A State-of-the-Art Roadmap for Biomarker-Driven Drug Development in the Era of Personalized Therapies.

Advances in biotechnology have enabled us to assay human tissue and cells to a depth and resolution that was never possible before, redefining what we know as the "biomarker", and how we define a "disease". This comes along with the shift of focus from a "one-drug-fits-all" to a "personalized approach", placing the drug development industry in a highly dynamic landscape, having to navigate such disruptive trends. In response to this, innovative clinical trial designs have been key in realizing biomarker-driven drug development. Regulatory approvals of cancer genome sequencing panels and associated targeted therapies has brought personalized medicines to the clinic. Increasing availability of sophisticated biotechnologies such as next-generation sequencing (NGS) has also led to a massive outflux of real-world genomic data. This review summarizes the current state of biomarker-driven drug development and highlights examples showing the utility and importance of the application of real-world data in the process. We also propose that all stakeholders in drug development should (1) be conscious of and efficiently utilize real-world evidence and (2) re-vamp the way the industry approaches drug development in this era of personalized medicines.

First-in-Human Phase I Study of Aprutumab Ixadotin, a Fibroblast Growth Factor Receptor 2 Antibody-Drug Conjugate (BAY 1187982) in Patients with Advanced Cancer.

BACKGROUND: Fibroblast growth factor receptor (FGFR) 2 is overexpressed in several tumor types, including triple-negative breast cancer and gastric cancer, both of which have a high unmet medical need. Aprutumab ixadotin (BAY 1187982) is the first antibody-drug conjugate (ADC) to target FGFR2 and the first to use a novel auristatin-based payload. OBJECTIVE: This first-in-human trial was conducted to determine the safety, tolerability, and maximum tolerated dose (MTD) of aprutumab ixadotin in patients with advanced solid tumors from cancer indications known to be FGFR2-positive. PATIENTS AND METHODS: In this open-label, multicenter, phase I dose-escalation trial (NCT02368951), patients with advanced solid tumors received escalating doses of aprutumab ixadotin (starting at 0.1 mg/kg body weight), administered intravenously on day 1 of every 21-day cycle. Primary endpoints included safety, tolerability, and the MTD of aprutumab ixadotin; secondary endpoints were pharmacokinetic evaluation and tumor response to aprutumab ixadotin. RESULTS: Twenty patients received aprutumab ixadotin across five cohorts, at doses of 0.1-1.3 mg/kg. The most common grade ≥ 3 drug-related adverse events were anemia, aspartate aminotransferase increase, proteinuria, and thrombocytopenia. Dose-limiting toxicities were thrombocytopenia, proteinuria, and corneal epithelial microcysts, and were only seen in the two highest dosing cohorts. The MTD was determined to be 0.2 mg/kg due to lack of quantitative data following discontinuations at 0.4 and 0.8 mg/kg doses. One patient had stable disease; no responses were reported. CONCLUSIONS: Aprutumab ixadotin was poorly tolerated, with an MTD found to be below the therapeutic threshold estimated preclinically; therefore, the trial was terminated early. CLINICALTRIALS. GOV IDENTIFIER: NCT02368951.

[A Case of Laparoscopic Gastric Local Resection for Dedifferentiated Gastric Liposarcoma].

A 73 year-old-woman visited our emergency department with a sudden stomach ache. A 7 cm tumor was found on the greater curvature side of the stomach by contrast-enhanced CT, and showed mosaic pattern when visualized with a contrast agent. An esophagogastroduodenoscopy showed normal mucosal gastric surface with compression findings by the gastric submucosal tumor, and therefore she was admitted to our department for surgery. Abdominal ultrasound revealed an uneven gastric submucosal tumor containing cystic components with a clear border, and gastric GIST was suspected due to its appearance, and therefore, laparoscopic gastric local resection was performed. The gastric tumor was located on the dorsal side of the greater curvature and adhered highly to the retroperitoneum and spleen. The omental incision was conducted first, and the adhesion around the tumor was carefully detached, following which wedge resection was performed using Endo-GIA®at the base of the tumor. The pathological findings of the resected specimens were mainly spindle-shaped tumor cells rich in polymorphism with a high degree of necrosis, and did not seem to be conclusively GIST; as such, various immunological tests were performed.c -kit(-), DOG-1(-), S-100 p(-), desmin(-), a-SMA(focal+), p16(+), MDM2(+), CDK4(+) results led to the diagnosis of dedifferentiated liposarcoma. The patient is currently being followed up with and is alive without recurrence 10 months after the operation.

