A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors

All subjects provided informed consent, and the study was conducted in accordance with both the Declaration of Helsinki and Good Clinical Practices (GCP), including the archiving of essential documents. The study was approved by the institutional review board of study site, and this study was registered at ClinicalTrials.gov as NCT01943292. The main eligibility criteria were as follows: Japanese patient with histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumor malignancies that had experienced disease progression on, were intolerant of, or not eligible for standard therapy; aged 20 years or older; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and adequate hematologic, hepatic, and renal functions. Key exclusion criteria included cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy, biologic, or immunotherapy, etc.) within 28 days of the first dose of study drug or 5 half-lives, whichever was shorter, a gastrointestinal condition which could have interfered with the swallowing or absorption of study medication, corrected QT interval (QT_c) ≥470 ms (as calculated by the Fridericia correction formula), uncontrolled or severe concurrent medical condition (including uncontrolled brain metastases), and uncontrolled or severe cardiovascular disease. Potent CYP3A4 inhibitors or inducers and systemic anticoagulation were prohibited.

This was a phase 1, open-label, dose-escalation study to evaluate the safety and PK of VS-6063, a FAK inhibitor in Japanese subjects with advanced solid tumor malignancies. This study was expected to enroll up to 18 evaluable subjects with non-hematologic malignancies if 6 subjects were assigned at each of the 3 planned dose levels of 200, 400, and 600 mg BID. VS-6063 was administered orally, BID, in continuous 21 day cycles. Subject enrollment proceeded according to a standard 3 + 3 design. In the absence of DLT, each subject received oral VS-6063 (BID) for a minimum of 21 days of continuous daily dosing (1 cycle) and could continue to receive additional cycles of study treatment until disease progression was documented or other treatment discontinuation criteria were met. All patients within a cohort were required to complete 1 cycle (21 days) of dosing with <1 of 3 or <2 of 6 subjects experiencing a DLT prior to escalation to the next dose level in a new cohort. Three subjects were to be treated at each dose level until the first instance of DLT, after which up to 6 subjects were to be treated at that dose level. If a second DLT was observed in up to 6 subjects, the DLT dose level was reached. DLTs included Grade 4 neutropenia lasting ≥7 days without growth factor support; Grade ≥3 febrile neutropenia; Grade 4 thrombocytopenia, Grade 3 or 4 nonhematologic toxicities (excluding nausea, vomiting, or diarrhea unless uncontrolled with supportive care), Grade ≥3 QT_c interval prolongation, or any treatment-related toxicities that resulted in failure to receive at least approximately 85 % of the planned doses for that cycle (e.g., failure to complete at least 18 days of treatment in a continuous 21-day regimen) despite maximal (as judged by the investigator) supportive care measures. The MTD was defined as the highest dose level studied at which <1 subject out of 3 or <2 subjects out of 6 experienced a DLT. The RP2D was to be determined in discussion among the sponsor, medical monitor, and investigators. Observations related to PK and any VS-6063-related toxicities were included in the rationale supporting the RP2D. Safety and tolerability was assessed by the incidence and severity of AEs as determined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v4.03). The antitumor activity of study treatment was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).

A total of 9 subjects received VS-6063 between September 2013 and June 2014. All were Asian (of Japanese descent). The study population was predominantly male (77 %), with an ECOG performance status of 0 or 1 (100 %). The most common cancer type was rectal cancer (3 patients). Other cancer types, including esophageal, lung, mesothelioma, Paget’s carcinoma, colon, and thymic cancer, were each reported in 1 subject. Eight subjects overall had received prior systemic therapy for their cancer, with a median of 7 prior therapies across dose cohorts. Six subjects, 2 in each dose cohort, had prior surgery. Only 1 subject, in the 200 mg cohort, had received prior radiation therapy (Table 1).

