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.

Poziotinib treatment in patients with HER2-positive advanced breast cancer who have received prior anti-HER2 regimens.

PURPOSE: Poziotinib is an irreversible pan-inhibitor of the human epidermal growth factor receptor (HER) that has shown acceptable tolerability and antitumor activity in phase I and II trials in patients with advanced solid tumors. In the present open-label, multicenter phase II study, we demonstrate safety, tolerability, and preliminary efficacy data from two different dosing schedules in patients with HER2-positive advanced breast cancer. PATIENTS AND METHODS: Patients who had received at least two prior HER2-directed therapy lines for advanced disease, received 24 mg poziotinib on an intermittent dosing schedule (cohort 1) or 16 mg poziotinib once daily on a continuous dosing schedule (cohort 2). The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), disease control rate (DCR), and time to progression (TTP). Secondary endpoints additionally included safety and pharmacokinetics. RESULTS: A total of 67 patients were enrolled. The ORR was 30% in both groups (p = 0.98). DCR was 60% vs 78% (p = 0.15) and median PFS and TTP were 4.1 vs 4.9 months (both p = 0.30) for cohorts 1 and 2, respectively. The most common treatment related adverse events (AEs) of any grade included diarrhea (88% vs 85%, p = 0.76), rash (88% vs 88%, p = 0.96), and stomatitis (64% vs 56%, p = 0.52), with grade 3-4 diarrhea occurring in 33% vs 32% of patients (p = 0.93) and grade 3-4 rash in 27% vs 35% of patients (p = 0.48) in cohort 1 vs cohort 2, respectively. CONCLUSION: Poziotinib demonstrated evidence of clinical activity in patients with pre-treated HER2-positive advanced breast cancer, although high levels of toxicity may preclude further studies at this time.

Interaction of Anagrelide drug molecule on pristine and doped boron nitride nanocages: a DFT, RDG, PCM and QTAIM investigation.

Nowadays, a nanostructure-based drug delivery system is one of the most noticeable topics to be studied, and in this regard, boron nitride nanoclusters are promising drug carriers for targeted drug delivery systems. In this article, the interaction mechanism of Anagrelide (AG) drug with B12N12 and Al- and Ga-doped B12N12 nanocages have been investigated using DFT with B3LYP/6-31 G (d, p) method in both gas and water media. All our studied complexes are thermodynamically stable, and doped nanocage complexes have higher negative adsorption energy (EAd.) and negative solvation energy than AG/B12N12 complexes which correspond to the stability of these systems in both media. The negative highest EAd value is 64.98 kcal/mol (63.17 kcal/mol) and 65.69 kcal/mol (65.11 kcal/mol) in gas (water) media for complex F (AG/AlB11N12) and complex I (AG/GaB11N12) respectively, which refers to the highest stability of these systems. The enhanced values of dipole moment (from 12.40 (12.65) Debye to 17.21 (17.69) Debye in complex F (complex I)) also confirm their stability. The QTAIM and RDG analysis endorse the strong adsorption nature of the AG drug onto the AlB11N12, and GaB11N12 nanocages, which is consistent with the adsorption energy as chemisorption occurs for these complexes. According to the electronic properties, doped nanocages show high sensitivity that infers their promising nature for drug delivery purposes. Thus, complex F and complex I are promising drug delivery systems, and doped nanocages (AlB11N12 and GaB11N12) are better carriers than pristine nanocages for the AG drug delivery system.Communicated by Ramaswamy H. Sarma.

Evaluation of the inhibitory effect of quercetin on the pharmacokinetics of tucatinib in rats by a novel UPLC-MS/MS assay.

