at the 15.5 mg/m 2 ombrabulin dose level (with breast cancer). In a previous Phase 1 study in Caucasians (9), a significant increase in circulating endothelial cells (CECs), a potential predictive/prognostic biomarker for anti-angiogenic treatment efficacy (12,13) and quantitative pharmacodynamic biomarker of vascular disrupting agent (VDA) bioactivity (14), was reported in 11 of 15 patients treated with 50 mg/m 2 ombrabulin, potentially reflecting maximal acute vascular damage, and 1 patient showed PR. In addition, Soria et al. conducted a study combining cisplatin with ombrabulin and found that VDA treatment led to a burst in CECs followed by acute mobilization of circulating endothelial progenitor cells, providing a mechanistic rationale for combining VDA with other anticancer agents (7). The terminal half-life of the active metabolite RPR was ~6 h, which is much longer than that of ombrabulin (~12 min [0.2 h]). The ombrabulin volume of distribution at steady state in patients treated at the 25 mg/m 2 dose level was ~86 l (geometric mean: ~52 l), suggesting that ombrabulin may penetrate both intercellularly and intracellularly. When administered in combination with cisplatin, ombrabulin exposure was comparable with that observed in ombrabulin monotherapy in Japanese patients with advanced solid tumors (10). In addition, pharmacokinetic parameters for total and free cisplatin appeared to be comparable with those previously reported in Japanese patients (15,16). Therefore, it is unlikely that drug drug interactions exist between ombrabulin and cisplatin. Based on the results of previous Phase 1 studies with ombrabulin, exposure to ombrabulin plus cisplatin in Caucasian patients (7,17,18) was comparable with that observed with ombrabulin monotherapy in Japanese patients (10). Similarly, the results of ombrabulin plus cisplatin exposure in Japanese patients were comparable with the results of ombrabulin monotherapy in Japanese patients. In conclusion, ombrabulin in combination with cisplatin in Japanese patients was well tolerated, which was consistent with the results of prior clinical studies in non-japanese and Japanese patients. The RD for Japanese patients was defined as 25 mg/m 2 ombrabulin combined with 75 mg/m 2 cisplatin, identical to that observed in Caucasian patients. Notably, the sponsor of this study has recently announced the discontinuation of the development program of ombrabulin worldwide. The basis of this decision was the result of a pivotal Phase 3 study in soft-tissue sarcoma that did not demonstrate sufficient clinical benefit despite reaching its primary endpoint of progression-free survival. Therefore, all clinical studies conducted in Japan have also been permanently terminated. Clinical trial registration ID ClinicalTrials.gov number, NCT Acknowledegments We thank the study coordinators, nurses and patients involved in the study; Hironobu Minami of Kobe University Hospital and Takao Kato of International University of Health and Welfare, Mita Hospital (previously Nippon Medical School) for providing medical advice; Tetsu Shinkai of Shonan-East General Hospital (previously Shikoku Cancer Center) and Noriyuki Masuda of Kitasato University School of Medicine for participating as members of the study s Efficacy and Safety Evaluation Committee; and Media Research, Inc., for writing assistance. Funding This study was supported by Sanofi K. K. 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