Raltitrexed Chemotherapy Regimen Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer: A Prospective Multicenter Phase II Trial.

OBJECTIVES: Clinical studies have shown that bevacizumab plus chemotherapy significantly improves efficacy in metastatic colorectal cancer (mCRC). This prospective study aims to investigate the efficacy and safety of changing second-line treatment to raltitrexed-based chemotherapy regimens plus bevacizumab in mCRC patients who have failed the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab. METHODS: This is a prospective, open-label, multicenter, phase II clinical study. A total of 100 patients with mCRC after failure of the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab were enrolled from November 2016 to October 2021, and received second-line raltitrexed-based chemotherapy regimen plus bevacizumab. Patients were treated for 6 cycles, and efficacy evaluation over stable disease were followed by maintenance treatment of bevacizumab and raltitrexed until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and toxicity. RESULTS: Ninety-four patients were treated with SALIRI (raltitrexed + irinotecan) plus bevacizumab, and six patients with SALOX (raltitrexed + oxaliplatin) plus bevacizumab. Median PFS was 8.4 (95% CI: 6.2-11.0) months, including 8.2 (95% CI 6.2, 11.0) months in the SALIRI group and 11.6 (95% CI 3.1, NA) months in the SALOX group. Median OS was 17.6 (95% CI 15.2, 22.0) months in the SALIRI group and 17.1 (95% CI 4.1, NA) months in the SALOX group. ORR and DCR were 25.5% and 87.2% in the SALIRI group, and 33.3% and 83.3% in the SALOX group, respectively. A low incidence of grade 3-4 adverse events was observed. CONCLUSIONS: Raltitrexed-based chemotherapy regimens plus bevacizumab improved survival duration in mCRC patients with failed first-line therapy. Therefore, treatment with raltitrexed-based chemotherapy regimens plus bevacizumab could be a superior therapeutic option for second-line chemotherapy in mCRC (ClinicalTrials.gov registration number: NCT03126071).

Efficacy of hepatic arterial infusion chemotherapy in patients with primary liver cancer with portal vein tumor thrombosis: a comparative analysis of different perfusion chemotherapeutic regimens.

BACKGROUND: Portal vein tumor thrombosis (PVTT) commonly occurs in patients with primary liver cancer (PLC). Transarterial chemoembolization (TACE) is a treatment for patients with PLC and PVTT. Some studies have shown that combining TACE therapy with hepatic arterial infusion chemotherapy (HAIC) might improve the survival rate of PLC patients with PVTT. However, few studies have compared the different regimens of PLC with PVTT. We aimed to compare the differences between the oxaliplatin + raltetrexed regimen and FOLFOX regimen. METHODS: We divided the 248 patients into two groups. There were 60 patients in the oxaliplatin + ratitetrexed group and 74 patients in the FOLFOX group. The primary endpoints were OS and PFS. The secondary endpoints were ORR and adverse events. We used SPSS software, the Kaplan-Meier method, the t test, and the rank sum test to compare the differences between the two groups. RESULTS: The median OS was 10.82 months in the oxaliplatin + raltitrexed group and 8.67 months in the FOLFOX group. The median PFS time was greater in the oxaliplatin + raltitrexed group (10.0 months) than that in the FOLFOX group (7.1 months). The ORR was greater in the oxaliplatin + raltitrexed group than that in the FOLFOX group (18.3% vs. 13.5%; P = 0.445). The DCR in the oxaliplatin + raltitrexed group was higher than that in the FOLFOX group (70.0% vs. 64.8%; P = 0.529). However, in the subgroup analysis, the difference between them was more significant in the type II PVTT subgroup. The OS was 12.08 months in the oxaliplatin + raltitrexed group and 7.26 months in the FOLFOX group (P = 0.008). The PFS was 11.68 months in the oxaliplatin + raltitrexed group and 6.26 months in the FOLFOX group (P = 0.014). In the right branch of type II PVTT, the OS was 13.54 months in the oxaliplatin + raltitrexed group and 6.89 months in the FOLFOX group (P = 0.015), and the PFS was 13.35 months in the oxaliplatin + raltitrexed group and 6.27 months in the FOLFOX group (P = 0.030). The incidence of adverse reactions was similar between the two groups. CONCLUSIONS: Compared with the FOLFOX regimen, the oxaliplatin + raltitrexed chemoembolization regimen had longer OS, PFS time and ORR and DCR and it was safe and tolerable.