CONTEXT: Tucatinib (CYP2C8 substrate) and quercetin (CYP2C8 inhibitor) are two common drugs for the treatment of cancer. However, the effect of quercetin on the metabolism of tucatinib remains unknown. OBJECTIVE: We validated a sensitive method to quantify tucatinib levels in rat plasma based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), which was successfully employed to explore the effect of quercetin on tucatinib pharmacokinetics in rats. MATERIALS AND METHODS: An Acquity UPLC BEH C18 column was applied to achieve the separation of tucatinib and internal standard (IS) talazoparib after protein precipitation with acetonitrile. Then, we used this assay to investigate the effect of different doses of quercetin (25, 50 and 100 mg/kg) on the exposure of orally administered tucatinib (30 mg/kg) in 24 Sprague-Dawley (SD) rats, which were randomly divided into three quercetin pre-treated groups and one control group (n = 6). RESULTS: Our developed assay was verified in all aspects of bioanalytical method validation, involving lower limit of quantification (LLOQ), selectivity, accuracy and precision, calibration curve, extraction recovery, matrix effect and stability. After pre-treatment with 100 mg/kg quercetin, AUC0→t, AUC0→∞ and Cmax of tucatinib were remarkably increased by 75.4%, 75.8% and 59.1% (p < 0.05), respectively, while CLz/F was decreased significantly by 47.3% (p < 0.05) when compared with oral administration of 30 mg/kg tucatinib alone. This change is dose-dependent. CONCLUSIONS: This study will help better understand the pharmacokinetic properties of tucatinib with concurrent use with quercetin, and more clinical verifications were inspired to confirm whether this interaction has clinical significance in humans.

Repurposing Vandetanib plus Everolimus for the Treatment of ACVR1-Mutant Diffuse Intrinsic Pontine Glioma.

Somatic mutations in ACVR1 are found in a quarter of children with diffuse intrinsic pontine glioma (DIPG), but there are no ACVR1 inhibitors licensed for the disease. Using an artificial intelligence-based platform to search for approved compounds for ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (K d = 150 nmol/L) and reduce DIPG cell viability in vitro but has limited ability to cross the blood-brain barrier. In addition to mTOR, everolimus inhibited ABCG2 (BCRP) and ABCB1 (P-gp) transporters and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination was well tolerated in vivo and significantly extended survival and reduced tumor burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Four patients with ACVR1-mutant DIPG were treated with vandetanib plus an mTOR inhibitor, informing the dosing and toxicity profile of this combination for future clinical studies. SIGNIFICANCE: Twenty-five percent of patients with the incurable brainstem tumor DIPG harbor somatic activating mutations in ACVR1, but there are no approved drugs targeting the receptor. Using artificial intelligence, we identify and validate, both experimentally and clinically, the novel combination of vandetanib and everolimus in these children based on both signaling and pharmacokinetic synergies.This article is highlighted in the In This Issue feature, p. 275.

Phase I study of cediranib, an oral VEGFR inhibitor, in combination with selumetinib, an oral MEK inhibitor, in patients with advanced solid malignancies.

PURPOSE: Targeting the vascular endothelial growth factor (VEGF) pathway improves progression free survival in multiple advanced malignancies but durable responses are uncommon. Inhibition of the VEGF pathway at multiple levels of signal transduction may improve clinical outcomes. Preclinical data with cediranib, an inhibitor of all 3 VEGF receptors, in combination with selumetinib, an inhibitor of MEK 1/2, demonstrated improved tumor control experimentally. This phase I trial was designed to test the two agents in combination to evaluate the tolerability, safety and assess disease response. METHODS: Patients with advanced solid malignancies were enrolled into this phase I trial. Cediranib and selumetinib were dosed using a toxicity-adaptive isotonic design for the dose escalation/de-escalation of each agent. Both cediranib and selumetinib were administered daily and continuously. Cycles were 28 days in length. RESULTS: Eighteen patients were enrolled. At all dose levels, dose limiting toxicities (DLT) were observed, which limited dose escalation and further evaluation. The maximum tolerated dose of cediranib and selumetinib in combination could not be determined. The best response of stable disease was observed in eight patients. CONCLUSIONS: Cediranib and selumetinib in combination on a continuous schedule was not tolerable, with patients experiencing cardiovascular and other DLTs. Intermittent schedules may be needed to establish a safe and tolerable combination of cediranib and selumetinib.

Regulations of expressions of rat/human sulfotransferases by anticancer drug, nolatrexed, and micronutrients.

