Cancer Chemotherapy and Pharmacology

Effect of ethnicity on vinorelbine pharmacokinetics: a population pharmacokinetics analysis Abstract Background Pharmacokinetics of vinorelbine is mainly known from studies conducted in European patients. Interethnic differences in drug disposition may, however, induce interethnic variation in drug exposure. This paper aimed to evaluate the effect of ethnicity on the bioavailability and clearance of oral and intravenous vinorelbine. Methods Oral and intravenous vinorelbine pharmacokinetics data in Asian patients were pooled from two-phase II studies of patients with non-small-cell lung cancer or advanced breast cancer in China. Blood vinorelbine and its active metabolite, 4′-O-deacetylvinorelbine, were quantified using liquid chromatography–tandem mass spectrometry. Bayesian pharmacokinetic parameters were calculated and vinorelbine monotherapy results (intravenous 25 mg/m2; oral 60 mg/m2) of the Asian data set were compared to a reference European data set (intravenous 30 mg/m2; oral 80 mg/m2). Subsequently, a population pharmacokinetics analysis was conducted in a combined cohort (Asian data set + historical vinorelbine pharmacokinetics database) to investigate for a potential effect of ethnicity. Results Pharmacokinetics data from the Asian data set (oral: n = 47; intravenous: n = 34) was compared to the European reference data set (oral: n = 48; intravenous: n = 48). Mean apparent clearance of oral vinorelbine and mean absolute clearance of intravenous vinorelbine was comparable between the Asian and reference European data set. A population pharmacokinetic analysis (oral: n = 222; intravenous: n = 111) demonstrated no influence of ethnicity on oral and intravenous vinorelbine bioavailability and clearance. Conclusion Vinorelbine pharmacokinetics were found to be comparable between Asian and European patients. No relevant influence of ethnicity on vinorelbine bioavailability and clearance for oral and intravenous routes of administration was observed.

SN-38, the active metabolite of irinotecan, inhibits the acute inflammatory response by targeting toll-like receptor 4 Abstract Purpose Anticancer-drug efficacy seems to involve the direct interaction with host immune cells. Although topoisomerase I (Top I) inhibitors have been suggested to block LPS-evoked inflammation, the interaction between these drugs and toll-like receptor 4 (TLR4) is unaddressed. Methods SN-38, the active metabolite of the Top I inhibitor irinotecan, and TLR4 interaction was assessed using the in vitro luciferase nuclear factor-κB reporter assay, neutrophil migration to murine air-pouch, in silico simulation, and the thermal shift assay (TSA). Topotecan was used as a positive anti-inflammatory control. Results Non-cytotoxic concentrations of SN-38 attenuated LPS (a TLR4 agonist)-driven cell activation without affecting peptidoglycan (a TLR2 agonist)-activating response. Similarly, topotecan also prevented LPS-induced inflammation. Conversely, increasing concentrations of LPS reversed the SN-38 inhibitory effect. In addition, SN-38 abrogated LPS-dependent neutrophil migration and reduced TNF-α, IL-6, and keratinocyte chemoattractant levels in the air-pouch model, but failed to inhibit zymosan (a TLR2 agonist)-induced cell migration. A two-step molecular docking analysis indicated two potential binding sites for the SN-38 in the MD-2/TLR4 complex, the hydrophobic MD-2 pocket (binding energy of − 8.1 kcal/mol) and the rim of the same molecule (− 6.9 kcal/mol). The topotecan also bound to the MD-2 pocket. In addition, not only the lactone forms, but also the carboxylate conformations of both Top I inhibitors interacted with the MD-2 molecule. Furthermore, the TSA suggested the interaction of SN-38 with MD-2. Conclusions Therefore, SN-38 inhibits acute inflammation by blocking LPS-driven TLR4 signaling. This mechanism seems to be shared by other Top I inhibitors.

