Phase I dose‐escalation study of capmatinib (INC280) in Japanese patients with advanced solid tumors

Capmatinib is a highly specific, potent and selective MET inhibitor. This was an open‐label, multicenter, dose‐escalation, phase I study conducted in Japanese patients with advanced solid tumors (not selected based on their MET status). The primary objective was to determine the maximum tolerated dose (MTD) and/or highest studied dose being safe. Secondary objectives included safety, pharmacokinetics and preliminary antitumor activity. Dose escalation was guided by a Bayesian Logistic Regression Model dependent on dose‐limiting toxicities (DLT) in cycle 1. Of 44 adult Japanese patients with confirmed advanced solid tumors enrolled, 29 received capmatinib capsules (doses ranging from 100 mg once daily [q.d.] to 600 mg twice daily [b.i.d.]) and 15 received tablets (200 mg b.i.d. and 400 mg b.i.d.). DLT occurred in two patients: grade 2 suicidal ideation (600 mg b.i.d. capsule) and grade 3 depression (400 mg b.i.d. tablet). MTD was not reached. The highest studied dose determined to be safe as tablet was 400 mg b.i.d., whereas it is not yet determined for capsules. Most common adverse events suspected to be drug‐related were increased blood creatinine, nausea, decreased appetite, vomiting and diarrhea. Following repeated daily dosing up to day 15 by q.d. or b.i.d. regimen using capsules, median time to reach maximum plasma drug concentration (T_max) was 1.0‐4.0 hours; absorption was more rapid after dosing using tablets, with median T_max of 1.0 hour on both days 1 and 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib.     

Future perspectives of chemotherapy for advanced gastric cancer

According to the results of two recent randomized studies of treatment for metastatic gastric cancer in Japan, S-1 could replace infusional 5-fluorouracil and S-1 plus cisplatin showed a significant survival advantage over S-1 monotherapy, with a favorable toxicity profile. However, no globally accepted standards have been established yet and we have to wait for the results of other ongoing international studies, including studies of S-1 and its combinations, to achieve such standards. There are two major approaches to achieve further progress in the treatment of advanced gastric cancer. The first is to optimize the use of conventional cytotoxic agents (regimens) in the continuum of treatment for this disease. Several randomized studies of such regimens as second-line treatments are being planned in Japan, for which definitions of eligibility criteria and primary endpoints should be fully discussed in the design of the protocols. The second approach is to incorporate new active agents, particularly molecular targeting agents. Several molecular targeting agents that have shown survival advantages in patients with other tumor types are now under investigation for the treatment of gastric cancer in international randomized studies, including Japan and Korea. The next generation of targeting agents is also being evaluated in early clinical studies. Biological research has become essential for developing new targeting agents. For such biological studies, the tumor tissues of gastric cancer are easily obtainable via endoscopy, and such studies may constitute new frontiers in biological therapy. We expect that these studies will provide not only further clinical advantages but that they will also lead to tailored medicine.     

Ever-advancing chronic myeloid leukemia treatment

Treatment of chronic myeloid leukemia (CML) has been drastically changed by the emergence of the ABL tyrosine kinase inhibitor (TKI), imatinib mesylate. However, resistance and intolerance have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the ABL kinase domain that interfere with imatinib binding are the most critical cause of imatinib resistance. To overcome this resistance, four second-generation ATP competitive ABL TKIs, dasatinib, nilotinib, bosutinib and bafetinib, have been developed. Dasatinib and nilotinib also demonstrated higher efficacy than imatinib in previously untreated CML patients in chronic phase. Despite promising clinical results, the frequently observed mutant T315I is not effectively targeted by any of the second-generation ABL TKIs. Thus, a third-generation ABL TKI, ponatinib, was developed to inhibit all mutated BCR-ABL and showed clinical efficacy in CML cells harbouring T315I. CML treatment is rapidly progressing and further evolution is surely expected. Moreover, it was recently reported that some CML patients who achieved sustained complete molecular response could stop TKI. CML may become the first human cancer to be conquered solely with oral medicines.     

