A phase 1/1b, open-label, dose-escalation study of PD-1 inhibitor, cetrelimab alone and in combination with FGFR inhibitor, erdafitinib in Japanese patients with advanced solid tumors.

Immune checkpoint inhibitors are the leading approaches in tumor immunotherapy. The aim of the study was to establish recommended phase 2 doses (RP2Ds) of intravenous cetrelimab, a checkpoint inhibitor, alone and with oral erdafitinib in Japanese patients with advanced solid tumors. This open-label, non-randomized, dose-escalation phase 1/1b study enrolled adults with advanced solid tumors who were ineligible for standard therapy. Study was conducted in two parts: phase 1a assessed cetrelimab at three dosing levels (80 mg every 2 weeks [Q2W], 240 mg Q2W, and 480 mg Q4W); phase 1b assessed cetrelimab+erdafitinib at two dosing levels (240 mg Q2W + 6 mg once daily [QD] and 240 mg Q2W + 8 mg QD). Primary endpoint was frequency and severity of dose-limiting toxicities (DLTs) of cetrelimab ± erdafitinib. In total 22 patients (phase 1a, n = 9; phase 1b, n = 13) were enrolled. Median duration of follow-up was 8.64 months in phase 1a and 2.33 months in phase 1b. In phase 1a, DLTs weren't reported while in phase 1b, 1 patient who received 240 mg cetrelimab + 6 mg erdafitinib reported Stevens-Johnson syndrome (grade 3, immune-related). Overall, 88.9% patients in phase 1a (grade ≥ 3: 44.4%) and 100.0% in phase 1b (grade ≥ 3: 53.8%) experienced ≥ 1 treatment-related adverse events (TEAEs); 33.3% in phase 1a and 38.5% in phase 1b reported serious TEAEs, of which 11.1% patients in phase 1a and 15.4% in phase 1b had TEAEs which led to treatment discontinuation. Cetrelimab alone and in combination with erdafitinib showed manageable safety in Japanese patients with advanced solid tumors. RP2Ds were determined as 480 mg cetrelimab Q4W for monotherapy, and cetrelimab 240 mg Q2W + erdafitinib 8 mg QD for combination therapy.

Efficacy of endoscopic ultrasound-guided gastroenterostomy using self-expandable metallic stent for afferent loop syndrome: A single-center retrospective study.

BACKGROUND AND AIM: Endoscopic ultrasound-guided gastroenterostomy is a procedure used to connect the stomach and dilated afferent loop using a stent under endoscopic ultrasound for afferent loop syndrome. However, the actual efficacy and safety of this procedure remain unclear. Therefore, this retrospective study aimed to evaluate the efficacy and safety of endoscopic ultrasound-guided gastroenterostomy using a laser-cut-type fully covered self-expandable metallic stent and an anchoring plastic stent for afferent loop syndrome. METHODS: Technical and clinical success rates, adverse events, recurrent intestinal obstruction rates, time to recurrent intestinal obstruction, and technical and clinical success rates of re-intervention were evaluated in intended patients who underwent endoscopic ultrasound-guided gastroenterostomy for afferent loop syndrome from October 2018 to August 2022. RESULTS: In 25 intended patients with afferent loop syndrome who intended endoscopic ultrasound-guided gastroenterostomy, the technical success rate was 100% (25/25), whereas the clinical success rate was 96% (24/25). Two patients experienced grade ≥ 3 early adverse events, including one with intra-abdominal abscess and one with hypotension. Both events were attributed to intestinal fluid leakage. No late adverse events were observed. The recurrent intestinal obstruction rate was 32% (8/25), and the median time to recurrent intestinal obstruction was 6.5 months (95% confidence interval: 2.8-not available). The technical and clinical success rates of re-intervention were both 100% (8/8). CONCLUSIONS: Endoscopic ultrasound-guided gastroenterostomy using a fully covered self-expandable metallic stent and an anchoring plastic stent is effective and safe as a treatment procedure for afferent loop syndrome.

Phase II trial of niraparib for BRCA-mutated biliary tract, pancreatic and other gastrointestinal cancers: NIR-B.