CHRONOS-4: phase 3 study of copanlisib plus rituximab-based immunochemotherapy in relapsed indolent B-cell lymphoma.

ABSTRACT: Copanlisib, a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α and δ isoforms, previously demonstrated durable responses as monotherapy and improved progression-free survival (PFS) in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma (iNHL). CHRONOS-4 was a phase 3, randomized, double-blind, placebo-controlled study to investigate the efficacy and safety of copanlisib in combination with standard immunochemotherapy in patients with relapsed iNHL. Patients (n = 524) were randomized (1:1) to copanlisib (60 mg IV) plus immunochemotherapy (rituximab and bendamustine [R-B] or placebo plus R-B). Copanlisib/placebo were administered with R-B (days 1, 8, and 15 of each 28-day cycle) for ≤6 cycles and as monotherapy from cycle 7 up to 12 months. The primary study end point was PFS. Median exposure was 8.5 months (0.2-12.9) for copanlisib plus R-B and 11.4 months (0.1-12.6) for placebo plus R-B. Median PFS was 32.9 months (95% confidence interval [CI], 24.4-38.6) for copanlisib plus R-B and 33.3 months (95% CI, 27.8-42.8) for placebo plus R-B (hazard ratio, 1.13; 95% CI, 0.88-1.44; P = .83). No differences between treatment arms were observed in overall survival (data not yet mature), objective response rate, and duration of response for the overall population or individual histology types. Overall, copanlisib plus R-B was associated with higher rates of serious treatment-emergent adverse events (TEAEs), grade 4 and 5 TEAEs, and treatment discontinuation. A number of serious TEAEs were infections. Overall, copanlisib plus R-B did not provide clinical benefit vs placebo plus R-B and was associated with worse tolerability in patients with relapsed iNHL. This trial was registered at www.ClinicalTrials.gov as #NCT02626455.

A Phase II, Open-Label, Randomized Trial of Durvalumab With Olaparib or Cediranib in Patients With Mismatch Repair-Proficient Colorectal or Pancreatic Cancer.

BACKGROUND: The use of immunotherapy in mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC) is associated with limited efficacy. DAPPER (NCT03851614) is a phase 2, basket study randomizing patients with pMMR CRC or PDAC to durvalumab with olaparib (durvalumab + olaparib) or durvalumab with cediranib (durvalumab + cediranib). METHODS: PDAC or pMMR-CRC patients were randomized to either durvalumab+olaparib (arm A), or durvalumab + cediranib (arm B). Co-primary endpoints included pharmacodynamic immune changes in the tumor microenvironment (TME) and safety. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples were analyzed by multiplexed immunohistochemistry and RNA-sequencing. RESULTS: A total of 31 metastatic pMMR-CRC patients were randomized to arm A (n = 16) or B (n = 15). In 28 evaluable patients, 3 patients had stable disease (SD) (2 patients treated with durvalumab + olaparib and 1 patient treated with durvalumab + cediranib) while 25 had progressive disease (PD). Among patients with PDAC (n = 19), 9 patients were randomized to arm A and 10 patients were randomized to arm B. In 18 evaluable patients, 1 patient had a partial response (unconfirmed) with durvalumab + cediranib, 1 patient had SD with durvalumab + olaparib while 16 had PD. Safety profile was manageable and no grade 4-5 treatment-related adverse events were observed in either arm A or B. No significant changes were observed for CD3+/CD8+ immune infiltration in on-treatment biopsies as compared to baseline for pMMR-CRC and PDAC independent of treatment arms. Increased tumor-infiltrating lymphocytes at baseline, low baseline CD68+ cells and different immune gene expression signatures at baseline were associated with outcomes. CONCLUSIONS: In patients with pMMR-CRC or PDAC, durvalumab + olaparib and durvalumab + cediranib showed limited antitumor activity. Different immune components of the TME were associated with treatment outcomes.

