Uncertainty and the unmet informational needs of patients with cancer of unknown primary (CUP): a cross-sectional multi-site study.

OBJECTIVE: This study aimed to determine the healthcare experiences, quality of life, and psychosocial needs of patients with cancer of unknown primary (CUP) early after diagnosis; comparing their experiences to patients with advanced cancer of a known primary (non-CUP control patients) and published general population reference data where available. METHODS: This study was a cross-sectional, multi-site study comparing CUP patients (n = 139) compared to non-CUP controls (n = 45). Demographic, clinical information and patient-reported outcome questionnaire data were collected at baseline. RESULTS: Differences in healthcare experienced were found between CUP and non-CUP controls with CUP patients reporting higher scores for unmet medical communication/information needs compared with non-CUP control patients (p = 0.013) as well as greater uncertainty in illness (p = 0.042). Whilst no differences were found between CUP and non-CUP controls on the EORTC and PROMIS measures, of those that 'received written information about your cancer…' and asked '…how useful was it?' fewer CUP patients reported finding the information useful 40% vs 61%, and more were likely to not have received written information at all 59% vs 32%; (p = 0.002). Additionally, of those that found information about their cancer online, fewer patients with CUP reported finding it useful 32% vs 48% control patients (p = 0.005). CONCLUSIONS: CUP patients have unmet medical communication/information needs and greater uncertainty in illness but do not differ in health-related quality of life domains compared to patients with advanced cancer of a known primary.

Evaluation of fosaprepitant-associated hypersensitivity reactions at a National Cancer Center.

INTRODUCTION: At our institution, an increased incidence of hypersensitivity reactions was reported following standardization of fosaprepitant as the preferred agent for the prophylaxis of chemotherapy induced nausea and vomiting (CINV) caused by highly emetogenic therapies. The purpose of this evaluation was to assess the incidence of systemic hypersensitivity reactions (HSRs) to fosaprepitant infusions compared to available literature. METHODS: This evaluation is a retrospective review of electronic health records of adult patients who received their first dose of fosaprepitant for CINV prophylaxis beginning January 1, 2017 through June 30, 2017 at the University of Colorado Cancer Center outpatient infusion center. Subjects were identified using medication administration reports. Individual chart reviews were performed for all patients who received fosaprepitant during the specified timeframe and had a reaction reported on the same date. RESULTS: A total of 868 patients received fosaprepitant in the outpatient infusion center during the study time period. Four patients (0.461%) had a systemic HSR attributed to fosaprepitant. Two of the reactions were reported as HSRs in the adverse reaction reporting system and two were found in provider notes during chart review. Due to the small sample size, risk factors for HSRs to fosaprepitant were not able to be determined. CONCLUSION: The incidence of HSRs to fosaprepitant at our institution was found to be consistent with the <1% incidence currently noted in literature. Based on these findings, opportunities have been identified for education on fosaprepitant-associated HSRs, proper documentation and patient-specific precautions.

A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction.

AIMS: The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic. METHODS: We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction. RESULTS: Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m2 /day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m2 in patients with normal liver function, compared to 542, 505 and 444 mL/min/m2 in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease. CONCLUSION: While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.

Pharmacokinetic determinants of cisplatin-induced subclinical kidney injury in oncology patients.

PURPOSE: The ability to predict and detect clinical and subclinical nephrotoxicity early in the course of therapy has the potential to improve long-term outcomes in cancer patients receiving cisplatin chemotherapy. Pharmacokinetic parameters could serve as predictors of cisplatin-induced nephrotoxicity. METHODS: Participants [n = 13] were treated with a 1-h cisplatin infusion [30-75 mg/m2]. Blood was collected pre-dose and up to 6 h post-dose. Urinary biomarkers [KIM-1, calbindin, clusterin, GST-pi, ß2M, albumin, NGAL, osteopontin, clusterin, MCP-1, cystatin C, and TFF3] were measured at baseline, days 3 and 10. Total and unbound platinum concentrations were measured using ICP/MS. Noncompartmental analysis was performed, and correlation and regression analyses evaluated the relationships between platinum pharmacokinetics and nephrotoxicity. RESULTS: Peak platinum urinary concentrations correlated with urinary levels of KIM-1, calbindin, clusterin, GST-pi, ß2M, albumin, NGAL, osteopontin, clusterin, cystatin C, and TFF3 at day 10. Unbound platinum plasma concentrations at 2 h also correlated with urinary clusterin, ß2M, cystatin C, NGAL, osteopontin, and TFF3 at day 3. Regression analyses suggested 2-h total plasma platinum concentrations greater than 2000 ng/ml, and peak urinary platinum concentrations above 24,000 ng/ml may serve as potential approximations for elevated risk of nephrotoxicity. Platinum area under the plasma concentration time curve was associated with serum creatinine and estimated glomerular filtration rate. CONCLUSIONS: Peak plasma and urinary platinum concentrations and pharmacokinetic parameters were associated with risk of subclinical cisplatin-induced kidney injury as assessed using novel urinary biomarkers. Future studies will examine these relationships in larger clinical populations of cisplatin-induced acute kidney injury.

Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement From the American Heart Association.

Heart failure is a common, costly, and debilitating syndrome that is associated with a highly complex drug regimen, a large number of comorbidities, and a large and often disparate number of healthcare providers. All of these factors conspire to increase the risk of heart failure exacerbation by direct myocardial toxicity, drug-drug interactions, or both. This scientific statement is designed to serve as a comprehensive and accessible source of drugs that may cause or exacerbate heart failure to assist healthcare providers in improving the quality of care for these patients.

Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin.

Nephrotoxicity is a dose limiting side effect associated with the use of cisplatin in the treatment of solid tumors. The degree of nephrotoxicity is dictated by the selective accumulation of cisplatin in renal tubule cells due to: (1) uptake by organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1); (2) metabolism by glutathione S-transferases (GSTs) and γ-glutamyltransferase 1 (GGT1); and (3) efflux by multidrug resistance-associated protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). The purpose of this study was to determine the significance of single nucleotide polymorphisms that regulate the expression and function of transporters and metabolism genes implicated in development of acute kidney injury (AKI) in cisplatin treated patients. Changes in the kidney function were assessed using novel urinary protein biomarkers and traditional markers. Genotyping was conducted by the QuantStudio 12K Flex Real-Time PCR System using a custom open array chip with metabolism, transport, and transcription factor polymorphisms of interest to cisplatin disposition and toxicity. Traditional and novel biomarker assays for kidney toxicity were assessed for differences according to genotype by ANOVA. Allele and genotype frequencies were determined based on Caucasian population frequencies. The polymorphisms rs596881 (SLC22A2/OCT2), and rs12686377 and rs7851395 (SLC31A1/CTR1) were associated with renoprotection and maintenance of estimated glomerular filtration rate (eGFR). Polymorphisms in SLC22A2/OCT2, SLC31A1/CTRI, SLC47A1/MATE1, ABCC2/MRP2, and GSTP1 were significantly associated with increases in the urinary excretion of novel AKI biomarkers: KIM-1, TFF3, MCP1, NGAL, clusterin, cystatin C, and calbindin. Knowledge concerning which genotypes in drug transporters are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, in order to prevent AKI.

Claims analysis of hypertension occurrence, severity changes and patterns of antihypertensive use in cancer patients receiving vascular endothelial growth factor inhibitors.