Due to the widespread use of cancer genetic testing in gastrointestinal cancer, the BRCA1/2 genetic mutation has been identified in biliary tract cancer as well as pancreatic cancer. Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert their cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations, via the mechanism of synthetic lethality. The aim of this phase II NIR-B trial is to evaluate the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer or other gastrointestinal cancers with germline or somatic BRCA1/2 mutations revealed by genetic testing. The primary end point is an investigator-assessed objective response rate in each cohort.Clinical Trial Registration: jRCT2011200023 (ClinicalTrials.gov).

A clinical study to confirm the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with the BRCA genetic mutation: the NIR-B trial.BRCA gene is involved in repairing DNA injury and plays an important role in cancer growth. Cells with a mutation in the BRCA gene cannot repair DNA using a method called homologous recombination repair. Niraparib is part of a class of drugs called 'PARP inhibitors' that inhibit enzymes called 'PARP' involved in repairing DNA injury, and has shown efficacy against cancers with BRCA gene mutations. BRCA gene mutations are infrequent but have been found in a variety of cancers. The NIR-B trial is a clinical trial to evaluate the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with BRCA gene mutations.

Immune-related adverse event-associated sclerosing cholangitis due to immune checkpoint inhibitors: imaging findings and treatments.

OBJECTIVES: Immune-related adverse event-sclerosing cholangitis caused by treatment with immune checkpoint inhibitors is rare, and the diagnostic criteria and treatment strategy remain unclear. In this study, we confirmed the clinicopathological features of immune-related adverse event-sclerosing cholangitis and clarified its diagnosis and appropriate management. METHODS: We retrospectively evaluated 10 patients diagnosed with immune-related adverse event-sclerosing cholangitis and identified by electronic database searches. RESULTS: Blood tests revealed liver dysfunction with a predominance of biliary tract enzymes in all patients; however, jaundice was present in only one patient. Contrast-enhanced computed tomography revealed diffuse hypertrophy of the extrahepatic bile duct wall as the most frequent finding; however, endoscopic retrograde cholangiopancreatography showed various imaging features, such as the pruned-tree appearance of intrahepatic bile ducts, in all patients. Transpapillary bile duct biopsy showed inflammatory cell infiltration using immunostaining, with a predominance of cluster of differentiation 8-positive T cells in 63% of the cases. Initial steroid therapy was effective in two cases. Mycophenolate mofetil and tacrolimus were used in steroid-refractory cases. Although six patients showed improvements, all of the remaining patients died owing to immune-related adverse event-sclerosing cholangitis. CONCLUSIONS: Various bile duct imaging findings of immune-related adverse event-sclerosing cholangitis were revealed; transpapillary bile duct biopsy may be useful in the diagnosis of immune-related adverse event-sclerosing cholangitis. Despite the combination of multiple immunosuppressive agents, prognosis of immune-related adverse event-sclerosing cholangitis remains poor. Longer follow-up and larger clinical studies are necessary to establish its treatment strategy.

First-in-human study of ONO-4578, an antagonist of prostaglandin E2 receptor 4, alone and with nivolumab in solid tumors.

EP4, a prostaglandin E2 receptor, has shown an immunosuppressive activity on cancer cells. This first-in-human study evaluated ONO-4578, a highly selective EP4 antagonist, as monotherapy and in combination with nivolumab in patients with advanced or metastatic solid tumors. A daily dose ranging from 30 mg to 100 mg of ONO-4578 monotherapy and that ranging from 2 mg to 60 mg of ONO-4578 with biweekly nivolumab 240 mg were administered. A total of 31 patients were enrolled, 10 receiving monotherapy and 21 receiving combination therapy. Overall, 26 patients experienced treatment-related adverse events. Dose-limiting toxicities were observed in three patients; one of six patients receiving 100 mg monotherapy developed grade 3 duodenal ulcer and two of six patients receiving 60 mg combination therapy developed either grade 3 erythema multiforme or grade 3 increased amylase and grade 4 increased lipase. One patient with small-cell lung cancer who received 40 mg combination therapy had a partial response, and three patients with monotherapy and six patients with combination therapy had stable disease. Pharmacodynamics analyses showed that ONO-4578 had EP4 antagonistic activity at doses as low as 2 mg. In conclusion, the maximum tolerated dose of ONO-4578 alone or in combination with nivolumab was not reached. ONO-4578 was well tolerated at the tested doses and showed signs of antitumor activity. Considering safety, efficacy, and pharmacokinetics/pharmacodynamics results, ONO-4578 40 mg daily with nivolumab 240 mg biweekly was selected as the recommended dose for future clinical trials. (Registration: JapicCTI-173,496 and NCT03155061).