Cancer is related to the cellular proliferative state. Increase in cell-cycle regulatory function augments cellular folate pool. This pathway is therapeutically targeted. A number of drugs influences this metabolism, that is, folic acid, folinic acid, nolatrexed, and methotrexate. Our previous study showed methotrexate influences on rat/human sulfotransferases. Present study explains the effect of nolatrexed (widely used in different cancers) and some micronutrients on the expressions of rat/human sulfotransferases. Female Sprague-Dawley rats were treated with nolatrexed (01-100 mg/kg) and rats of both sexes were treated to folic acid (100, 200, or 400 mg/kg) for 2-weeks and their aryl sulfotransferase-IV (AST-IV; ß-napthol sulfation) and sulfotransferase (STa; DHEA sulfation) activities, protein expression (western blot) and mRNA expression (RT-PCR) were tested. In human-cultured hepatocarcinoma (HepG2) cells nolatrexed (1 nM-1.2 mM) or folinic acid (10 nM-10 µM) were applied for 10 days. Folic acid (0-10 µM) was treated to HepG2 cells. PPST (phenol catalyzing), MPST (dopamine and monoamine), DHEAST (dehydroepiandrosterone and DHEA), and EST (estradiol sulfating) protein expressions (western-blot) were tested in HepG2 cells. Present results suggest that nolatrexed significantly increased sulfotransferases expressions in rat (protein, STa, F = 4.87, P < 0.05/mRNA, AST-IV, F = 6.702, P < 0.014; Student's t test, P < 0.01-0.05) and HepG2 cells. Folic acid increased sulfotransferases activity/protein in gender-dependant manner. Both folic and folinic acid increased several human sulfotransferases isoforms with varied level of significance (least or no increase at highest dose) in HepG2 cells pointing its dose-dependent multiphasic responses. The clinical importance of this study may be furthered in the verification of sulfation metabolism of several exogenous/endogenous molecules, drug-drug interaction and their influences on cancer pathophysiological processes. Further studies are necessary.

The Effect of Oral Letermovir Administration on the Pharmacokinetics of a Single Oral Dose of P-Glycoprotein Substrate Digoxin in Healthy Volunteers.

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor approved in the United States, Canada, Japan, and the European Union for prophylaxis of CMV infection and disease in CMV-seropositive, allogeneic, hematopoietic stem-cell transplant recipients. In vitro, letermovir is a substrate and potential modulator of P-glycoprotein. The potential of letermovir to alter the pharmacokinetics of digoxin (a P-glycoprotein substrate) upon coadministration in healthy subjects was therefore investigated in a phase 1 trial (EudraCT: 2011-004516-39). Oral letermovir 240 mg was administered twice daily for 12 days with a single oral digoxin 0.5-mg dose on day 7; after a washout period, oral digoxin 0.5 mg was administered on day 35 (sequence 1). The period order was reversed after a 28-day washout for sequence 2. Pharmacokinetics and safety were evaluated. The presence of steady-state letermovir reduced digoxin area under the plasma concentration-time curve from administration until last quantifiable measurement by 12% and maximum plasma concentration by 22% compared with digoxin alone; digoxin half-life and elimination rate remained similar in both conditions. The between-subject variability of digoxin maximum plasma concentration was higher with letermovir than without (42% vs 31%) and similar for digoxin area under the plasma concentration-time curve in both periods. No specific safety or tolerability concerns were identified. Overall, letermovir had no clinically relevant effect on concomitant administration with digoxin.

Epigenetic therapy combination of UNC0638 and CI-994 suppresses breast cancer via epigenetic remodeling of BIRC5 and GADD45A.

BACKGROUND: There is currently a growing interest in the roles of epigenetic mechanisms in the diagnosis, prognosis, and therapies associated with precision oncology for breast cancer (BC). This study aimed to demonstrate the clinical significance of euchromatic histone lysine methyltransferase 2 (EHMT2), histone deacetylase 1 (HDAC1) and HDAC2 in BC, to evaluate the antitumor effectiveness of a combination of the selective inhibitors UNC0638 and CI-994 (U+C), and to clarify the underlying mechanisms. METHODS: Multi-omic analysis was used to study the clinical significance of the biomarkers of interest. The effects of U+C treatment were evaluated by detecting cell viability, cell cycle, apoptosis, and representative gene expressions. RNA-Seq and Gene Set Enrichment Analysis (GSEA) were employed to identify over-represented genes associated with the treatment. Chromatin immunoprecipitation and qPCR (ChIP-qPCR) assay were applied to verify epigenetic profiling on the identified promoters. RESULTS: The significance of elevated expressions of EHMT2, HDAC1, and HDAC2 in tumor tissue and BC basal-like subtype in predicting a poor prognosis was noted. The U+C combined treatment showed an enhanced suppressive effect as compared to single agent treatment, perturbed the cell cycle, induced apoptosis, reduced expressions of the genes representing anti-apoptosis, stemness, drug resistance and basal-like state, while increasing luminal-like state genes. In addition, the combined U+C treatment suppressed xenograft tumor growth. The epigenetic reprogramming of histones was identified in the down-regulated BIRC5 and upregulated GADD45A. CONCLUSION: These findings demonstrate that selectively targeting EHMT2, HDAC1, and HDAC2 by concurrent U+C treatment suppresses BC tumor progression via epigenetic remodeling of BIRC5 and GADD45A.