Treatment-related adverse events (AEs) occurring in at least two subjects are summarized in Table 2. The most commonly reported AEs overall were unconjugated hyperbilirubinemia (7 patients, 78 %), fatigue (6 patients, 67 %), decreased appetite (4 patients, 44 %), and diarrhea (3 patients, 33 %). Only one patient in the 200 mg dose cohort experienced a Grade 3 AE of unconjugated hyperbilirubinemia. All other toxicities were manageable and were predominantly mild in intensity (Grade 1 or Grade 2) in severity. There were no AEs leading to death or SAEs, and no AEs leading to early study withdrawal. No DLTs were reported in any dose cohort. Hyperbilirubinemia was asymptomatic and its onset typically occurred within the first 2 weeks of initiating treatment. Patients with Grade 1 or 2 unconjugated hyperbilirubinemia were able to continue dosing, although bilirubin levels tended to fluctuate during treatment. Hyperbilirubinemia was reported across all dose cohorts, for 3 (100 %) patients in the 200 mg dose cohort, 2 (67 %) patients in the 400 mg dose cohort, and 2 (67 %) patients in the 600 mg dose cohort. One event of hyperbilirubinemia (200 mg cohort) was Grade 3 in severity. This patient had Grade 1–2 hyperbilirubinemia starting on Day 7; the Grade 3 event began on Day 42 and resolved 6 days after onset following interruption of study drug. All reports of hyperbilirubinemia were considered to be related to defactinib. None of these subjects had concurrent increases in ALT or AST above ULN. The most common events of gastrointestinal disorders were diarrhea reported in 3 (33 %) subjects and nausea reported in 2 (22 %). Diarrhea was reported in 1 (33 %) subject in the 400 mg dose cohort and 2 (67 %) subjects in the 600 mg dose cohort. Nausea was reported in 1 (33 %) subject in the 200 mg dose cohort, and 1 (33 %) subject in the 600 mg dose cohort. Both reports of nausea were mild in severity as were 2 of the 3 reports of diarrhea; 1 subject in the 600 mg group experienced diarrhea of moderate intensity. No clinically meaningful changes in any ECG parameter were observed for any dose cohort and no subject had a QT_c interval ≥500 ms or QT_c increase from baseline >30 ms.

VS-6063 was rapidly absorbed, with median T _max observed at 2.0 h (range 0.5–4.0 h) postdose following oral doses of 200–600 mg BID. Plasma VS-6063 exposure (C _max and AUC) increased in a less than dose proportional manner and the mean AUC0-12 and AUC0-24 values remained relatively consistent across the full dose range evaluated (Fig. 1). Doses above 400 mg BID did not result in a significant increase in VS-6063 exposure. A similar C _max was observed in the 400 and 600 mg BID dose cohorts on both Days 1 and 15 and mean AUC values were relatively consistent across the 200–600 mg BID dose range. Clearance appeared to be increased with dose on both Days 1 and 15, which is consistent with the less than dose proportional increase in exposure. Median half-life values ranged from 2.3 to 4.3 h across all dose regimens and both PK study days. The Day 1 mean CL/F values were 45.6, 105, and 204 L/h for the 200, 400, and 600 mg doses, respectively. The Day 15 mean CL/F values were 32. 1, 70, and 123 L/h for the 200, 400, and 600 mg doses, respectively (Table 3). VS-6063 was detected in the urine of all patients and appeared consistent across all dose cohorts. The mean renal clearance (CLr) values ranged from 0.0855 to 0.179 L/h, and the percent relative to the total dose administered ranged from 0.0439 to 0.356 %. All 9 subjects had systemic concentrations of the 4 metabolites of VS-6063 that were evaluated (M2, M3, M4, and M5). Median plasma T _max values for all metabolites were observed at 2.0–4.0 h postdose administration for all cohorts on both PK sampling days. Based on the relative plasma C _max and AUC0-12 values for the metabolites compared to VS-6063 values, M2 was the most abundant metabolite, followed by M4, M3, and then M5. Both the M2 and M4 exposures appeared to be >10 % of the parent exposure, while M3 and M5 had exposures that were <10 % of the parent exposure. In the urine, the M2 metabolite was the most abundant and was excreted in amounts greater than the parent compound.

The best response overall was stable disease for 3 (33 %) out of 9 subjects, 1 subject in each dose cohort. Remarkably, durable stable diseases by RECIST criteria were maintained for 169 days (24 weeks) in a subject with mesothelioma in the 400 mg cohort, and for 162 days (23 weeks) in a subject with rectal cancer in the 600 mg dose cohort. The overall median time to disease progression for all subjects was 63 days (9 weeks) and ranged from 61 to 64 days across dose cohorts.