A prospective multicenter phase II study of FOLFIRINOX as a first-line treatment for patients with advanced and recurrent biliary tract cancer.

Given the promising activity and tolerability of FOLFIRINOX as a second-line treatment for advanced biliary tract cancer (BTC), it can be an attractive first-line treatment option as well. This is a single-arm, open-label, multicenter phase II study to evaluate the safety and efficacy of FOLFIRINOX as a first-line treatment for patients with advanced BTC. Primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall survival (OS), tumor response and safety. This study defined primary endpoint might be met when the lower limit value of 80% confidence interval [CI] of the median PFS ≥ 6.0 months. Between June 2016 and March 2020, 35 BTC patients (21 intrahepatic, 10 extrahepatic, 2 gallbladder, 2 ampulla) including 26 unresectable and 9 recurrent disease were enrolled. After a median follow-up of 13.9 months, the median PFS and OS were 7.4 (80% CI, 5.5-7.5) and 14.7 (80% CI, 11.8-15.7) months, respectively. Complete response was achieved in 1 (2.9%) and partial response in 10 (28.6%), giving an objective response rate of 31.4% and disease control rate of 74.3%. Major grade 3-4 adverse events included neutropenia (54.3%), leukopenia (34.4%), febrile neutropenia (17.1%), thrombocytopenia (8.6%), cholangitis (8.6%), anemia, nausea, diarrhea, and peripheral sensory neuropathy (2.9% each). FOLFIRINOX was well tolerable in patients with advanced BTC, however, this study did not meet the primary endpoint to conduct a phase III trial. Thus, further explorations are required to find a subset of patients and/or certain clinical scenario which might be beneficial from FOLFIRINOX.

Ocular toxicity of investigational anti-cancer drugs in early phase clinical trials.

Ocular toxicities arising from anti-cancer drugs occur sporadically and are sometimes underestimated because they are not life-threatening. Reports focusing on ocular toxicities from cancer therapy are limited. We investigated the detailed progress of ocular toxicities of anti-cancer drugs including first-in-class ones. A retrospective review of medical records was conducted for patients who were involved in early phase clinical trials with scheduled ophthalmologic examinations according to their protocols between January 2014 and August 2021. Patients with ocular toxicity suspected to be related to the investigational drugs in the ophthalmic examination were investigated in detail. In total, 37 ocular toxicities related to investigational drugs occurred in 7.6% of patients (33/434). The median age of the 33 patients was 61 years (range, 33-76 years), and 20 were male. Causal drugs with a high incidence of ocular toxicities were HSP90 inhibitors and FGFR inhibitors. Retinopathy was most frequent, while conjunctivitis, dry eye, keratitis, keratopathy, and uveitis were also observed. Dim vision as a subjective finding was a unique adverse event. Most patients developed ocular toxicities even though their dose was below the drug's maximum tolerated dose. Except for one case, all ocular toxicities occurred bilaterally. About 60% (22/37) of ocular toxicity cases needed a temporary hold of the drug. All except for three cases fully recovered. This study reported the risks and timing of the onset of a variety of ocular toxicities of anti-cancer drugs, which were fundamentally controllable. (Trial registration number. Retrospectively registered).

Clinical features of germline BRCA1/2 or ATM pathogenic variant positive pancreatic cancer in Japan.