Efficacy, safety and pharmacokinetics of tedizolid versus linezolid in patients with skin and soft tissue infections in Japan - Results of a randomised, multicentre phase 3 study.

The objective of this open-label, randomised (i.e. 2:1 ratio), Phase 3 study was to compare the efficacy and safety of tedizolid phosphate 200 mg, once-daily treatment with that of linezolid 600 mg, twice-daily treatment for 7-14 days in Japanese adult patients (N = 125) with skin and soft tissue infections (SSTIs) and/or for 7-21 days for those with SSTI-related bacteraemia, caused by confirmed or highly suspected methicillin-resistant Staphylococcus aureus (MRSA). Primary outcome was clinical cure rate at test-of-cure (TOC, in SSTI: 7-14 days, in bacteraemia: 4-6 weeks after end-of-therapy [EOT]) time point in the microbiologically evaluable MRSA (ME-MRSA) population (N = 39). Secondary endpoints were clinical and microbiological response rates at EOT. Safety parameters were evaluated in the safety analysis population up to follow up. Data analysis was descriptive in nature. Baseline characteristics of patients were similar between treatment groups. At TOC in the ME-MRSA population, clinical cure rate was similar in tedizolid phosphate (92.6%) and linezolid (88.9%) groups. At EOT, clinical cure (tedizolid phosphate: 93.1%, linezolid: 90.0%) and microbiological success (tedizolid phosphate: 93.1%, linezolid: 100.0%) rates were similar in the ME-MRSA population. Both treatments were well tolerated; overall treatment-emergent adverse events (TEAEs) in tedizolid phosphate (79.5%) and linezolid (75.6%) treatment groups were similar. Drug-related TEAEs were numerically lower with tedizolid phosphate versus linezolid (30.1%; 39.0%, respectively), as well as gastrointestinal (21.7%; 26.8%) and myelosuppression-related (2.4%; 22.0%) TEAEs. One death occurred in the linezolid group. Tedizolid phosphate may be an appropriate antibiotic for the treatment of SSTIs in Japanese adult patients. International clinical trial registration number: NCT01967225. Japanese clinical trial registration number: JapicCTI-132308.

[Two Cases of Colon Metastasis of Gastric Cancer by Different Metastasis Pathway].

We treated 2 cases ofcolon metastasis ofgastric cancer considered to be caused by different pathway. Case 1 was a 55- year-old male with gastric cancer associated with metastases for lymph node, gallbladder, and liver. Curative surgical treatment of distal gastrectomy, partial hepatectomy, cholecystectomy and lymph node dissection was performed. The final find- ing was, L, Less, Type 3, pT4b(GB), tub2, pN3a(10/20), sP0, CY0, pH1, pM1, Stage IV , R0. Ten months after, ileocecal resection was performed, as a tumor was detected in the cecum. It was a submucosal tumor of well to moderately differentiated adenocarcinoma, and diagnosed as a metastasis ofgastric cancer. Case 2 was a 59-year-old male who received total gastrectomy. The final finding was UE, Less, Type 4, tub2-por2, pT4a, pN2(5/19), cM0, sP0, CY0, Stage III B, R1. One year and 10 months later, unevenness and redness in the mucosal membrane ofthe transverse colon occurred. Signet-ring cells were observed by the endoscopic biopsy, and colon metastasis ofstomach cancer was diagnosed. Consequently, transverse colectomy was performed. Diffused invasion of cancer cells was observed in all layers of the wall, which was considered as metastasis via gastrocolic ligament. Although colon metastasis ofstomach cancer is rare, its pathway varies, such as infiltration, direct invasion, hematogenous, and lymphogenous. Form oflesion also varies. For diagnosis ofcolon lesion occurring during follow-up after gastric cancer, these points should be noted.

[Laparoscopic Transverse Colectomy by Cranial Approach Preceding Medial Approach after Stenting for Obstructive Transverse Colon Cancer].

