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Despite recent advance in immunotherapy agents, safe new therapies that enhance the effects of immune checkpoint inhibitors are still required to develop. We previously demonstrated that hemagglutinating virus of Japan-envelope (HVJ-E) induced not only direct tumor cell death but also antitumor immunity through the activation of T and natural killer (NK) cells, thereafter, developed a manufacturing process of HVJ-E (GEN0101) for clinical use. We here performed a phase Ia clinical trial of intratumoral GEN0101 administration in six patients with stage IIIC or IV malignant melanoma. The primary aim was to evaluate the safety and tolerability of GEN0101, and the secondary aim was to examine the objective tumor response. Patients were separated into two groups (n = 3 each) and received a low dose of 30,000 and high dose of 60,000 mNAU of GEN0101. All patients completed a two-week follow-up evaluation without severe adverse events. The overall response rate was 33% (2 of 6), with 2 partial responses in the high-dose group and 2 with stable disease, and 2 with progressive disease in the low-dose group. Local complete or partial responses were observed in 11 of 18 (61%) target lesions. One patient demonstrated shrinkage of lung metastases after the treatment. The activity of NK cells and interferon-γ levels were increased in the circulation, indicating augmentation of antitumor immunity by GEN0101. This trial showed not only the safety and tolerability but also the significant antitumor effect of GEN0101, suggesting that GEN0101 might be a promising new drug for patients with advanced melanoma. [ABSTRACT FROM AUTHOR]

Purpose: Ipilimumab (IPI), a monoclonal antibody against immune-checkpoint receptor cytotoxic T lymphocyte antigen-4, is designed to enhance antitumor T cell function. IPI 10 mg/kg plus dacarbazine (DTIC) significantly improved overall survival in a phase 3 study involving predominantly Caucasian patients, with an adverse event (AE) profile similar to that of IPI monotherapy. We conducted a single-arm, phase 2 study to evaluate the safety and efficacy of IPI plus DTIC in Japanese patients.Methods: Previously untreated patients with unresectable stage III or IV melanoma received IPI 10 mg/kg plus DTIC 850 mg/m(2) every 3 weeks for four doses (q3w × 4), followed by DTIC q3w × 4 and then IPI every 12 weeks until disease progression or intolerable toxicity.Results: All 15 treated patients reported drug-related AEs, the most common of which were increases in alanine aminotransferase (n = 12, 80 %) and aspartate aminotransferase (n = 11, 73 %). Treatment-related serious AEs were reported in 11 (73 %) patients. Nine patients (60 %) discontinued treatment due to drug-related toxicities. Immune-related AEs (irAEs) were reported in 14 patients (93 %). The most frequent irAEs were liver (n = 12, 80 %) and skin (n = 10, 67 %) toxicities. Five deaths were reported; all were caused by progressive disease. Efficacy evaluation showed one complete response, one partial response and four patients with stable disease. Best overall response rate was 13 % (2/15), and the disease control rate was 40 % (6/15). The study was terminated early due to frequent, high-grade liver toxicities.Conclusions: IPI 10 mg/kg plus DTIC 850 mg/m(2) was not considered tolerable in the Japanese patient population. ClinicalTrials.gov identifier: NCT01681212. [ABSTRACT FROM AUTHOR]

Background ‘Public domain application’ is a flexible drug approval system in Japan, similar to the fast track designation in the United States. Methods From 1999 to 2009, four drugs and three regimens received approval from `Public domain application'. The data from the review reports were extracted, and the reviewing process was critically re-evaluated. Results The study drugs were categorized into three groups according to the sizes of the studies and evidence levels in the original articles that were submitted. Carboplatin was categorized into the first group with a large number of study patients and a high evidence level; the review report had studies with more than 15 000 total patients and 8 phase III studies. The ifosfamide and vinblastine regimen was categorized into the second group, with a low number of study patients and a low evidence level; the review report had studies with less than 1000 total patients and 1 phase III study. Dacarbazine; cytarabine; methotrexate, vinblastine, doxorubicin, and cisplatin; bleomycin, etoposide, and cisplatin; and fludarabine were categorized into the remaining third group, with a moderate number of study patients and evidence level. Conclusions Drugs with various backgrounds, including evidence levels and physicians' experiences, were approved via `Public domain application'. The approvals of most drugs were evaluated to be appropriate. [ABSTRACT FROM AUTHOR]