BACKGROUND: There has been increasing interest into the role of germline BRCA1/2 pathogenic variants (gBRCA PV) and gATM PV and likely PV (PV and LPV; PV + LPV) in the carcinogenesis and treatment of pancreatic cancer (PC), but the clinical features have not been well described. METHODS: Patients with confirmed gBRCA PV and gATM PV + LPV PC treated at our hospital between April 2016 and December 2021, were retrospectively evaluated for clinical characteristics and outcomes. RESULTS: Twenty-two patients harbored gBRCA PV and three patients harbored gATM PV + LPV. Of the gBRCA PV patients, 81.8 % received platinum-based chemotherapy with favorable treatment outcomes with an objective response rate of 50.0 % (95 % CI: 23.0-77.0), median progression free survival (PFS) of 334 days, and median overall survival (OS) of 926 days from the initiation of first-line chemotherapy. The annual number of patients with gBRCA PV was two patients per year before January 2021 (when BRACAnalysis became available in Japan), and ten patients during the 10 months thereafter. Four patients (20 %) with gBRCA PV developed soft-tissue metastasis with progression. Two patients with gATM PV + LPV received platinum-based chemotherapy and the best response of those patients was partial response and stable disease and their OS from the initiation of first-line chemotherapy was 1192 and 989 days, and PFS was 579 and 140 days, respectively. CONCLUSION: The diagnosis of gBRCA PV-positive PC has increased revealed in recent years. These tumors appear to be sensitive to platinum-based chemotherapy, with long term survival observed in gATM PV + LPV-positive patients.

Cabozantinib in Japanese patients with advanced hepatocellular carcinoma: Final results of a multicenter phase II study.

AIM: Cabozantinib showed a favorable benefit-risk profile in Japanese patients with advanced hepatocellular carcinoma (HCC) in an open-label, phase II study (NCT03586973). This analysis presents cumulative data to final database lock. METHODS: Patients with previously treated, advanced HCC received cabozantinib 60 mg/day. Progression-free survival (PFS) and tumor response rates in prior-sorafenib and sorafenib-naïve cohorts were assessed by independent radiology committee (IRC) and an investigator. Liver function was evaluated by albumin-bilirubin (ALBI) score. RESULTS: Median cabozantinib exposure was 5.6 months. In the prior-sorafenib cohort (n = 20), median PFS was 7.4 months per IRC assessment and 5.6 months per investigator assessment. In the sorafenib-naïve cohort (n = 14), median PFS was 3.6 and 4.4 months per IRC and investigator assessment, respectively. Six-month PFS rate per IRC and investigator assessment in the prior-sorafenib cohort was 59.8% and 49.5%, respectively, and in the sorafenib-naïve cohort was 16.7% and 35.7%, respectively. Disease control rate by both IRC and investigator assessment was 85.0% in the prior-sorafenib cohort and 64.3% in the sorafenib-naïve cohort. Median overall survival (Kaplan-Meier estimate) was 19.3 and 9.9 months in the prior-sorafenib and sorafenib-naïve cohort, respectively. Mean ALBI score remained relatively constant in patients able to continue treatment. The most frequent adverse events were palmar-plantar erythrodysesthesia syndrome, diarrhea, hypertension, and decreased appetite. No new safety concerns were identified. CONCLUSIONS: Cabozantinib showed efficacy and a manageable safety profile in Japanese patients with advanced HCC.

Fine-needle biopsy with 19G needle is effective in combination with endoscopic ultrasound-guided tissue acquisition for genomic profiling of unresectable pancreatic cancer.

OBJECTIVES: Comprehensive genomic profiling (CGP) has been approved in Japan since June 2019, enabling mutation-specific therapy. Although tissue sampling via endoscopic ultrasound-guided tissue acquisition (EUS-TA) is standard in pancreatic cancer, reports on obtaining appropriate samples for CGP, especially for the OncoGuide NCC Oncopanel System (NOP) and FoundationOne CDx (FOne), are lacking. Therefore, we investigated the success rate and factors related to appropriate EUS-TA sampling for CGP analysis suitability in unresectable pancreatic ductal adenocarcinoma (UR-PDAC). METHODS: Participants comprised 150 UR-PDAC patients who underwent EUS-TA and tumor sample evaluation for CGP analysis suitability between June 2019 and December 2021. The proportion of patients meeting the criteria was evaluated considering tumor size, puncture lesion, presence of metastasis, type and size of puncture needle, suction method, number of punctures, and puncture route. RESULTS: In total, 39.2% (60/153) of samples met NOP analysis suitability criteria and 0% met FOne analysis suitability criteria. The suitability rate was significantly higher with 19G fine-needle biopsy (FNB) (56.0%; 42/75) than with 22G FNB (32.6%; 14/43) and 22G fine-needle aspiration (11.4%; 4/35). Nineteen-gauge needle (odds ratio [OR] 2.53; 95% confidence interval [CI] 1.15-5.57; P = 0.021) and FNB (OR 3.57; 95% CI 1.05-12.20; P = 0.041) were independent factors contributing to NOP analysis suitability. Among 30 patients who underwent actual NOP analysis, the analysis success rate was 100% (30/30). CONCLUSION: In sample collection via EUS-TA, 19G and FNB needles contribute to NOP analysis suitability.