BACKGROUND: Vascular endothelial growth factor inhibitors such as bevacizumab, sorafenib, and sunitinib are utilized in the treatment of multiple cancers. Although these agents are associated with hypertension, there is a lack of evidence describing patterns of antihypertensive use in patients with vascular endothelial growth factor inhibitor-associated hypertension in a non-trial, "real-world" setting. OBJECTIVE: To describe the occurrence and severity of vascular endothelial growth factor inhibitor-associated hypertension, patterns of antihypertensive use and occurrence of cardiovascular complications in a non-trial population, and to describe patterns of initial antihypertensive therapy in patients developing hypertension during treatment with a vascular endothelial growth factor inhibitor. METHODS: This retrospective cohort study utilized claims data from the Medstat MarketScan Commercial Claims and Encounter database to identify patients with claims for a vascular endothelial growth factor inhibitor and a diagnosis of cancer using International Classification of Diseases, 9th Revision, Clinical Modification codes, Healthcare Common Procedure Coding System J-codes and National Drug Codes. The study period encompassed claims from one year before the patient's first claim for a vascular endothelial growth factor inhibitor, and continued through one year after the initial vascular endothelial growth factor inhibitor claim. Patients meeting study criteria were classified into cohorts A1, patients with no hypertension throughout the study period; A2, patients without hypertension at baseline who developed hypertension after starting a vascular endothelial growth factor inhibitor; and cohort B, patients with hypertension prior to receiving a vascular endothelial growth factor inhibitor. We utilized medical and pharmacy claims data to describe the presence of hypertension, its severity, and the occurrence of cardiovascular complications throughout the study period. Initial antihypertensive use in cohort A2 was described. RESULTS: In all, 2177 patients met study criteria and were categorized into cohorts A1 (n = 708), A2 (n = 333) and B (n = 1136). Approximately 32% of patients without hypertension at baseline had claims suggestive for hypertension during the study period. Life-threatening (Grade 4) hypertension increased throughout the study period for cohorts A1, A2, and B, to 3.4%, 10.2%, and 16.4%, respectively (p < 0.001 for all). Claims suggestive of Grade 3 hypertension occurred in more patients in cohort B (45.8%) than in cohort A2 (32.7%, p < 0.001). Cardiovascular complications occurred in 4.7%, 15.6%, and 22.7% of patients in cohorts A1, A2, and B, respectively. Initial antihypertensive agent selection did not impact the occurrence of cardiovascular complications in cohort A2. CONCLUSION: Our study provides valuable insight into non-trial patterns of vascular endothelial growth factor inhibitor-associated hypertension occurrence and severity, and is consistent with prior claims analysis. Identification of optimal strategies to manage vascular endothelial growth factor inhibitor-associated hypertension remain to be clarified with the advent of more comprehensive data sets.

Vismodegib: an inhibitor of the Hedgehog signaling pathway in the treatment of basal cell carcinoma.

OBJECTIVE: To review vismodegib, the first Food and Drug Administration (FDA)-approved Hedgehog (Hh) signaling pathway inhibitor, in the treatment of advanced basal cell carcinoma (BCC). DATA SOURCES: MEDLINE and PubMed were searched using the terms vismodegib, GDC-0449, RG3616, and basal cell carcinoma for relevant clinical trials through September 2013. The FDA Web site, the National Clinical Trials registry, and abstracts from the American Society of Clinical Oncology (ASCO) were also evaluated to identify unpublished data and future clinical trials. STUDY SELECTION/DATA EXTRACTION: All identified clinical and preclinical studies published in the English language were assessed, including selected references from the bibliographies of articles. DATA SYNTHESIS: Activation of the Hh signaling pathway is well documented in BCC. Vismodegib is a small-molecule inhibitor of Hh signaling that acts by antagonizing the protein Smoothened (SMO), thereby preventing downstream transcriptional activation of genes involved in cell proliferation and survival. Vismodegib was approved by the FDA in January 2012 for the treatment of recurrent, locally advanced BCC (laBCC), or metastatic BCC (mBCC) for which surgery or radiation cannot be utilized. A pivotal phase 2 trial evaluating 104 patients demonstrated that treatment with vismodegib, 150 mg orally once daily, resulted in a 30% and 43% objective response rate in patients with mBCC and laBCC, respectively. The most common adverse effects from vismodegib were mild to moderate and included muscle spasms, dysgeusia, decreased weight, fatigue, alopecia, and diarrhea. However, clinical studies noted a high incidence of discontinuation of therapy by patients for reasons other than disease progression. CONCLUSIONS: The approval of vismodegib represents the only targeted, prospectively studied treatment option for patients with advanced BCC. Further research assessing the utility of vismodegib in the treatment of other malignancies and the development of resistance patterns will more clearly define the role of Hedgehog inhibition in the broader scheme of oncological disorders.

Pharmacokinetic study of capivasertib and the CYP3A4 substrate midazolam in patients with advanced solid tumors.