Triple gene-deleted oncolytic herpes simplex virus vector double-armed with interleukin 18 and soluble B7-1 constructed by bacterial artificial chromosome-mediated system

Conditionally replicating herpes simplex virus type 1 (HSV-1) vectors are promising therapeutic agents for cancer. Certain antitumor functions may be added to oncolytic activities of recombinant HSV-1 vectors by inserting transgenes into the viral genome. Because conventional homologous recombination techniques had required time-consuming processes to create "armed" oncolytic HSV-1 vectors, we established an innovative construction system using bacterial artificial chromosome and two recombinase systems (Cre/loxP and FLPe/FRT). Using G47Delta, a safe and efficacious oncolytic HSV-1 with triple gene mutations, as the backbone, this system allowed a rapid generation of multiple vectors with desired transgenes inserted in the deleted ICP6 locus. Four oncolytic HSV-1 vectors, expressing murine interleukin 18 (mIL-18), soluble murine B7-1 [B7-1-immunoglobulin (B7-1-Ig)], both, or none, were created simultaneously within 3 months. In vitro, all newly created recombinant vectors exhibited virus yields and cytopathic effects similar to the parental G47Delta. In two immunocompetent mouse tumor models, TRAMP-C2 prostate cancer and Neuro2a neuroblastoma, the vector expressing both mIL-18 and B7-1-Ig showed a significant enhancement of antitumor efficacy via T-cell-mediated immune responses. The results show that "arming" with multiple transgenes can improve the efficacy of oncolytic HSV-1 vectors. The use of our system may facilitate the development and testing of various armed oncolytic HSV-1 vectors.     

Survivin expression is regulated by coexpression of human epidermal growth factor receptor 2 and epidermal growth factor receptor via phosphatidylinositol 3-kinase/AKT signaling pathway in breast cancer cells

Survivin, a member of the inhibitor of apoptosis protein family, is widely expressed in a variety of human cancer tissues. Survivin inhibits activation of caspases, and its overexpression can lead to resistance to apoptotic stimuli. In this study, survivin protein expression was assessed by immunohistochemical staining of 195 invasive breast cancer specimens. Overall, 79.5% of the tumors were positive for survivin. The expression of epidermal growth factor receptor (EGFR) family, human epidermal growth factor receptor 2 (HER2) and EGFR, was also examined in 53 cases, and consequently, it was indicated that survivin positivity might be correlated with the coexpression of HER2 and EGFR. To clarify the regulatory mechanism of survivin expression in breast cancer cells, the effect of HER2 and/or EGFR expression on the survivin levels was examined. It was revealed that the survivin protein level was up-regulated by the coexpression of HER2 and EGFR, leading to the increased resistance against etoposide-induced apoptosis in breast cancer cells. Conversely, survivin levels and apoptosis resistance were decreased when cells were treated with HER2-specific inhibitor, Herceptin. Although Herceptin could down-regulate both phosphatidylinositol 3-kinase (PI3K)/AKT signal and mitogen-activated protein/extracellular signal-related kinase (ERK) kinase 1 (MEK1)/ERK signal in HER2-positive breast cancer cells, PI3K-specific inhibitor but not MEK1-specific inhibitor could decrease the survivin levels. The present study clarified the regulatory mechanism of HER2 in the expression of survivin protein in breast cancer cells.     

Photodynamic therapy as salvage treatment for local failure after chemoradiotherapy in patients with esophageal squamous cell carcinoma: a phase II study

Local failure at the primary site is a major problem after chemoradiotherapy (CRT) in patients with esophageal squamous cell carcinoma (ESCC). Salvage surgery is the only treatment option with curative intent, but it is associated with high morbidity and mortality. The aim of this study was to evaluate the efficacy and safety of salvage photodynamic therapy (PDT) after CRT. Patients with histologically proven local failure limited to the submucosal layer, and without any metastasis after definitive CRT (≥50 Gy) for ESCC were enrolled in the study. PDT began with intravenous administration of 2 mg/kg of porfimer sodium followed 48-72 hr later by excimer dye laser irradiation with a fluence of 75 J/cm2. The primary endpoint was a complete response (CR) to treatment with PDT, and the secondary endpoints were toxicity related to PDT, progression-free survival (PFS) and overall survival (OS). Twenty-five patients were enrolled in the study. A CR was attained in 19 of 25 patients treated with PDT (CR rate, 76%; 95% CI, 55-91%). One treatment-related death (4%) caused by gastrointestinal hemorrhage at the irradiated site occurred 33 days after PDT. No adverse events greater than grade 3 were related to PDT in the other patients. After a median follow-up of 48 months after PDT, the PFS and OS at 3 years were 40% (95% CI, 21-59%) and 38% (95% CI, 17-60%), respectively. PDT is a potentially curative and tolerable salvage treatment after CRT for carefully selected patients with local failure without any metastasis.     