Phase I Study of Tremelimumab Monotherapy or in Combination With Durvalumab in Japanese Patients With Advanced Solid Tumors or Malignant Mesothelioma.

BACKGROUND: The primary objective of this phase I, open-label trial was to assess safety and tolerability of tremelimumab monotherapy and combination therapy with durvalumab in Japanese patients with advanced cancer. Tremelimumab is a fully human monoclonal antibody against CTLA-4 in clinical trials; durvalumab is a monoclonal antibody against PD-L1 for the treatment of bladder and lung cancer. METHODS: In part 1, tremelimumab 3 or 10 mg/kg was given every 4 weeks (Q4W) for 6 doses, and thereafter every 12 weeks until discontinuation (n = 8); subsequently tremelimumab 10 mg/kg Q4W for 6 doses/Q12W and thereafter until discontinuation was administered in 41 patients with malignant pleural or peritoneal mesothelioma (MPM). In part 2, tremelimumab 10 mg/kg (Q4W for 6 doses followed by Q12W for 3 doses) was given in combination with durvalumab 15 mg/kg (Q4W for 13 doses) in cohort 1 (n = 4). In cohort 2 (n = 6), tremelimumab 1 mg/kg (Q4W for 4 doses) was given in combination with durvalumab 20 mg/kg (Q4W for 4 doses followed by 10 mg/kg Q2W for 22 doses), while in cohort 3 (n = 6), fixed-dose tremelimumab 75 mg Q4W for 4 doses plus durvalumab 1500 mg Q4W for 13 doses was given. RESULTS: In part 1, no dose-limiting toxicities (DLTs) for tremelimumab 3 or 10 mg/kg (Q4W for 6 doses/Q12W thereafter until discontinuation) were observed. Six (75%) patients reported treatment-related adverse events (trAEs). In the MPM dose-expansion cohort, 38 (92.7%) patients reported trAEs. In part 2, one DLT (Grade 4 myasthenia gravis) was reported for tremelimumab 10 mg/kg (Q4W for 6 doses/Q12W for 3 doses) plus durvalumab 15 mg/kg (Q4W for 13 doses). One DLT (Grade 4 hyperglycemia) was reported for tremelimumab 75 mg (Q4W for 4 doses) plus durvalumab 1500 mg (Q4W for 13 doses). Fourteen (87.5%) patients reported trAEs. Tremelimumab demonstrated low immunogenicity; 1 (16.7%) patient developed antidrug antibodies. CONCLUSION: Tremelimumab 10 mg/kg (Q4W/Q12W), tremelimumab 1 mg/kg (Q4W) plus durvalumab 20 mg/kg (Q4W/10 mg/kg Q2W), and fixed-dose tremelimumab 75 mg (Q4W) plus durvalumab 1500 mg (Q4W) were safe and tolerable.ClinicalTrials.gov Identifier: NCT02141347 (https://clinicaltrials.gov/ct2/show/NCT02141347).

Phase I study of envafolimab (KN035), a novel subcutaneous single-domain anti-PD-L1 monoclonal antibody, in Japanese patients with advanced solid tumors.

Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody. This open-label, multicenter Phase 1 trial assessed the safety, tolerability, pharmacokinetic (PK) profile, and efficacy of envafolimab as a single agent in Japanese patients with advanced solid tumors. In the dose-escalation phase, 10 patients received subcutaneous (SC) envafolimab QW at 1.0 mg/kg, 2.5 mg/kg and 5.0 mg/kg. In the dose-expansion phase, 16 patients were treated at 2.5 or 5.0 mg/kg Q2W in part-1 and 9 patients received SC envafolimab 300 mg Q4W in part-2. No dose-limiting toxicities (DLTs) were reported. Envafolimab was well tolerated and no new safety signals were identified compared with other marketed products of the same class. Three patients reported Grade ≥ 3 envafolimab-related treatment-emergent adverse events (TEAE), including adrenal insufficiency, cerebral infarction, and immune-mediated enterocolitis. Envafolimab demonstrated dose-proportional increases in area under the time-concentration curve (AUC) and maximum serum concentration (Cmax). The overall response rate (ORR) was 11.4% (n = 4) and disease control rate (DCR) was 34.3% (n = 12). Consistent with that observed in other envafolimab Phase 1 trials and approved PD-1/PD-L1 inhibitors, the safety profile of SC envafolimab in Japanese patients with advanced solid tumors was well tolerated with efficacy comparable to IV administered treatments. Pharmacokinetics data and preliminary anti-tumor response support dose regimens with longer dosing intervals (Q2W or Q4W). As such, envafolimab offers patients a more convenient treatment option than currently available intravenously administered PD-1/PD-L1 inhibitors. CLINICALTRIALS.GOV IDENTIFIER: NCT03248843(August 14, 2017).

Practical consideration for successful sequential tumor biopsies in first-in-human trials.

In first-in-human (FIH) trials, sequential tumor biopsies, i.e., two consecutive tumor biopsies, the first performed at baseline (pretreatment) and the second during the early treatment period (on-treatment), provide proof of concept in investigational new drugs. We evaluated the success of sequential tumor biopsies in FIH trials, and explored approaches for improved success rates. We retrospectively reviewed the sequential tumor biopsies required in 17 of 52 FIH trials conducted from 2015 to 2020. One hundred and thirty-eight patients were identified. Success of either pretreatment or on-treatment biopsy alone, and of sequential tumor biopsies, was defined as the acquisition of viable tumor cells and as obtaining tumor cells from both biopsy specimens, respectively. The success rates of pretreatment and on-treatment biopsy were 98.6% and 94.2%, respectively, and of sequential tumor biopsies was 70.3%. Adverse events associated with the pretreatment biopsies (33.3% positive; 72.0% negative) and timing of the first imaging assessment (before on-treatment biopsy = 40.0%; after on-treatment biopsy = 82.7%) correlated with successful sequential tumor biopsies. The reasons for unsuccessful sequential tumor biopsies could be categorized into two groups: 1) patient refusal of the on-treatment biopsy (most frequently due to early disease progression); and 2) absence of tumor cells in the pretreatment or on-treatment biopsy specimen. We propose an approach to achieving greater success in sequential tumor biopsies in FIH trials; the first imaging assessment during the study should be scheduled after on-treatment biopsy. (Registration number UMIN000042487, Date of registration November 18, 2020).

Phase I/II study of streptozocin monotherapy in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: This phase I/II study was conducted to evaluate the efficacy, safety and pharmacokinetics of streptozocin (STZ) in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors. METHODS: Twenty-two patients received up to 4 cycles of intravenous STZ at either 500 mg/m2 once daily for 5 consecutive days every 6 weeks (daily regimen) or at 1000-1500 mg/m2 once weekly for 6 weeks (weekly regimen). Tumor response was evaluated using the modified RECIST criteria ver. 1.1, and adverse events were assessed by grade according to the National Cancer Institute CTCAE (ver. 4.0). RESULTS: Fourteen (63.6%) patients completed the study protocol. No patients had complete response; partial response in 2 (9.1%), stable disease in 17 (77.3%), non-complete response/non-progressive disease in 2 (9.1%) and only 1 (4.5%) had non-evaluable disease. Excluding the latter, the response rate in the daily and weekly regimens was 6.7% (1/15) and 16.7% (1/6), respectively, with an overall response rate of 9.5% (2/21). However, the best overall response in each patient showed that the disease control rate was 100%.Adverse events occurred in all 22 patients, including 17 grade 3 adverse events in 11 patients; however, no grade 4 or 5 adverse events were reported. Prophylactic hydration and antiemetic treatment reduced the severity and incidence of nephrotoxicity, nausea and vomiting. Plasma STZ concentrations decreased rapidly after termination of infusion, with a half-life of 32-40 min. Neither repeated administration nor dose increases affected pharmacokinetic parameters. CONCLUSIONS: STZ may be a useful option for Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

Safety, tolerability, pharmacokinetics, and antitumour activity of oleclumab in Japanese patients with advanced solid malignancies: a phase I, open-label study.