Clinical Pharmacokinetics and Pharmacodynamics of Letermovir in Allogenic Hematopoietic Cell Transplantation.

Letermovir is a newly developed antiviral agent used for the prophylaxis of human cytomegalovirus infections in patients undergoing allogeneic hematopoietic cell transplantation. This novel anti-cytomegalovirus drug, used for the prophylaxis of cytomegalovirus reactivation until approximately 200 days after transplantation, effectively reduces the risk of clinically significant cytomegalovirus infection. No human counterpart exists for the terminase complex; letermovir is virus specific and lacks some toxicities previously observed with other anti-cytomegalovirus drugs, such as cytopenia and nephrotoxicity. The absolute bioavailability of letermovir in healthy individuals is estimated to be 94% based on a population-pharmacokinetic analysis. In contrast, oral administration of letermovir to patients undergoing hematopoietic cell transplantation results in lower exposure than that in healthy individuals. Renal or hepatic impairment does not influence the intrinsic clearance of letermovir. Co-administration of letermovir may alter the plasma concentrations of other drugs, including itself, as it acts as a substrate and inhibitor/inducer of several drug-metabolizing enzymes and transporters. In particular, attention should be paid to the drug-drug interactions between letermovir and calcineurin inhibitors or azole antifungal agents, which are commonly used in patients undergoing hematopoietic cell transplantation. This article reviews and summarizes the clinical pharmacokinetics and pharmacodynamics of letermovir, focusing on patients undergoing hematopoietic cell transplantation, healthy individuals, and specific patient subsets.

Tocopherol-human serum albumin nanoparticles enhance lapatinib delivery and overcome doxorubicin resistance in breast cancer.

Introduction: HER2, a tyrosine kinase receptor, is amplified in HER2-positive breast cancer, driving cell signaling and growth. Aim: This study aimed to combat multidrug resistance in Dox-insensitive breast adenocarcinoma by creating a nanoformulation therapy with a tyrosine kinase inhibitor. Methodology: Human serum albumin (HSA) was conjugated with α-D-tocopherol succinate to form nanoaggregates loaded with lapatinib (Lapa). Results: The resulting Lapa@HSA(VE) NPs were 117.2 nm in size and demonstrated IC50 values of 10.25 µg/ml on MCF7 (S) and 8.02 µg/ml on MCF7 (R) cell lines. Conclusion: Lapa@HSA(VE) NPs showed no hepatotoxicity, unlike free Lapa, as seen in acute toxicity studies in rats.

[Box: see text].

Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial.

The vascular endothelial growth factor pathway plays a key role in the pathogenesis of gastric cancer. In the multicenter, double-blind phase 3 FRUTIGA trial, 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma who progressed on fluorouracil- and platinum-containing chemotherapy were randomized (1:1) to receive fruquintinib (an inhibitor of vascular endothelial growth factor receptor-1/2/3; 4 mg orally, once daily) or placebo for 3 weeks, followed by 1 week off, plus paclitaxel (80 mg/m2 intravenously on days 1/8/15 per cycle). The study results were positive as one of the dual primary endpoints, progression-free survival (PFS), was met (median PFS, 5.6 months in the fruquintinib arm versus 2.7 months in the placebo arm; hazard ratio 0.57; 95% confidence interval 0.48-0.68; P < 0.0001). The other dual primary endpoint, overall survival (OS), was not met (median OS, 9.6 months versus 8.4 months; hazard ratio 0.96, 95% confidence interval 0.81-1.13; P = 0.6064). The most common grade ≥3 adverse events were neutropenia, leukopenia and anemia. Fruquintinib plus paclitaxel as a second-line treatment significantly improved PFS, but not OS, in Chinese patients with advanced gastric or gastroesophageal junction adenocarcinoma and could potentially be another treatment option for these patients. ClinicalTrials.gov registration: NCT03223376 .