Genetic mutual relationship between PTEN and p53 in gastric cancer

Both PTEN (encoding phosphate and tensin homologue) and p53 are known as cancer suppressor genes, and they are assumed that their gene mutations and loss of heterozygosity (LOH) occur frequently in various types of carcinoma. In the present study, we investigated both the p53 mutation and LOH of PTEN in 113 gastric cancer patients. We observed the LOH of PTEN in 11.1% of the patients with normal p53s and 46.2% of the patients with p53 gene mutations. The result that LOH of PTEN was frequently observed in the cases with p53 gene mutations and other data in this study suggested that both PTEN and p53 have complimentary roles in gastric carcinoma development.     

IFN-beta down-regulates the expression of DNA repair gene MGMT and sensitizes resistant glioma cells to temozolomide

Alkylating agents, such as temozolomide, are among the most effective cytotoxic agents used for malignant gliomas, but responses remain very poor. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) plays an important role in cellular resistance to alkylating agents. IFN-beta can act as a drug sensitizer, enhancing toxicity against a variety of neoplasias, and is widely used in combination with other antitumor agents such as nitrosoureas. Here, we show that IFN-beta sensitizes glioma cells that harbor the unmethylated MGMT promoter and are resistant to temozolomide. By means of oligonucleotide microarray and RNA interference, we reveal that the sensitizing effect of IFN-beta was possibly due to attenuation of MGMT expression via induction of the protein p53. Our study suggests that clinical efficacy of temozolomide might be improved by combination with IFN-beta using appropriate doses and schedules of administration.     

Patterns of care study: comparison of process of post-mastectomy radiotherapy (PMRT) in Japan and the USA

BACKGROUND: The Patterns of Care Study (USPCS) by the American College of Radiology (ACR) has made significant contributions to improvements in the procedures of care for patients with breast cancer in the USA. The purpose of this study was to identify problems associated with the process of care for patients undergoing post-mastectomy radiotherapy (PMRT) in Japan compared with those in the USA. METHODS: The Japanese Patterns of Care Study Subgroup (JPCS) conducted a national survey in 1998-2000, involving 79 institutions and using two-stage cluster sampling of institutions and patients, which showed that between 1995 and 1997 PMRT was performed on 258 patients. The survey of the USPCS, involving 55 institutions, found that 407 patients received PMRT between 1998 and 1999. RESULTS: More than three axillary positive nodes were detected in 54% of the patients covered by the JPCS and in 46% of those covered by the USPCS. The clinical set-up of radiation treatment was planned without the aid of computed tomography or X-ray simulation for 25% of the JPCS patients and for 6% of the USPCS patients. The chest wall of 31% of the JPCS patients and of 98% of the USPCS patients was irradiated. The JPCS showed that inappropriate radiation techniques such as parallel opposed fields for chest wall irradiation were used for 3% of the patients in academic facilities, but for 25% of those in non-academic facilities (P = 0.0002). CONCLUSION: There is ample room for improvement in radiation treatment planning and chest wall irradiation techniques in Japan.     

A case of advanced cancer with liver metastasis and paraaortic lymph node metastasis responding remarkably to combination chemotherapy of low-dose CDDP, 5-FU and CPT-11

A 57-year-old male patient with upper epigastric discomfort was introduced to our hospital from another clinic because of gastric cancer. Several examinations showed massive liver metastasis and paraaortic lymph node metastasis from Type-3 gastric cancer beneath the posterior wall of the pyloric antrum. First we tried infusion of CDDP (10 mg/day for days 1-5 and 8-12) and continuous infusion of 5-FU (500 mg/day for 14 days). Concurrently, we added infusion of CPT-11 (80 mg/day on days 1,8). After 3 courses of chemotherapy, the tumor had decreased remarkably in size. Moreover, liver metastasis and paraaortic lymph node metastasis had vanished. This regimen thus appears to be effective for advanced gastric carcinoma.