Exposure time versus cytotoxicity for anticancer agents Abstract Purpose Time is a critical factor in drug action. The duration of inhibition of the target or residence time of the drug molecule on the target often guides drug scheduling. Methods The effects of time on the concentration-dependent cytotoxicity of approved and investigational agents [300 compounds] were examined in the NCI60 cell line panel in 2D at 2, 3, 7 and in 3D 11 days. Results There was a moderate positive linear relationship between data from the 2-day NCI60 screen and the 3-, 7- and 11-day and a strong positive linear relationship between 3-, 7- and 11-day luminescence screen IC50s by Pearson correlation analysis. Cell growth inhibition by agents selective for a specific cell cycle phase plateaued when susceptible cells were growth inhibited or killed. As time increased the depth of cell growth inhibition increased without change in the IC50. DNA interactive agents had decreasing IC50s with increasing exposure time. Epigenetic agents required longer exposure times; several were only cytotoxic after 11 days’ exposure. For HDAC inhibitors, time had little or no effect on concentration response. There were potency differences amongst the three BET bromodomain inhibitors tested, and an exposure duration effect. The PARP inhibitors, rucaparib, niraparib, and veliparib reached IC50s < 10 μM in some cell lines after 11 days. Conclusions The results suggest that variations in compound exposure time may reflect either mechanism of action or compound chemical half-life. The activity of slow-acting compounds may optimally be assessed in spheroid models that can be monitored over prolonged incubation times.

Moxetumomab pasudotox-tdfk for relapsed/refractory hairy cell leukemia: a review of clinical considerations Abstract Purpose Hairy cell leukemia (HCL) is a rare mature B cell leukemia. Purine analogs are the mainstay of treatment of HCL, but relapse after purine analog therapy is common. Outcomes of treatment of relapsed/refractory HCL typically diminish with each successive line of therapy. Moxetumomab pasudotox-tdfk is a novel recombinant immunotoxin approved for the treatment of patients with relapsed/refractory HCL who have received at least two prior therapies, including a purine analog. This article reviews HCL treatment, focusing on moxetumomab pasudotox-tdfk, its place in therapy, considerations for preparation and administration, and strategies for prevention and management of toxicities. Methods A literature search was conducted in the PubMed database from inception to January 2019, using the following terms: moxetumomab, hairy cell leukemia, relapsed/refractory hairy cell leukemia, immunotoxin, and CD22. The package insert and available posters and abstracts were also reviewed. Results FDA approval of moxetumomab pasudotox-tdfk was based on a phase III single-arm, open-label trial in 80 patients. Treatment with moxetumomab pasudotox-tdfk yielded a durable complete response rate of 30% with a median duration of response that had not yet been reached at a median follow-up of 16.7 months. The objective response rate was 75% based on blinded independent central review. The most common adverse reactions were infusion-related reactions, edema, nausea, fatigue, headache, pyrexia and anemia. Serious adverse events include capillary leak syndrome and hemolytic uremic syndrome. Conclusions Clinicians providing care for patients receiving moxetumomab pasudotox-tdfk should be aware of the strategies required for safe administration, including the management of serious adverse events.

Cancer immunotherapy: the art of targeting the tumor immune microenvironment Abstract For many decades, cancer treatment has been strongly directed toward the development of cytotoxic and cytostatic drugs, quite often leading to disappointing results due to the inter- and intra-tumoral heterogeneity. Lately, this intra-cellular look has given way to the understanding of the tumor microenvironment, thus enabling modification of the immunological dynamics between tumor cells and their host. An era of new drugs aiming to unlock the host immune system against tumor cells is steadily increasing. Strategies involving adoptive cell therapy, therapeutic vaccines, immune checkpoint inhibitors and so on have provided spectacular clinical responses and increased survival in previously refractory settings and “hard-to-treat” cancers. Based on a comprehensive search in the main scientific databases, annals of recent renowned oncology congresses and platforms of ongoing trials, the clinical pharmacology characteristics of the main classes of immunotherapeutic agents, as well as the new treatment strategies related to immunotherapy in solid tumors, are carefully discussed throughout this review.