PURPOSE: Capivasertib, a potent, selective inhibitor of all three AKT serine/threonine kinase (AKT) isoforms, is being evaluated in phase 3 trials in advanced breast and prostate cancer. This study evaluated the drug-drug interaction risk of capivasertib with the cytochrome P450 3A substrate midazolam in previously treated adults with advanced solid tumors. METHODS: Patients received oral capivasertib 400 mg twice daily (BID) on an intermittent schedule (4 days on/3 days off) starting on day 2 of cycle 1 (29 days) and on day 1 of each 28-day cycle thereafter. In cycle 1 only, patients received oral midazolam (1 mg) on day 1 (alone), and days 8 and 12 (3rd day off and 4th day on capivasertib, respectively). Midazolam pharmacokinetics on days 8 and 12 were analyzed versus day 1. Capivasertib, with or without standard-of-care treatment, was continued in patients deemed likely to benefit. Safety and exploratory efficacy analyses were conducted. RESULTS: Capivasertib-midazolam coadministration increased midazolam exposure (n = 21): geometric mean ratio (90% confidence interval) AUCinf and Cmax was 1.13 (0.97-1.32) and 1.15 (0.99-1.33) for day 8 versus day 1, and 1.75 (1.50-2.05) and 1.25 (1.08-1.46) for day 12 versus day 1. The capivasertib safety profile was manageable when administered with or without midazolam. Two patients had partial responses to treatment. CONCLUSION: The up to 1.75-fold increase in midazolam exposure indicates capivasertib is a weak CYP3A inhibitor at 400 mg BID on an intermittent schedule. Capivasertib was well tolerated; exploratory efficacy analysis demonstrated evidence of clinical activity in this heavily pre-treated population. CLINICALTRIALS: gov: NCT04958226.

A Phase Ib Expansion Cohort Evaluating Aurora A Kinase Inhibitor Alisertib and Dual TORC1/2 Inhibitor Sapanisertib in Patients with Advanced Solid Tumors.

BACKGROUND: This study further evaluated the safety and efficacy of the combination of alisertib and sapanisertib in an expansion cohort of patients, including a subset of patients with refractory pancreatic adenocarcinoma, with further evaluation of the pharmacodynamic characteristics of combination therapy. METHODS: Twenty patients with refractory solid tumors and 11 patients with pancreatic adenocarcinoma were treated at the recommended phase 2 dose of alisertib and sapanisertib. Adverse events and disease response were assessed. Patients in the expansion cohort were treated with a 7-day lead-in of either alisertib or sapanisertib prior to combination therapy, with tumor tissue biopsy and serial functional imaging performed for correlative analysis. RESULTS: Toxicity across treatment groups was overall similar to prior studies. One partial response to treatment was observed in a patient with ER positive breast cancer, and a patient with pancreatic cancer experienced prolonged stable disease. In an additional cohort of pancreatic cancer patients, treatment response was modest. Correlative analysis revealed variability in markers of apoptosis and immune cell infiltrate according to lead-in therapy and response. CONCLUSIONS: Dual targeting of Aurora A kinase and mTOR resulted in marginal clinical benefit in a population of patients with refractory solid tumors, including pancreatic adenocarcinoma, though individual patients experienced significant response to therapy. Correlatives indicate apoptotic response and tumor immune cell infiltrate may affect clinical outcomes.

Crizotinib: a new treatment option for ALK-positive non-small cell lung cancer.

OBJECTIVE: To review the characteristics and clinical trial data of crizotinib in ALK-positive non-small cell lung cancer (NSCLC). DATA SOURCE: A literature search using PubMed/MEDLINE (up to December 2012) was performed using the terms crizotinib, ALK-positive, non-small cell lung cancer, and PF-02341066. STUDY SELECTION/DATA EXTRACTION: Phase 1, 2, and 3 trials evaluating the safety and efficacy of crizotinib in a cohort of patients with ALK rearrangements and advanced NSCLC were evaluated. All peer-reviewed articles with clinically relevant information were reviewed. DATA SYNTHESIS: ALK rearrangement results in an aberrant EML4-ALK fusion oncogene that constitutively activates ALK tyrosine kinase, resulting in inhibition of apoptosis and promotion of tumor cell proliferation. Approximately 3-5% of NSCLC exhibit this rearrangement. Crizotinib is an oral selective inhibitor of ALK and mesenchymal epithelial growth factor tyrosine kinases. Early phase trials with crizotinib showed improved response rates of 50-57% and extended duration of response of 6-10 months. Results of these studies led to accelerated Food and Drug Administration (FDA) approval of crizotinib. Further clinical trial results confirmed improvement in response rates, duration of response, as well as progression-free survival in ALK-positive patients with NSCLC receiving crizotinib. The drug undergoes hepatic metabolism by CYP3A4 and demonstrates autoinhibition of CY3A4, thus predisposing it to drug interactions. The most frequent toxicities with crizotinib include mild visual disturbances, nausea, vomiting, diarrhea, constipation, edema, and generally reversible, sometimes severe, elevations in aspartate aminotransferase and alanine aminotransferase. CONCLUSIONS: Crizotinib is a novel targeted anticancer agent that appears to be a favorable treatment option for patients with locally advanced or metastatic NSCLC that is ALK-positive as detected by an FDA-approved test.