BACKGROUND: Cluster of differentiation (CD) 73-targeted immunotherapy and CD73 inhibition may reduce adenosine production, which can augment the host and/or immunotherapy response to tumours. We aimed to assess the safety and tolerability, pharmacokinetics, and antitumour activity of oleclumab, an anti-CD73 monoclonal antibody, in adult Japanese patients with advanced solid malignancies resistant to standard therapy. METHODS: In this phase I, single-centre, open-label study, patients received oleclumab 1500 mg (Cohort 1) or 3000 mg (Cohort 2) intravenously every 2 weeks. RESULTS: In total, six patients were enrolled in the study (three in each cohort), and all six patients received the study treatment. The median patient age was 56.0 years and 4/6 were males. All patients (100%) reported adverse events (AEs) during the study; five (83.3%) patients reported AEs related to the study treatment. One (16.7%) patient reported a Grade 3 AE (neutrophil count decreased) that was not related to the study treatment. No AEs with an outcome of death were reported, and no patients reported AEs or serious AEs leading to oleclumab discontinuation/dose interruption. No dose-limiting toxicities were reported, and no patient discontinued due to an AE related to the study treatment. Oleclumab exposure increased dose proportionally. No patient achieved disease control at 8 weeks, and all six patients developed progressive disease. CONCLUSIONS: Oleclumab was well tolerated in adult Japanese patients with advanced solid malignancies and no unexpected safety concerns were raised; oleclumab exposure increased with dose. Future studies on combination therapy with other agents are warranted.

The influence of UGT1A1 polymorphisms on modified FOLFIRINOX dose in double-variant-type patients with advanced pancreatic cancer.

BACKGROUND: UGT1A1 polymorphisms should be considered when using irinotecan-containing regimens, especially in patients with a double-variant-type (DV), including homozygous for UGT1A1*28 and UGT1A1*6 and heterozygous for both UGT1A1*28 and UGT1A1*6. We investigated the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) (irinotecan 80 mg/m2) in patients having DV. METHODS: Patients with advanced pancreatic cancer who had received FOLFIRINOX between January 2015 and December 2019 were included in this study. Non-DV patients received the standard mFOLFIRINOX (irinotecan 150 mg/m2) as first-line (non-DV1) or second-line therapy (non-DV2); however, DV patients received mFOLFIRINOX (irinotecan 80 mg/m2) as the second-line therapy (DV2). We retrospectively evaluated the safety and efficacy of the lowered irinotecan dose in the DV2 group relative to the non-DV1 (safety) or non-DV2 (safety and efficacy) groups. RESULTS: A total of 235 patients were eligible for this study with 118 patients in the non-DV1, 106 in the non-DV2, and 11 in the DV2 groups. Major grade 3-4 adverse events were neutropenia (33.9, 31.1, and 18.2%) and febrile neutropenia (6.8, 3.8, and 9.1%) in the non-DV1, non-DV2, and DV2 groups, respectively. The median progression-free survival was 3.4 months in the non-DV2 group, and 4.4 months in the DV2 group. The overall survival from the date of starting second-line chemotherapy was 8.8 months in the non-DV2 group and 11.5 months in the DV2 group. CONCLUSIONS: Based on our findings, the safety and efficacy of mFOLFIRINOX (irinotecan 80 mg/m2) in DV patients were comparable with the standard mFOLFIRINOX (irinotecan 150 mg/m2) in non-DV patients.

First-in-human study of the cancer peptide vaccine TAS0313 in patients with advanced solid tumors.

TAS0313, a novel cancer vaccine cocktail, was developed to overcome the disadvantages of previously developed short and long peptide vaccines; it comprises several long peptides targeting multiple cancer antigens. We evaluated TAS0313 monotherapy in Japanese patients with advanced solid tumors for which no other therapies were available. In the dose-finding cohort, patients received TAS0313 (9 or 27 mg) on days 1, 8, and 15 of cycles 1 and 2, and then on day 1 of each subsequent 21-day cycle. The primary objective was the evaluation of safety and tolerability. Secondary objectives were evaluation of efficacy, tumor responses, and immune activation (CTL, IgG, and tumor-infiltrating lymphocyte [TIL] levels). The full analysis set contained 10 patients in the 9-mg group and seven in the 27-mg group. No dose-limiting toxicities were reported in cycle 1. All adverse drug reactions (ADRs) were grade 1 or 2; the most common ADRs were injection site-related events. The best response was stable disease in four of 17 patients. The median progression-free survival (PFS) duration was 2.2 (95% confidence interval, 1.0-2.3) months overall; patients with baseline low lymphocyte counts (≤750/µL) had shorter PFS. Compared with baseline, TILs were increased in five patients. Although CTLs, IgG, and TILs were induced, no correlative pattern with clinical outcomes was observed. The safety, tolerability, and induction of immune responses in patients with advanced solid tumors receiving TAS0313 were confirmed. Further evaluation of TAS0313's efficacy as monotherapy or in combination with pembrolizumab is underway. The study is registered at www.clinicaltrials.jp (JapicCTI-183824).