An open label phase 1 study evaluation safety, tolerability, and maximum tolerated dose of oral administration of irinotecan in combination with capecitabine Abstract Purpose Oral administration of chemotherapy offers several advantages in comparison with intravenous administration. Previously, data on a new oral formulation of irinotecan have been published. The aim of the present study was to evaluate the safety, tolerability, and Maximum Tolerated Dose (MTD) of the new oral irinotecan formulation in combination with oral capecitabine. Methods The study was an open label, phase 1, single center, extension part in which oral irinotecan was investigated in combination with capecitabine. The MTD of irinotecan in combination with capecitabine was 17.5 mg/m2 once daily for 14 consecutive days in combination with capecitabine 800 mg/m2 twice daily. Eligible patients were adults with metastatic or unresectable solid tumors for which no standard curative or palliative therapies existed. Results 14 patients were included in the extension part. No grade 3 or 4 hematologic toxicities were observed. Non-hematological toxicities included grade 1 and 2 diarrhea, fatigue, cholinergic syndrome, vomiting, and weight loss. Totally, 3 grade 3 toxicities and no grade 4 event were reported. No objective responses were observed. Five patients had stable disease lasting median 14 weeks. Conclusions Capecitabine in combination with oral irinotecan could be a new treatment option offering a more convenient and patient friendly treatment strategy compared to intravenous irinotecan. The combination is fairly tolerated; however, further investigations are needed to assess the efficacy of this regimen.

Postoperative chemotherapy as adjuvant treatment for endometrioid adenocarcinoma: early stage vs late stage Abstract Background Adjuvant chemotherapy treatment for different endometrial cancer stages is still debated. We aimed to evaluate the outcome of early (FIGO I–II) vs late stage (FIGO III–IV) endometrial cancer in an institutional experience using chemotherapy only after surgery. Method Charts of patients with endometrial carcinoma who underwent surgery with postoperative chemotherapy between February 2012 and December 2017 were retrospectively identified, and the recurrence as well as prognosis were assessed. Result Of the 272 eligible endometrioid adenocarcinoma (EA) patients, 127 had received chemotherapy, 145 did not receive chemotherapy; 37 were in late stage (FIGO III–IV) and 235 were in early stage (FIGO I–II). In the late stage group, patients with no chemotherapy had worse overall survival (OS) and recurrence-free survival (RFS) as compared to the patients taking chemotherapy (OS, 28.6% vs 76.4%, P = 0.059; RFS, 17.1% vs 66.4%, P = 0.053). However, in the early stage group, there was no significant difference between the OS and RFS between the patients that were receiving and not receiving chemotherapy (OS, 84.1% vs 93.3%, P = 0.789; RFS, 76.7% vs 72.4%, P = 0.924). Independent predictive factors of recurrence were age over 53 years, histological grade G3, as well as late stages (FIGO III–IV), while independent predictive factors of OS were age over 53 years, deeper depth of myometrial invasion, and late stages (FIGO III–IV). Conclusion In late stages, patients with chemotherapy had lower recurrence rate and favorable OS as compared to patients not taking chemotherapy, which was the benefit of postoperative adjuvant chemotherapy, and chemotherapy might be strongly considered in late stage EA.

Phase I study of ipatasertib as a single agent and in combination with abiraterone plus prednisolone in Japanese patients with advanced solid tumors Abstract Purpose Ipatasertib is a selective inhibitor of Akt, a frequently activated protein kinase in human cancers. The current study assessed the safety, tolerability, and pharmacokinetics of ipatasertib in Japanese patients with solid tumors. Methods This was a phase I, open-label, 3 + 3 dose-escalation study conducted in two stages. In stage I, Japanese patients with solid tumors were administered ipatasertib 200, 400, or 600 mg/day for 21 days of a 28-day cycle. In stage II, Japanese patients with castration-resistant prostate cancer were administered ipatasertib 200 or 400 mg/day in combination with abiraterone and prednisolone in 28-day cycles. Dose-limiting toxicity (DLT) was assessed at each dose before enrolling patients at a higher dose; DLT was used to determine the maximum tolerated dose (MTD) and maximum administered dose (MAD). Pharmacokinetic parameters were assessed after a single dose and at steady state. Results Fifteen patients were enrolled in Stage I and six in Stage II. The ipatasertib MTD was 600 mg as monotherapy and MAD was 400 mg in combination with abiraterone and prednisolone. Ipatasertib plasma exposure was dose proportional across the dose range, and was not markedly affected by concurrent administration of abiraterone plus prednisolone. Stable disease (SD) was observed in eight patients treated with ipatasertib monotherapy (53.3%); four patients had SD and one had complete response with ipatasertib plus abiraterone and prednisolone. Conclusions Ipatasertib, at the monotherapy MTD of 600 mg/day and MAD of 400 mg/day in combination with abiraterone and prednisolone, was safe and tolerable in Japanese patients with solid tumors.