Afatinib or Bevacizumab in combination with Osimertinib efficiently control tumor development in orthotopic murine models of non-small lung cancer.

Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account. We have established cell lines expressing the luciferase gene from lines with varied genetic backgrounds, commonly encountered in patients with pulmonary adenocarcinoma. We have characterized these lines by testing their response to multiple drugs. Thus, we have developed orthotopic preclinical mouse models of NSCLC with very high engraftment efficiency. These models allow the easy monitoring of tumor growth, particularly in response to treatment, and of tumor cells dissemination in the body. We show that concomitant treatment with osimertinib (3rd generation tyrosine kinase inhibitor targeting mutated EGFR) and bevacizumab (anti-angiogenic targeting VEGF) can have a beneficial therapeutic effect on EGFR-mutated tumors. We also show that the addition of afatinib to osimertinib-treated tumors in escape leads to tumor growth inhibition. No such effect is observed with selumetinib or simvastatin. These preclinical mouse models therefore make it possible to test innovative therapeutic combinations and are also a tool of choice for studying resistance mechanisms.

Phase Ib dose-escalation trial of taselisib (GDC-0032) in combination with HER2-directed therapies in patients with advanced HER2+ breast cancer.

BACKGROUND: In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired resistance, potentially mediated through phosphoinositide-3-kinase (PI3K) signaling. We investigated adding taselisib, an α-selective potent oral inhibitor of PI3K, to different HER2-directed regimens in order to improve disease control. PATIENTS AND METHODS: Patients (n = 68) with advanced HER2+ breast cancer were enrolled to this open-label, dose-escalation phase Ib study. The primary endpoint was defining the maximal tolerated dose (MTD) for the various taselisib-containing combinations. The secondary endpoint was safety. Exploratory endpoints included circulating tumor DNA analysis. The study included four cohorts: (A) taselisib + trastuzumab emtansine (T-DM1), (C) taselisib + trastuzumab and pertuzumab (TP), (D) taselisib + TP + paclitaxel, and (E) taselisib + TP + fulvestrant. RESULTS: Following dose escalation, the taselisib MTD was defined as 4 mg once daily. Treatment was associated with significant toxicities, as 34 out of 68 patients experienced grade ≥3 adverse events (AEs) attributed to taselisib, the most common all-grade AEs being diarrhea, fatigue, and oral mucositis. At a median follow-up of 43.8 months, median progression-free survival (PFS) for the MTD-treated population in cohorts A, C, and E was 6.3 [95% confidence interval (CI) 3.2-not applicable (NA)] months, 1.7 (95% CI 1.4-NA) months, and 10.6 (95% CI 8.3-NA) months, respectively. The median PFS for patients in cohort A with prior T-DM1 use was 10.4 (95% CI 2.7-NA) months. CONCLUSIONS: PIK3CA targeting with taselisib in combination with HER2-targeted therapies was associated with both promising efficacy and substantial toxicities.

Vandetanib in locally advanced or metastatic differentiated thyroid cancer refractory to radioiodine therapy.