Surgery for obstructive colon cancer was highly invasive due to poor nutritional status of patients, risk of emergency surgery, and unavoidable colostomy formerly. However, recently, we have been able to perform laparoscopic elective surgery safely without colostomy, by using self-expanding metallic stents(SEMS). Laparoscopic colectomy for transverse colon cancer is inherently very difficult because of variations in the vascular system, small number of patients, and absence of large, randomized trials. Laparoscopic complete mesocolic excision(CME)for colectomy has been shown to be technically feasible and effective. We report the treatment strategy for obstructive transverse colon cancer which involves laparoscopic transverse colectomy by cranialapproach preceding medialapproach after successfuldecompression by stenting, along with a review of relevant literature. We consider it a s minimally invasive treatment for obstructive transverse colon cancer.

[A Very Elderly Patient Successfully Treated by Multimodality Treatment for Pancreas Cancer with Synchronous Multiple Liver Metastases and Liver Dysfunction].

We report an 86-year-old patient successfully treated by multimodality treatment for advanced pancreatic cancer with synchronous multiple liver metastases and liver dysfunction. Systemic chemotherapy(SC)(gemcitabine[GEM]1 g and 5-FU 1 g biweekly)was initiated. Two weeks after, the radiation therapy(55 Gy/25 days)was added. Three weeks after, the short period's high dose hepatic artery infusion(SPHDHAI)(5-FU[1 g]×3 days: 1 day rest: 5-FU[1 g]×3 days)was started. By these treatments, liver dysfunction was completely improved and abdominal pain was disappeared. After 2 times of weekly high dose hepatic artery infusion(WHDHAI)(5-FU 1,500mg), the mixed chemotherapy(MC)(GEM 800 mg[systemic] and 5-FU 1,500 mg hepatic artery infusion:[HAI]biweekly)were started. She could live without admission for about 1 year. About 13 months after lung metastases was appeared and she died about 19 months after first chemotherapy. Our multimodality treatment(systemic and HAI therapy and radiation)was effective for keeping patient quality of life and for improving the survival even if the patient was a very old age and showed liver dysfunction.

[Laparoscopy-Assisted Surgery for Descending Colon Cancer in a Patient with Persistent Descending Mesocolon-A Case Report].

Persistent descending mesocolon(PDM)is caused by absence of fusion of the descending colon to the retroperitoneum. We report a case of laparoscopy-assisted surgery for descending colon cancer in a patient with PDM. An 88-year-oldfemale patient complaining of abdominal pain was diagnosed with bowel obstruction, and referred to our hospital. A computed tomography(CT)scan showed bowel obstruction due to descending colon cancer. After decompression of the colon by insertion of a transanal drainage tube, she underwent laparoscopy-assistedleft hemicolectomy. Intraoperatively it was observed that the descending colon was not fixed to the retroperitoneum, and the patient was diagnosed with persistent descending mesocolon. The accessory middle colic artery and the inferior mesenteric vein branched radially. In patients with PDM, the inferior mesenteric artery often branches radially. However, the various morphologies of branching of the accessory middle colic artery and the inferior mesenteric vein have not been reported. It is not clear whether the radial branching of the accessory middle colic artery and the inferior mesenteric vein is characteristic of patients with PDM. We should however expect radial branching of the accessory middle colic artery and the inferior mesenteric vein in such cases.

[Combination Treatments to the Huge Ovarian Cancer with Liver Metastases].

We report a CR case of huge ovarian cancer with peritoneal and liver metastases who was operated bilateral ovaries, uterus and peritoneal metastases at first, followed by systemic chemotherapy and performed 4 times of radiofrequency ablation (RFA)and 2 times of liver resection(LR). The case was a 50-year-old woman. She suffered with bowel enlargement from over 1 year ago. Preoperative MRI finding was huge ovarian serous cyst with partial solid tumor inside. The major axis was about 30 cm. CA125 and CA19-9 levels were elevated. Tumor reduction surgery was performed with bilateral salpingooophorectomy and hysterectomy with resecting peritoneal metastatic lesions. Postoperative systemic chemotherapy(carbo- platin 550mg/day 1 plus paclitaxel 130mg/day 1, 8, 15)(CBDCA plus PTX)were performed amount 6 courses. Unfortu- nately liver metastases at S3, S4, S6, S7 and S8/5 appeared about 7months after operation.We restarted the CBDCA plus PTX therapy from 15 months after operation when the tumor maker elevated. After 18 courses of CBDCA plus PTX therapy liver metastases remained only at S3. But gradually tumors grew up and size of tumors increased in spite of 3 more courses of CBDCA plus PTX therapy. So we challenged 2 times of RFA at S8/5 metastases that grew most rapidly and the values of increasing tumor makers stopped elevating. Then we performed LR at S3 and S4 metastases and the values of tumor makers returned to the normal level. But next S6 and S7 metastases appeared, we chose the RFA at first. At last recurrence of S7 was resected and all of liver metastases were treated. We checked no peritoneal metastases twice at the time of operation. The values of tumor makers became the normal level. Now she is alive well without metastases over 6 years after first operation. RFA and LR were effective at liver metastases from ovarian cancer that became resistant to systemic chemotherapy.