Exposure-Response Analyses of Letermovir Following Oral and Intravenous Administration in Allogeneic Hematopoietic Cell Transplantation Recipients.

The cytomegalovirus (CMV) viral terminase inhibitor letermovir is approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic hematopoietic stem cell transplantation recipients. In a phase III trial (NCT02137772), letermovir significantly reduced clinically significant CMV infection (CS-CMVi) rate vs. placebo through Week 24 (primary end point) and Week 14 (secondary end point) post transplantation. Here, exposure-response relationships were investigated using efficacy and selected safety end points from the phase III trial to inform the proposed clinical dose. Post hoc exposure estimates were derived from a population pharmacokinetic model. No significant exposure dependencies were found for CS-CMVi through Week 24 or Week 14 among letermovir-treated participants. Evaluated covariates had no impact on exposure-efficacy relationships and letermovir plasma exposure did not affect time of CS-CMVi onset. There was no dependence between adverse event incidence and letermovir exposure. These results support current dosing recommendations in several countries and regions, including the United States and European Union.

AZD3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and Janus kinase-1.

AZD3759 is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) on the basis of gefitinib and has been proven to enter the central nervous system. Although the promising antitumor effects of AZD3759 on non-small cell lung cancer (NSCLC) have been demonstrated in clinical trials, the regulatory effects of this inhibitor on the antitumor efficacy of radiation (RA) are unclear. The present study aimed to compare the effects of AZD3759 and osimertinib on RA efficacy in NSCLC and explore the potential mechanism of action of AZD3759. We found that the survival in RA-treated NSCLC cells was significantly decreased by treatment with 500 nM AZD3759 and osimertinib at the RA dosage of 8 Gy. The apoptotic rate, cell cycle arrest, and DNA damage in RA-treated NSCLC cells and brain metastasis in RA-treated xenograft nude mice were significantly enhanced by the co-administration of AZD3759 and osimertinib, respectively. In addition, AZD3759 showed a significantly stronger efficacy than osimertinib did. Mechanistically, the receptor tyrosine kinase signaling antibody array revealed that Janus kinase-1 (JAK1) was specifically inhibited by AZD3759, but not by osimertinib. The effects of AZD3759 on RA efficacy in PC-9 cells and in a brain metastasis animal model were significantly abolished by the overexpression of JAK1. Collectively, our results suggested that AZD3759 promoted RA antitumor effects in NSCLC by synergistic blockade of EGFR and JAK1.

Detection of cancer stem cells by EMT-specific biomarker-based peptide ligands.

The occurrence of epithelial-mesenchymal transition (EMT) within tumors, which enables invasion and metastasis, is linked to cancer stem cells (CSCs) with drug and radiation resistance. We used two specific peptides, F7 and SP peptides, to detect EMT derived cells or CSCs. Human tongue squamous carcinoma cell line-SAS transfected with reporter genes was generated and followed by spheroid culture. A small molecule inhibitor-Unc0642 and low-dose ionizing radiation (IR) were used for induction of EMT. Confocal microscopic imaging and fluorescence-activated cell sorting analysis were performed to evaluate the binding ability and specificity of peptides. A SAS xenograft mouse model with EMT induction was established for assessing the binding affinity of peptides. The results showed that F7 and SP peptides not only specifically penetrated into cytoplasm of SAS cells but also bound to EMT derived cells and CSCs with high nucleolin and vimentin expression. In addition, the expression of CSC marker and the binding of peptides were increased in tumors isolated from Unc0642/IR-treated groups. Our study demonstrates the potential of these peptides for detecting EMT derived cells or CSCs and might provide an alternative isolation method for these subpopulations within the tumor in the future.

Quinazoline-containing Hydrazydes of Dicarboxylic Acids and Products of Their Structural Modification: A Novel Class of Anti-inflammatory Agents.