The VERIFY study aimed to determine the efficacy of vandetanib in patients with differentiated thyroid cancer (DTC) that is either locally advanced or metastatic and refractory to radioiodine (RAI) therapy. Specifically, VERIFY is a randomized, double-blind, multicenter phase III trial aimed to determine the efficacy and safety of vandetanib in tyrosine kinase inhibitor-naive patients with locally advanced or metastatic RAI-refractory DTC with documented progression (NCT01876784). Patients were randomized 1:1 to vandetanib or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included best objective response rate, overall survival (OS), safety, and tolerability. Patients continued to receive randomized treatment until disease progression or for as long as they were receiving clinical benefit unless criteria for treatment discontinuation were met. Following randomization, 117 patients received vandetanib, and 118 patients received a placebo. Median PFS was 10.0 months in the vandetanib group and 5.7 months in the placebo group (hazard ratio: 0.75; 95% CI: 0.55-1.03; P = 0.080). OS was not significantly different between treatment arms. Common Terminology Criteria for Adverse Events (CTCAE) of grade ≥3 were reported in 55.6% of patients in the vandetanib arm and 25.4% in the placebo arm. Thirty-three deaths (28.2%; one related to study treatment) occurred in the vandetanib arm compared with 16 deaths (13.6%; two related to treatment) in the placebo arm. No statistically significant improvement was observed in PFS in treatment versus placebo in patients with locally advanced or metastatic, RAI-refractory DTC. Moreover, active treatment was associated with more adverse events and more deaths than placebo, though the difference in OS was not statistically significant.

Once daily cediranib and weekly paclitaxel to prevent malignant bowel obstruction in at-risk patients with platinum-resistant ovarian cancer (CEBOC): a single-arm, phase II safety trial.

OBJECTIVE: Cytotoxic chemotherapy for ovarian cancer can be augmented by co-administration of vascular endothelial growth factor inhibitors but these are contraindicated in patients with bowel obstruction due to the risk of gastrointestinal perforation. We evaluated the safety and feasibility of paclitaxel plus cediranib to treat patients with platinum-resistant ovarian cancer at risk of malignant bowel obstruction. METHODS: A phase II trial included eligible patients between March 2018 and February 2021, identified by clinical symptoms and radiographic risk factors for malignant bowel obstruction. Cediranib (20 mg/day) was added to paclitaxel (70 mg/m2/week) within 9 weeks of starting paclitaxel if pretreatment bowel symptoms had improved. The primary endpoint was the number of patients treated for ≥5 days with cediranib that were free of grade 3-5 gastrointestinal perforation or fistula. Secondary endpoints were hospitalization for bowel obstruction, grade ≥3 adverse events, treatment compliance assessed by relative dose intensity, objective response, progression-free survival, and overall survival. RESULTS: Thirty patients were recruited. Of these, 12 received paclitaxel alone and 17 received paclitaxel and cediranib in combination. One patient died before starting treatment. No patient developed a grade 3-5 gastrointestinal perforation or fistula (one sided 95% confidence interval (CI) upper limit 0.16). One patient required hospitalization for bowel obstruction but recovered with conservative management. The most common cediranib-related grade ≥3 adverse events were fatigue (3/17), diarrhorea (2/17), and hypomagnesemia (2/17). Relative dose intensity for paclitaxel was 90% (interquartile range (IQR) 85-100%; n=29) and for cediranib 88% (IQR 76-93%; n=17). The objective response in patients who received paclitaxel and cediranib was 65.0% (one complete and 10 partial responses). Median progression-free survival was 6.9 months (95% CI 4.4-11.5 months; n=17) and overall survival was 19.4 months (95% CI 10.1-20.4 months; n=17). Median follow-up was 12.4 months (8.9-not reached; n=17). CONCLUSIONS: The unexpectedly high withdrawal rate during paclitaxel alone, before introducing cediranib, meant we were unable to definitely conclude that paclitaxel plus cediranib did not cause gastrointestinal perforation or fistula. The regimen was however tolerated. TRIAL REGISTRATION NUMBER: EudraCT 2016-004618-93.

A phase 2 trial exploring the significance of homologous recombination status in patients with platinum sensitive or platinum resistant relapsed ovarian cancer receiving combination cediranib and olaparib.