BNCT is a radiotherapeutic method for cancer treatment that uses tumor-targeting 10B-compounds. BNCT for cutaneous melanoma using BPA, a phenylalanine derivative, was first initiated by Mishima et al. in 1987. This article reviews the radiobiological basis of melanoma control and damage to normal tissues as well as the results of clinical studies. Experimental studies showed that the compound biological effectiveness (CBE) values of the 10B (n, α)7Li reaction for melanoma control ranged from 2.5 to 3.3. The CBE values of the 10B (n, α)7Li reaction for skin damage ranged from 2.4 to 3.7 with moist desquamation as the endpoint. The required single radiation dose for controlling human melanoma was estimated to be 25 Gy-Eq or more by analyzing the 50% tumor control dose data of conventional fractionated radiotherapy. From the literature, the maximum permissible dose to human skin by single irradiation was estimated to be 18 Gy-Eq. With respect to the pharmacokinetics of BPA in patients with melanoma treated with 85–350 mg/kg BPA, the melanoma-to-blood ratio ranged from 2.1–3.8 and the skin-to-blood ratio was 1.31 ± 0.22. Good local tumor control and long-term survival of the patients were achieved in two clinical trials of BNCT conducted in Japan. [ABSTRACT FROM AUTHOR]

Background Although taxanes (TAX) are effective for advanced cutaneous angiosarcoma (CAS) and stand as a current first-line treatment, no standardized second-line treatment has yet been established. Eribulin methylate (ERB), a non-taxane microtubule inhibitor, improved the overall survival (OS) of patients with advanced sarcoma compared to dacarbazine in a randomized, phase 3 trial. Based on this study, ERB was approved to use for all types of sarcoma in Japan. We hypothesized that ERB would be most active in patients with TAX-resistant CAS as both TAX and ERB target microtubules but through different mechanisms. Methods We designed a single-arm, prospective observational study of ERB administered at a dose of 1.4mg/m2 on days 1 and 8 in a 21-day cycle. Advanced, TAX-resistant CAS patients scheduled for ERB use were enrolled. The primary endpoint was OS and the secondary endpoints were response ratio (RR), progression-free survival (PFS), and toxicity assessment. Results The last patient was enrolled in January 2018 and the data was locked at the end of March 2019. In total, 25 patients with CAS (median age 74) were enrolled. All patients had prior TAX exposure and 5 patients had 2 or more prior therapy courses. All patients except 1 had their primary tumours in the head and neck while 10 patients had distant metastasis. Performance status (PS) was generally good; 14 were PS0, 8 were PS1, and 3 were PS2. The median follow-up period was 250 (16-849) days. The rate of OS and PFS at 6 months estimated by Kaplan-Meier method was 67% and 24%, respectively. Median OS and PFS were 8.6 and 3.0 months, respectively. RR at week 7, 13, and 25 were 24% (6/25), 16.7% (4/25) and 13% (3/23), respectively. Although 10 patients experienced severe toxicity (8 had neutropenia, 2 had anemia and 1 had a retroperitoneal abscess), they all recovered. Conclusions ERB showed a promising and durable response and was well-tolerated in TAX-resistant CAS. Both RR and OS were comparable to previous results where ANGIOTAX was used as a second-line treatment. The most common toxicity was neutropenia but this was manageable. Taken together, this study provides evidence to support ERB use in TAX-resistant CAS cases. Clinical trial identification UMIN000023331. Legal entity responsible for the study The authors. Funding Maruho Takagi Dermatology Foundation. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]