A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors.

Background This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017.

Raptor and rictor expression in patients with human papillomavirus-related oropharyngeal squamous cell carcinoma.

BACKGROUND: Despite reports of a link between human papillomavirus (HPV) infection and mechanistic target of rapamycin (mTOR) signaling activation, the role of the mTOR pathway, especially raptor and rictor, in HPV-related head and neck cancer is still unclear. The aim of the present study was to elucidate the role of the mTOR pathway in HPV-related oropharyngeal squamous cell carcinoma (OPSCC). METHODS: The present study involved two strategies. The first was to investigate the activity of mTOR and mTOR-related complexes in high-risk HPV-positive (UM-SCC47 and CaSki) and HPV-negative (SCC-4 and SAS) cancer cell lines. The second was to elucidate mTOR complex expression in 80 oropharyngeal cancer tissues and to examine the relationship between mTOR complex expression and survival in patients with OPSCC. RESULTS: The UM-SCC47 and CaSki cell lines showed high gene and protein expression of raptor. They also exhibited G1/S and G2/M phase cell cycle arrest following 24 h incubation with 6 µM temsirolimus, a rapamycin analog, and temsirolimus administration inhibited their growth. HPV-related OPSCC samples showed high gene and protein expression of raptor and rictor compared with HPV-unrelated OPSCC. In addition, HPV-related OPSCC patients with high raptor and rictor expression tended to have a worse prognosis than those with low or medium expression. CONCLUSIONS: These results suggest that raptor and rictor have important roles in HPV-related OPSCC and that temsirolimus is a potential therapeutic agent for patients with HPV-related OPSCC. This is the first report to reveal the overexpression of raptor and rictor in HPV-related OPSCC.

The safety, tolerability and pharmacokinetics of niraparib in Japanese patients with solid tumours: results of a phase I dose-escalation study.

BACKGROUND: Niraparib is the only poly (adenosine diphosphate-ribose)-polymerase (PARP) inhibitor available as oral monotherapy for maintenance, regardless of BRCA mutational status. METHODS: This phase I, open-label, non-randomized, dose-escalation study was conducted in Japan using a 3 + 3 design. Adults (≥20 years) with metastatic or locally advanced solid tumours were enrolled. Niraparib 200 mg (cohort 1) or 300 mg (cohort 2) was administered once daily in 21-day cycles (no drug holiday between cycles) until progressive disease (PD) or unacceptable toxicity. The primary objective was to evaluate the safety and tolerability of niraparib in Japanese patients with advanced solid tumours. The number of patients with dose-limiting toxicities in cycle 1 and number with treatment-emergent adverse events were primary endpoints. Secondary endpoints were pharmacokinetics and tumour response. RESULTS: There were three patients in cohort 1 and six patients in cohort 2. Only one patient, in cohort 2, developed a dose-limiting toxicity (grade 4 platelet count decreased). All patients in both cohorts developed treatment-emergent adverse events. The most common treatment-related treatment-emergent adverse events were decreased appetite (n = 2) in cohort 1, and platelet count decreased as well as aspartate aminotransferase increased (both n = 5) in cohort 2. Mean Cmax and AUC0-24 of niraparib increased dose-proportionally after multiple doses (accumulation ratio of between 1.64 and 3.65); median tmax was 3-4 h. Two patients, both in cohort 2, had a partial response to treatment. CONCLUSIONS: Niraparib (200 or 300 mg/day) was tolerable and had a favourable pharmacokinetic profile in Japanese patients with advanced solid tumours.