OBJECTIVE: Combination cediranib/olaparib has reported activity in relapsed ovarian cancer. This phase 2 trial investigated the activity of cediranib/olaparib in relapsed ovarian cancer and its association with homologous recombination deficiency (HRD). METHODS: Seventy patients were enrolled to cohorts of either platinum-sensitive or platinum-resistant ovarian cancer and received olaparib tablets 200 mg twice daily and cediranib tablets 30 mg once daily under a continuous dosing schedule. HRD testing was performed on pre-treatment, on-treatment and archival biopsies by sequencing key homologous recombination repair (HRR) genes and by genomic LOH analysis. The primary objective for the platinum-sensitive cohort was the association of HRD, defined as presence of HRR gene mutation, with progression-free survival (PFS). The primary objective for the platinum-resistant cohort was objective response rate (ORR), with a key secondary endpoint evaluating the association of HRD status with activity. RESULTS: In platinum-sensitive ovarian cancer (N = 35), ORR was 77.1% (95% CI 59.9-89.6%) and median PFS was 16.4 months (95% CI 13.2-18.6). Median PFS in platinum-sensitive HRR-HRD cancers (N = 22) was 16.8 months (95% CI 11.3-18.6), and 16.4 months (95% CI 9.4-NA) in HRR-HR proficient cancers (N = 13; p = 0.57). In platinum-resistant ovarian cancer (N = 35), ORR was 22.9% (95% CI 10.4-40.1%) with median PFS 6.8 months (95% CI 4.2-9.1). Median PFS in platinum-resistant HRR-HRD cancers (N = 7) was 10.5 months (95% CI 3.6-NA) and 5.6 months (95% CI 3.6-7.6) in HRR-HR proficient cancers (N = 18; p = 0.23). CONCLUSIONS: Cediranib/olaparib had clinical activity in both platinum-sensitive and -resistant ovarian cancer. Presence of HRR gene mutations was not associated with cediranib/olaparib activity in either setting.

Evaluation of Copanlisib in Combination with Eribulin in Triple-negative Breast Cancer Patient-derived Xenograft Models.

The PI3K pathway regulates essential cellular functions and promotes chemotherapy resistance. Activation of PI3K pathway signaling is commonly observed in triple-negative breast cancer (TNBC). However previous studies that combined PI3K pathway inhibitors with taxane regimens have yielded inconsistent results. We therefore set out to examine whether the combination of copanlisib, a clinical grade pan-PI3K inhibitor, and eribulin, an antimitotic chemotherapy approved for taxane-resistant metastatic breast cancer, improves the antitumor effect in TNBC. A panel of eight TNBC patient-derived xenograft (PDX) models was tested for tumor growth response to copanlisib and eribulin, alone or in combination. Treatment-induced signaling changes were examined by reverse phase protein array, immunohistochemistry (IHC) and 18F-fluorodeoxyglucose PET (18F-FDG PET). Compared with each drug alone, the combination of eribulin and copanlisib led to enhanced tumor growth inhibition, which was observed in both eribulin-sensitive and -resistant TNBC PDX models, regardless of PI3K pathway alterations or PTEN status. Copanlisib reduced PI3K signaling and enhanced eribulin-induced mitotic arrest. The combination enhanced induction of apoptosis compared with each drug alone. Interestingly, eribulin upregulated PI3K pathway signaling in PDX tumors, as demonstrated by increased tracer uptake by 18F-FDG PET scan and AKT phosphorylation by IHC. These changes were inhibited by the addition of copanlisib. These data support further clinical development for the combination of copanlisib and eribulin and led to a phase I/II trial of copanlisib and eribulin in patients with metastatic TNBC. SIGNIFICANCE: In this research, we demonstrated that the pan-PI3K inhibitor copanlisib enhanced the cytotoxicity of eribulin in a panel of TNBC PDX models. The improved tumor growth inhibition was irrespective of PI3K pathway alteration and was corroborated by the enhanced mitotic arrest and apoptotic induction observed in PDX tumors after combination therapy compared with each drug alone. These data provide the preclinical rationale for the clinical testing in TNBC.