The role of apoptosis defects in malignant mesothelioma pathogenesis with an impact on prognosis and treatment Abstract Malignant mesothelioma (MM) is a highly aggressive tumor that is strongly related to asbestos fiber exposure. The tumorigenesis procedure in MM is complex, and many pathogenetic mechanisms including chronic inflammation, deregulation of cell death, and the genomic copy-number losses and gains may contribute to carcinogenesis. MM cells are resistant to TRAIL-mediated apoptosis due to defects in extrinsic apoptotic pathway. CAPS, a regulator of cell cycle and death, may contribute to the MM development as well. BAP1 is the most frequently inactivated gene in MPM; BAP1 deficiency triggers malignant transformation via disruption of DNA repair, transcription regulation, cell metabolism, apoptosis, and ferroptosis. In addition, bcl-2 family proteins as well as abnormal activation of PI3 K/Akt/mTOR pathway and deregulation of the Wnt signaling pathway may result in MM tumorigenesis. Finally, the Hippo pathway plays a critical role in MPM development. Mutations of NF2 and LATS lead to YAP activation in MPM. Thus, inhibition of YAP activity by YAP inhibitors could be a potentially promising treatment option for MM. In conclusion, extensive genetic alterations exist in mesotheliomas associated with the signaling of apoptotic HM cells death. The comprehension of these pathways may contribute to enhancing survival via developing new effective therapeutic strategies.

MicroRNA-552 deficiency mediates 5-fluorouracil resistance by targeting SMAD2 signaling in DNA-mismatch-repair-deficient colorectal cancer Abstract Objective Although DNA-mismatch-repair-deficient (dMMR) status and aberrant expression of miRNAs are both critically implicated in the pathogenesis of resistance to 5-fluorouracil (5-FU) in colorectal cancer (CRC), whether these two factors regulate tumor response to 5-FU in a coordinated manner remains unknown. This study is designed to elucidate whether changes in miR-552 expression levels correlate to 5-FU-based chemoresistance in CRC, and to further identify the putative targets of miR-552 using multiple approaches. Methods miR-552 expression was assessed in 5-FU-resistant CRC tissues and cells using real-time PCR. Effects of miR-552 dysregulation on 5-FU resistance in CRC cells were determined by measuring cell viability, apoptosis and in vivo oncogenic capacity. Finally, we studied the posttranscriptional regulation of SMAD2 by miR-552 using multiple approaches including luciferase reporter assay, site-directed mutagenesis and transient/stable transfection, at molecular and functional levels. Results Expression of miR-552 was significantly downregulated in 5-FU-resistant CRC tissues and cells, and this downregulation, regulated by dMMR, was associated with poor postchemotherapy prognosis. Functionally, forced expression of miR-552 exhibited a proapoptotic effect and attenuated 5-FU resistance, whereas inhibition of miR-552 expression potentiated 5-FU resistance in CRC cells. Mechanically, miR-552 directly targeted the 3′-UTR of SMAD2, and stable ablation of SMAD2 neutralized the promoting effects of miR-552 deficiency-induced 5-FU resistance. Conclusions Overall, our findings have revealed a critical role of miR-552/SMAD2 cascade in modulating cellular response to 5-FU chemotherapy. miR-552 may act as an efficient mechanistic link synchronizing dMMR and 5-FU resistance in CRC.