[Single Incision Laparoscopic Ileocecal Resection for Small Intestinal Malignant Lymphoma - A Case Report].

A 76-year-old man with the chiefcomplaint ofmelena visited our hospital. A mass was palpable in the right lower abdomen. We diagnosed the illness as small intestinal malignant lymphoma in the terminal ileum and performed a single incision laparoscopic ileocecal resection "TANKO-ICR" with D3 lymph node dissection with the idea ofobtaining a wide visualization and surgical field. The Aesculap®internal organ retractor(B BRAUN)is very useful in such cases. We grasped the pedicle of the ileocecal artery using the retractor and pulled out the nylon line connected to the retractor by using ENDO CLOSETM (COVIDIEN)to extraabdomen for drawing the pedicle. Single incision laparoscopic surgery can be performed with only an umbilical wound; therefore, it is minimally invasive and has a superior aesthetic outcome. Small intestinal malignant lymphoma is a relatively rare malignant tumor ofthe digestive organs. We report this case demonstrating that single incision laparoscopic surgery was possible and provide a review ofthe relevant literature.

[The New Liver Retraction Method "V-Shape+1 Method" Using Penrose Drains for Laparoscopic Surgery of the Stomach].

Liver retraction is a necessary operative procedure for enabling greater visualization and a wider surgical field during laparoscopic surgery of the stomach. We have developed a new liver retraction method for laparoscopic surgery that uses penrose drains, is very easy to perform and in minimally invasive. We call this method the "V-Shape+1 method". We performed laparoscopic surgery using this method on 16 patients within 8.3(5.3-13.7)min(median). We analyzed the postoperative changes in the serum levels of AST, ALT, and T-Bil, which are indicators of liver function. The serum AST, ALT values were elevated at postoperative day 1. Thereafter, the values improved immediately. This early liver function failure is acceptable. We have not experienced any complication related to this method. Therefore, we believe this method is useful for obtaining wide visualization easily for not only laparoscopic gastrectomy but also for laparoscopic upper abdominal surgery.

[Two Year Recurrence Free Survival after Resection of Cutaneous Metastasis from Pancreatic Cancer - A Case Report].

The patient was a 73-year-old woman who underwent distalpancreatectomy for pancreas tailcancer (T3, N0, M0, stage III ). Hepatic arterialinfusion(HAI)using high-dose 5-fluorouracil(5-FU)(6,000mg/week)was performed 35 days after curative resection to prevent liver metastases. Although chemotherapy with gemcitabine(GEM)was administered for 2 weeks, the patient was aware of a nodule(1 cm in diameter)on the right lower quadrant of the abdomen. Resection of the cutaneous mass was performed and histological findings revealed metastatic adenocarcinoma from the pancreas cancer. Six courses of chemotherapy with GEM were administered as adjuvant therapy. Two years after the treatment with GEM, neurological symptoms appeared, and computed tomography(CT)and magnetic resonance imaging(MRI)revealed a solitary metastatic thalamus tumor(2 cm in diameter). After stereotactic radiotherapy, the patient was transferred to a different hospitalfor physicaltherapy. Herein, we report on a case of 2 year recurrence free survivalafter the resection of a cutaneous metastasis from pancreatic cancer.

[Pre-Operative Treatment with Transcatheter Arterial Chemoembolization (TACE) and Hepatic Arterial Infusion (HAI) for Liver Metastasis from Gastric Cancer--A Case Report].