The synthesis of hydrazides formed by quinazolin-4(3H)-ylidenehydrazine and dicarboxylic acids, as well as their further modification are described in the present manuscript. It was shown that above-mentioned hydrazides may be obtained via acylation of initial quinazolin-4(3H)-ylidenehydrazine by corresponding acylhalides, cyclic anhydrides and imidazolides of dicarboxylic acids monoesters. Obtained hydrazides were converted into [1,2,4]triazolo[1,5-c]quinazolines that were used as initial compounds for chemical modification aimed to the introduction of amide fragment to the molecule. The IR, 1H NMR and chromato-mass spectral data of obtained compounds were studied and discussed. Obtained substances were studied for anti-inflammatory activity using carrageenan-induced paw inflammation model. Amides of ([1,2,4]triazolo[1,5-c]quinazoline-2-yl)alkyl carboxylic acids were detected as promising class of anti-inflammatory agents for further purposeful synthesis and profound study of anti-inflammatory activity.

Functional evaluation of vandetanib metabolism by CYP3A4 variants and potential drug interactions in vitro.

AIM: To investigate the enzymatic properties of cytochrome P450 3A4 (CYP3A4) variants and their ability to metabolize vandetanib (VNT) in vitro, and to study potential drug interactions in combination with VNT. METHOD: Recombinant CYP3A4 cell microsomes were prepared using a Bac-to-Bac baculovirus expression system. Enzymatic reactions were carried out, and the metabolites were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: The activities of 27 CYP3A4 variants were determined to assess the degree of VNT metabolism that occurred. Analysis indicated that there was enhanced intrinsic clearance (Vmax/Km, CLint) for eight variants (CYP3A4.2, 3, 9, 15, 16, 29, 32, and 33), while there was a significant decrease in CYP3A4.5, 7, 8, 10-14, 17-20, 23, 24, 28, 31, and 34. Compared with CYP3A4.1, no significant differences were found for CYP3A4.6 and 30. Furthermore, the relative clearances were compared between VNT and cabozantinib, which were all metabolized by CYP3A4 with the same indications. When combined with ketoconazole, which is a CYP inhibitor, obvious differences were observed in the potency of VNT between different variants, including CYP3A4.2, 15, and 18. CONCLUSION: This comprehensive assessment of CYP3A4 variants provides significant insights into the allele-specific metabolism of VNT and drug interactions in vitro. We hope that these comprehensive data will provide references and predictions for the clinical application of VNT.

Efficacy of Icotinib, an EGFR Tyrosine Kinase Inhibitor in Non-Small Cell Lung Cancer Patients with Exon 19 Deletion and Exon 21 L858R: A Retrospective Analysis in China.

INTRODUCTION: The effect of icotinib on non-small cell lung cancer (NSCLC) patients with EGFR exon 19 deletions (19-Del) or L858R point mutation in exon 21 (21-L858R) remains inconsistent. This study aimed to evaluate the efficacy and safety of icotinib in patients with advanced NSCLC harboring these 2 EGFR mutations. METHODS: We retrospectively assessed the clinical effects of first-line icotinib on advanced NSCLC patients with 2 classic EGFR mutations. Kinase activity assays were used to reaffirm the preclinical efficacy. RESULTS: Among 2,757 patients, 2,365 (86%) harbored 19-Del (1,346/2,757, 49%) or 21-L858R (1,019/2,757, 37%) mutation. Patients with 19-Del had a higher response rate (ORR; 67.8 vs. 62.1%; p = 0.0039) and disease control rate (98.5 vs. 97.2%; p = 0.0223) than those with 21-L858R mutation. The median progression-free survival (PFS) in the 19-Del group (22.3 months, 95% confidence interval [CI]: 21.3-23.4) was significantly longer than that in the 21-L858R group (20.4 months, 95% CI: 19.5-21.7) (p = 0.004). In multivariate analysis, mutation types, clinical stage, and smoking history were significant factors for PFS. Additionally, an in vitro study indicated the 50% inhibitory concentrations (IC50) of icotinib was lower for EGFR 19-Del than 21-L858R. CONCLUSION: These results suggest that EGFR 19-Del confers superior PFS and response to the icotinib treatment compared to 21-L858R.

Alliance A011801 (compassHER2 RD): postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer.