The emergence of targeted therapy for HER2-low triple-negative breast cancer: a review of fam-trastuzumab deruxtecan.

INTRODUCTION: Metastatic triple-negative breast cancer (TNBC) is an aggressive sub-type of breast cancer. Despite recent advances, metastatic TNBC remains difficult to treat with limited targeted treatment options. Fam-trastuzumab deruxtecan (T-DXd), is a novel antibody-drug conjugate (ADC) targeting human epidermal growth factor receptor 2 (HER2) and is composed of a unique linker bound to the topoisomerase I inhibitor DXd. T-DXd has significant anti-tumor activity in patients with HER2-low TNBC. AREAS COVERED: This review reports on the mechanism, pre-clinical/clinical studies, efficacy, and tolerability of T-DXd. A literature search was conducted via PubMed using keywords such as 'fam-trastuzumab deruxtecan,' 'Enhertu,' and 'HER2-low cancers.' EXPERT OPINION: The Phase III Destiny-Breast04 Trial showed benefit in progression-free and overall survival in patients with HER2-low metastatic breast cancers treated with T-DXd compared to treatment of physician's choice chemotherapy. T-DXd is the first pharmaceutical to effectively target a HER2-low population with clinically meaningful efficacy in patients with HER2-low TNBC. Compared to chemotherapy, T-DXd has a similar safety profile, with the additional need for close monitoring for interstitial lung disease. Given the clinical activity of T-DXd in TNBC, it is likely there will be continued efforts to refine HER2-low diagnostics and to develop additional ADCs with other protein targets.

Everolimus: a new treatment option for advanced pancreatic neuroendocrine tumors.

OBJECTIVE: To present the current clinical evidence on everolimus for use in pancreatic neuroendocrine tumors (pNET). DATA SOURCES: A literature search was performed using PubMed and MEDLINE (1946-March 2012). Search terms were everolimus, RAD001, mTOR inhibitor, and pancreatic neuroendocrine tumors. Abstracts from the American Society of Clinical Oncology 2000-2012 meetings and Food and Drug Administration (FDA) reviews were searched to obtain otherwise unpublished data. The national clinical trials registry was searched for current and future studies of everolimus in pNET. STUDY SELECTION AND DATA EXTRACTION: Clinical studies available in the English language describing the pharmacology, pharmacokinetics, clinical activity, and safety of everolimus in pNET were included. All peer-reviewed, clinically relevant publications were reviewed for inclusion. DATA SYNTHESIS: Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor approved by the FDA in May 2011 for the treatment of progressive, advanced pNET. Everolimus exerts its effect by inhibiting multiple downstream pathways of mTOR, which decreases cell proliferation, survival, and angiogenesis. Its pNET indication was based on the results of RADIANT-3, a Phase 3 trial demonstrating increased median progression-free survival (11 months) with everolimus 10 mg orally once daily compared to placebo (4.6 months). Everolimus was well tolerated in clinical trials. The most commonly reported adverse events included stomatitis, rash, diarrhea, fatigue, infections, nausea, and decreased appetite. Grade 3/4 events including anemia, thrombocytopenia, pneumonitis, and hyperglycemia occurred in approximately 5% of patients. CONCLUSIONS: Based on review of the available literature, everolimus is a safe and effective treatment option for patients with low- to intermediate-grade, unresectable or metastatic pNET that have progressed on prior therapies. Until results of head-to-head, randomized controlled trials are conducted to compare everolimus to other treatment options, it cannot be said whether everolimus is more efficacious or tolerable than other treatment options.

Romidepsin: a histone deacetylase inhibitor for refractory cutaneous T-cell lymphoma.