The patient was an 83-year-old man who underwent distal gastrectomy for gastric cancer (T3, N1, M0, P0, M0, stage ⅡB) at a different hospital from ours. A metastatic lesion was detected in the liver 5 months after gastrectomy. Although chemotherapy with S-1 or bi-weekly CPT-11 was administered for 6 months, the liver tumor increased in size. The patient was referred to our hospital for treatment of the liver metastasis. Abdominal-computed tomography (CT) and magnetic resonance imaging (MRI) revealed a solitary metastatic liver tumor (9 cm in diameter: S7/S6/S8) with a hypervascular tumor stain. Transcatheter arterial chemoembolization (TACE) using degradable starch microspheres (DSM) plus mitomycin C, and hepatic arterial infusion (HAI) using high-dose 5-fluorouracil (5-FU) (6,000 mg/week), were performed 54 days before curative resection of the liver (S6+S7+S8+S5b/c). Histological findings revealed metastatic adenocarcinoma with a tumor thrombus in the posterior branch of the portal vein. The patient was treated with 2 courses of adjuvant chemotherapy with paclitaxel. No recurrence was observed 8 months after hepatectomy. This case suggests that combined treatment with TACE/HAI as a multimodal treatment might be effective in the management of hypervascular liver metastasis from gastric cancer.

[A Case Report of Huge Liver Synchronous Metastases of Colon Cancer that Occurred after Right Liver Lobectomy].

We report a patient who experienced a weight loss, general fatigue, and appetite loss and had huge hepatic metastases of colon cancer after right lobectomy for hepatic stone. After 2 courses of treatment with high-dose hepatic arterial infusion of 5-FU (HDHAI; 5-FU 6 g/week), the appetite loss decreased, and low anterior resection was performed. Unfortunately, the other symptoms continued, and she received 5 additional courses of HDHAI during about 6 months. Finally, all of the symptoms disappeared, and she could receive systemic chemotherapy and HAI. Bone metastasis at vertebra TH 9 was observed about 9 months after radiotherapy, and local recurrence at the anastomosis site was observed at about 1 year 1 months after radiotherapy. Both the metastasis and local recurrence were well controlled. Although the lung metastases were growing slowly (number and size), the patient was well enough to go to the hospital on her own and her weight loss almost disappeared. If liver metastases were the most threatening factor of life, HDHAI may be effective for the improvement of symptoms.

[Laparoscopic Surgery for Adult Intussusception Due to Rectal Cancer--A Case Report].

An 87-year-old woman with the chief complaint of bloody stool was referred to our hospital from an institution for the aged. The abdomen was soft and flat, and a tumor was not palpable on digital rectal examination. Tumor markers were within normal ranges. Abdominal enhanced CT scan showed a multiple concentric ring sign at the rectum. Colonoscopic and barium examination led to a diagnosis of rectal intussusception due to rectal cancer. We first tried to reposition it preoperatively, but it was impossible. She fortunately had no symptoms of ileus; therefore, we chose to perform laparoscopic surgery. We achieved the reposition intraoperatively and performed Hartmann's operation with D2 lymph node dissection because she was a very elderly patient with high-risk comorbidities. The pathological diagnosis was as follows: RS, 40×40 mm, type 2, tub2, pT3 (SS), pN0, ly0, v0, pStageⅡ, R0, Cur A. Adult intussusception due to rectal cancer is extremely rare. We report that in this case that laparoscopic surgery was possible, along with a review of the relevant literature.

Computational investigation of potential dosing schedules for a switch of medication from warfarin to rivaroxaban-an oral, direct Factor Xa inhibitor.

The long-lasting anticoagulant effect of vitamin K antagonists can be problematic in cases of adverse drug reactions or when patients are switched to another anticoagulant therapy. The objective of this study was to examine in silico the anticoagulant effect of rivaroxaban, an oral, direct Factor Xa inhibitor, combined with the residual effect of discontinued warfarin. Our simulations were based on the recommended anticoagulant dosing regimen for stroke prevention in patients with atrial fibrillation. The effects of the combination of discontinued warfarin plus rivaroxaban were simulated using an extended version of a previously validated blood coagulation computer model. A strong synergistic effect of the two distinct mechanisms of action was observed in the first 2-3 days after warfarin discontinuation; thereafter, the effect was close to additive. Nomograms for the introduction of rivaroxaban therapy after warfarin discontinuation were derived for Caucasian and Japanese patients using safety and efficacy criteria described previously, together with the coagulation model. The findings of our study provide a mechanistic pharmacologic rationale for dosing schedules during the therapy switch from warfarin to rivaroxaban and support the switching strategies as outlined in the Summary of Product Characteristics and Prescribing Information for rivaroxaban.