This report describes the rationale, purpose and design of A011801 (CompassHER2 RD), an ongoing prospective, multicenter, Phase III randomized trial. Eligible patients in the United States (US) and Canada with high-risk (defined as ER-negative and/or node-positive) HER2-positive (HER2+) residual disease (RD) after a predefined course of neoadjuvant chemotherapy and HER2-directed treatment are randomized 1:1 to adjuvant T-DM1 and placebo, versus T-DM1 and tucatinib. Patients have also received adjuvant radiotherapy and/or endocrine therapy, if indicated per standard of care guidelines. The primary objective of the trial is to determine if the invasive disease-free survival (iDFS) with T-DM1 plus tucatinib is superior to iDFS with T-DM1 plus placebo; other outcomes of interest include overall survival (OS), breast cancer-free survival (BCFS), distant recurrence-free survival (DRFS), brain metastases-free survival (BMFS) and disease-free survival (DFS). Correlative biomarker, quality of life (QoL) and pharmacokinetic (PK) end points are also evaluated.

Lay abstract In this research study (A011801; CompassHER2 RD), patients with early stage HER2-positive breast cancer who already received treatment with chemotherapy and anti-HER2 targeted therapies followed by surgery are mainly enrolled. If cancer is still present in the breast and/or lymph nodes at the time of surgery, there is a higher risk of a recurrence in the future, and enrollment on A011801 is an option. Usually, if there is tumor remaining after chemotherapy and anti-HER2 targeted therapies, the main treatment is the use of an FDA-approved intravenous drug called T-DM1. Additional treatment may also include radiotherapy and/or medications to block the activity of estrogen. The usual treatment approach reduces the likelihood of breast cancer recurring in the future. This study has been performed to answer the following question: Is the combination of T-DM1 and a newer drug tucatinib better than usual treatment with T-DM1 alone at preventing cancer from returning? Study participants will receive treatment with T-DM1 and placebo (a pill that looks like the study drug but contains no medication) or T-DM1 and tucatinib, for up to 14 cycles, unless their breast cancer returns or the side effects become too severe. Research bloods are taken on study along with standard blood work, and we also request a stored tumor sample from the original biopsy and from the breast cancer surgery for research purposes. Optional Quality of Life Questionnaires are also included in the trial. After the study, participants finish T-DM1 and placebo, or T-DM1 and tucatinib, and their doctor will continue to follow their condition with clinic visits every 6 months for 10 years and watch for side effects and for signs of breast cancer recurring. Clinical Trial Registration: NCT04457596 (ClinicalTrials.gov).

A phase II study of poziotinib in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

BACKGROUND: In phase I studies, poziotinib has shown meaningful efficacy against various types of cancers. This phase 2 study aimed to investigate the efficacy and safety of poziotinib in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M-HNSCC). METHODS: Overall, 49 patients were enrolled (median age, 62 years; age range, 21-78 years). Patients received a median of two prior treatments including chemotherapy and others and received 12 mg poziotinib orally once daily as part of a 28-day cycle. The primary endpoint was objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Targeted capture sequencing was performed using available tissues to identify translational biomarkers related to clinical response. RESULTS: ORR was 22.4%, median PFS was 4.0 months (95% confidence interval [CI], 1.8-6.2 months), and median OS was 7.6 months (95% CI, 4.4-10.8 months). The most common treatment-related adverse events were acneiform rash (85%) and mucositis (77%). A grade 3 or higher adverse event was acneiform rash (3%). Targeted capture sequencing was performed in 30 tissue samples. TP53 and PIK3CA were the most frequently mutated genes (43%), followed by CCND1 (33%) and EGFR (30%). Mutations in ERBB2, ERBB3, and ERBB4, which are HER family genes, were observed in 17%, 13%, and 10% samples, respectively. There was no difference in the frequency of somatic mutations in the HER family genes between the clinically benefitted and non-benefitted groups. CONCLUSION: Compared to other pan-HER inhibitors, poziotinib showed clinically meaningful efficacy in heavily treated R/M-HNSCC. CLINICAL TRIAL REGISTRATION NUMBER: NCT02216916.

Discovery of New 4-Indolyl Quinazoline Derivatives as Highly Potent and Orally Bioavailable P-Glycoprotein Inhibitors.

The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, YS-370. YS-370 effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. YS-370 bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, YS-370 stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of YS-370 in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that YS-370 is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.