Evaluating the efficacy and safety of letermovir compared to valganciclovir for the prevention of human cytomegalovirus disease in adult lung transplant recipients.

BACKGROUND: Lung transplant recipients are at high risk for severe cytomegalovirus (CMV) disease. Off-label use of letermovir (LET) may avert myelotoxicity associated with valganciclovir (VGCV), but data in lung transplantation are limited. This study aims to evaluate the outcomes of LET prophylaxis among lung transplant recipients. METHODS: This retrospective, matched cohort study included lung transplant recipients who received LET for primary CMV prophylaxis following VGCV intolerance. Patients were matched 1:1 to historical VGCV controls based on age, serostatus group, and time from transplant. The primary outcome was CMV breakthrough within 1 year post-LET initiation; secondary outcomes included hematologic changes. RESULTS: A total of 124 lung transplant recipients were included per group (32% CMV mismatch, D+R-), with LET initiated a median of 9.6 months post-transplantation. One CMV breakthrough event (0.8%) was observed in the LET group versus four (3.2%) in the VGCV group (p = .370). The median (interquartile range) white blood cell (WBC) count was 3.1 (2.1-5.6) at LET initiation which increased to 5.1 (3.9-7.2) at the end of follow-up (p <.001). For VGCV controls, WBC was 4.8 (3.4-7.2) at baseline and 5.4 (3.6-7.2) at the end of follow-up; this difference was not statistically significant (p = .395). Additionally, 98.4% of LET patients experienced ≥1 leukopenia episode in the year prior to LET compared to 71.8% the year after initiation (p <.001). Similar results were observed for neutropenia (48.4% and 17.7%, p <.001). CONCLUSION: LET prophylaxis was associated with a low rate of CMV reactivation and leukopenia recovery. LET may represent a reasonable prophylaxis option for lung transplant recipients unable to tolerate VGCV.

Inhibition of Amyloid-ß (Aß)-Induced Cognitive Impairment and Neuroinflammation in CHI3L1 Knockout Mice through Downregulation of ERK-PTX3 Pathway.

Several clinical studies reported that the elevated expression of Chitinase-3-like 1 (CHI3L1) was observed in patients suffering from a wide range of diseases: cancer, metabolic, and neurological diseases. However, the role of CHI3L1 in AD is still unclear. Our previous study demonstrated that 2-({3-[2-(1-Cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}culfanyl)-N-(4-ethylphenyl)butanamide, a CHI3L1 inhibiting compound, alleviates memory and cognitive impairment and inhibits neuroinflammation in AD mouse models. In this study, we studied the detailed correlation of CHI3L1 and AD using serum from AD patients and using CHI3L1 knockout (KO) mice with Aß infusion (300 pmol/day, 14 days). Serum levels of CHI3L1 were significantly elevated in patients with AD compared to normal subjects, and receiver operating characteristic (ROC) analysis data based on serum analysis suggested that CHI3L1 could be a significant diagnostic reference for AD. To reveal the role of CHI3L1 in AD, we investigated the CHI3L1 deficiency effect on memory impairment in Aß-infused mice and microglial BV-2 cells. In CHI3L1 KO mice, Aß infusion resulted in lower levels of memory dysfunction and neuroinflammation compared to that of WT mice. CHI3L1 deficiency selectively inhibited phosphorylation of ERK and IκB as well as inhibition of neuroinflammation-related factors in vivo and in vitro. On the other hand, treatment with recombinant CHI3L1 increased neuroinflammation-related factors and promoted phosphorylation of IκB except for ERK in vitro. Web-based gene network analysis and our results showed that CHI3L1 is closely correlated with PTX3. Moreover, in AD patients, we found that serum levels of PTX3 were correlated with serum levels of CHI3L1 by Spearman correlation analysis. These results suggest that CHI3L1 deficiency could inhibit AD development by blocking the ERK-dependent PTX3 pathway.

Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

A phase IV study to evaluate the safety of fruquintinib in Chinese patients in real-world clinical practice.

INTRODUCTION: Fruquintinib is approved in China for patients with metastatic colorectal cancer (CRC) who progressed after 2 lines of chemotherapy. This postmarketing study was conducted to evaluate the safety of fruquintinib in the Chinese population, including previously treated patients with advanced CRC and other solid tumors. METHODS: Patients in the first cycle of fruquintinib or expected to start fruquintinib within a week were enrolled. Fruquintinib was administrated according to the label or per physicians' discretion. Patient characteristics and safety information were collected at baseline, 1 month, and 6 months after consent (or 30 days after the last dose). RESULTS: Overall, 3005 patients enrolled between April 24, 2019 and September 27, 2022. All enrolled patients received at least one dose of fruquintinib. Most patients had metastases at baseline. The median age was 60 years. More than half (64.0%) of the patients started fruquintinib at 5 mg, and the median treatment exposure was 2.7 months. Nearly one-third (32.5%) of patients with CRC received fruquintinib with concomitant antineoplastic agents. Treatment-emergent adverse events (TEAEs) leading to dose modification were reported in 626 (20.8%) patients, and 469 (15.6%) patients experienced TEAEs leading to treatment discontinuation. The most common grade ≥ 3 TEAEs were hypertension (6.6%), palmar-plantar erythrodysesthesia syndrome (2.2%), and platelet count decreased (1.0%). Combination therapy did not lead to excessive toxicities. CONCLUSIONS: The safety profile of fruquintinib in the real world was generally consistent with that in clinical studies, and the incidence of TEAEs was numerically lower than known VEGF/VEGFR inhibitor-related AEs. Fruquintinib exhibited manageable safety and tolerability in Chinese patients in the real-world setting.

Reduction-sensitive polymeric carrier for the targeted delivery of a quinazoline derivative for enhanced generation of reactive oxygen species against cancer.

Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors and the development of effective therapeutics against HCC is urgently needed. A novel quinazoline derivative 04NB-03 (Qd04) has been proved to be highly effective against HCC without obvious toxic side-effects. However, the poor water solubility and low bioavailability in vivo severely limit its clinical application. In addition, Qd04 kills tumor cells by inducing an accumulation of endogenous reactive oxygen species (ROS), which is highly impeded by the overexpression of glutathione (GSH) in tumor cells. Herein, we designed a disulfide cross-linked polyamino acid micelle to deliver Qd04 for HCC therapy. The disulfide linkage not only endowed a tumor-targeted delivery of Qd04 by responding to tumor cell GSH but also depleted GSH to achieve increased levels of ROS generation, which improved the therapeutic efficiency of Qd04. Both in vitro and in vivo results demonstrated that the synthesized nanodrug exerted good anti-hepatoma effects, which provided a potential application for HCC therapy in clinics.

Metabolism, toxicity and management of fruquintinib: a novel drug for metastatic colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) is the third most diagnosed cancer globally and despite therapeutic strides, the prognosis for patients with metastatic disease (mCRC) remains poor. Fruquintinib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) targeting VEGFR -1, -2, and -3, and has recently received approval by the U.S. Food and Drug Administration for treatment of mCRC refractory to standard chemotherapy, anti-VEGF therapy, and anti-epidermal growth factor receptor (EGFR) therapy. AREAS COVERED: This article provides an overview of the pre-clinical data, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib, as well as the management of clinical toxicities associated with fruquintinib. EXPERT OPINION: Fruquintinib is a valuable additional treatment option for patients with refractory mCRC. The pivotal role of vigilant toxicity management cannot be understated. While fruquintinib offers a convenient and overall, well-tolerated treatment option, ongoing research is essential to determine its efficacy in different patient subsets, evaluate it in combination with chemotherapy and immunotherapy, and determine its role in earlier lines of therapy.