A comprehensive review of the pharmacokinetics of approved therapeutic monoclonal antibodies in Japan: Are Japanese phase I studies still needed?

Ethnic evaluation of the pharmacokinetics and safety of new drugs is required in Japan before implementing bridging or joining global studies. As therapeutic monoclonal antibodies (mAbs) show limited ethnic differences, their pharmacokinetics and safety in Japanese individuals could be estimated from prior non-Japanese studies. Therefore, there is potential to re-evaluate the development program for mAbs in Japan. We reviewed the pharmacokinetics of mAbs approved in Japan. Although some differences had been observed in pharmacokinetics of mAbs between Japanese and non-Japanese populations (mainly Caucasians), these differences were attributed to differences of body weight and/or antigen levels. Moreover, the influential factors can be estimated without conducting regional pharmacokinetic/safety studies. The pharmacokinetics of some mAbs is presumably non-linear and show differences between healthy volunteers and patients because of differences in antigen levels. However, for 10/24 mAbs approved in Japan, Japanese healthy volunteer studies were conducted before the patient studies. Additionally, for the mAbs that showed ethnic differences in pharmacokinetics, the doses selected in subsequent patient studies were the same as the doses approved in the United States. In this review, we discuss new drug development strategies in various regions, and assess the need for regional pharmacokinetics/safety studies before joining global studies.

[Five-year-survival in a case of large synchronous liver metastases from colon cancer treated with local (operation, HAI, RFA, and TAE) and systemic combined therapy].

A 58-year-old woman was suffering from abdominal pain due to large liver metastases(LM)and lung metastasis from sigmoid colon cancer. After laparoscopic sigmoidectomy, three 6 g/wk high dose hepatic arterial infusions(HDHAI)of5 - fluorouracil (5-FU) were administered and the tumor decreased in size. Unfortunately, the patient had an infectious pseudoaneurysm at the site of puncture. She was given a drainage and femoro-femoral(F-F)bypass. At last, a hepatectomy, radiofrequency ablation(RFA), and catheter insertion from gastroepiploic artery, were performed successfully. Subsequently, she received a half HDHAI and several systemic chemotherapy drugs. However, residual liver metastases developed thrice and we operated on all of them. Finally, when the hepatic arterial infusion(HAI)catheter became unavailable, we only continued the systemic therapy (Erbitux+FOLFIRI). However, inoperable residual liver metastases(maximum 13 cm in size)occurred. We chose to administer hepatic transarterial embolization(TAE)therapy 3 times. From the second time, we performed TAE from the right subphrenic artery and in the third time, we added 1-day HAI therapy. Finally, the tumor size decreased(maximum 9 cm). The patient is still an outpatient 5 years after the first HDHAI.

[A case of metastatic colon carcinoma following curative resection for advanced gastric cancer associated with metastases to the liver and gallbladder].

A 55-year-old man suffering from gastric cancer associated with metastases to the lymph node, gallbladder, and liver was administered chemotherapy with S-1 and cisplatin. Before initiation of therapy, the primary tumor, lymph node metastases, and liver metastases showed fluorodeoxyglucose (FDG) accumulation by positron emission tomography (PET). After 1 course of chemotherapy, the patient received curative surgical treatment including distal gastrectomy, partial hepatectomy, cholecystectomy, and lymph node dissection. The final pathological finding was moderately differentiated adenocarcinoma, T4b(SI), N3a(10/20), P0, CY0, pH1, pM1, Stage IV. Five months after surgery, the serum carcinoembryonic antigen (CEA) level was found to be increasing and PET examination identified an FDG-accumulating nodule in the ascending colon. Colonoscopy identified a submucosal tumor diagnosed as a metastasis from the gastric cancer. Right colectomy was performed 7 months after the first surgery resulting in a curative resection. In each surgery, PET examination indicated that no other distant metastases existed, and curative resection would be possible. Furthermore, although solitary metastatic colorectal lesions are rare, PET examination revealed them accurately. Thus, FDG-PET is very useful for identifying metastases in patients with gastric cancer.