OBJECTIVE: To evaluate the efficacy and safety of romidepsin in refractory cutaneous T-cell lymphoma (CTCL). DATA SOURCES: An English-language literature search of PubMed and MEDLINE (Nov 2011-April 2012) was performed using the terms romidepsin, CTCL, and depsipeptide (FK228). The National Comprehensive Cancer Network guidelines, American Society of Clinical Oncology abstracts, American Society of Hematology abstracts, clinical trial registry, and prescribing information from the manufacturer were reviewed for additional information. STUDY SELECTION AND DATA EXTRACTION: Phase 1 and 2 trials evaluating the efficacy and safety of romidepsin were reviewed with a specific focus on its use in cutaneous T-cell lymphoma. All peer-reviewed articles with clinically relevant information were evaluated for inclusion. DATA SYNTHESIS: In advanced stage CTCL, single or combination chemotherapy regimen responses are variable and lack durability. Romidepsin is a histone deacetylase inhibitor approved for refractory cutaneous T-cell lymphoma. Romidepsin has shown an improvement in duration of response and pruritus over traditional therapy. In 2 independent Phase 2 trials, romidepsin showed an overall response rate of 34% and durable response of 13-15 months in patients with refractory CTCL. The most frequent toxicities of romidepsin include nausea, vomiting, fatigue, or myelosuppression. Clinically insignificant QT interval changes have been observed but did not correlate with a decrease in left ventricular ejection fraction, or elevated laboratory markers of myocardial damage. CONCLUSIONS: Romidepsin is an effective, durable, and well-tolerated single-agent therapy in patients with refractory CTCL and should be considered for formulary addition in this population.

Comparative Pre-clinical Efficacy of Chinese and Indian Cultivars of Bitter Melon (Momordica charantia) against Pancreatic Cancer.

Given the high rates of incidence and mortality associated with pancreatic cancer (PanC), there is a need to develop alternative strategies to target PanC. Recent studies have demonstrated that fruits of bitter melon (Momordica charantia) exhibit strong anticancer efficacy against PanC. However, the comparative effects of different bitter melon varieties have not been investigated. This has important implications, given that several bitter melon cultivars are geographically available but their differential effects are not known; and that on a global level, individuals could consume different bitter melon varieties sourced from different cultivars for anti-PanC benefits. Considering these shortcomings, in the present study, comparative pre-clinical anti-PanC studies have been conducted using lyophilized-juice and aqueous-methanolic extracts of the two most widely consumed but geographically diverse bitter melon varieties (Chinese [bitter melon juice; BMJ] and Indian [bitter melon extract; BME] variants). We observed that both BMJ and BME possess comparable efficacy against PanC growth and progression; specifically, these preparations have the potential to (a) inhibit PanC cell proliferation and induce cell death; (b) suppress PanC tumor growth, proliferation, and induce apoptosis; (c) restrict capillary tube formation by human umbilical vein endothelial cells, and decrease angiogenesis in PanC tumor xenografts. Thus, given the comparable pre-clinical anti-PanC efficacy of bitter melon cultivars, the geographical non-availability of a certain cultivar should not be a limiting factor in selecting a variant for moving forward for future clinical use/clinical trials either as a preventive or a therapeutic alternative for targeting PanC.

Pharmacokinetics and safety of niraparib in patients with moderate hepatic impairment.

PURPOSE: The purpose of this study is to characterize niraparib pharmacokinetics (PK) and safety in patients with normal hepatic function (NHF) versus moderate hepatic impairment (MHI). METHODS: Patients with advanced solid tumors were stratified by NHF or MHI (National Cancer Institute-Organ Dysfunction Working Group criteria [bilirubin > 1.5-3 × upper limit of normal and any aspartate aminotransferase elevation]). In the PK phase, all patients received one 300 mg dose of niraparib. In the extension phase, patients with MHI received niraparib 200 mg daily; patients with NHF received 200 or 300 mg based on weight (< 77 kg, ≥ 77 kg)/platelets (< 150,000/µL, ≥ 150,000/µL). PK parameters included maximum concentration (Cmax), area under the curve to last measured concentration (AUClast) and extrapolated to infinity (AUCinf). Safety was assessed in both phases. Exposure-response (E-R) modeling was used to predict MHI effects on exposure and safety of niraparib doses ≤ 200 mg or 300/200 mg or 200/100 mg weight/platelet regimens. RESULTS: In the PK phase (NHF, n = 9; MHI, n = 8), mean niraparib Cmax was 7% lower in patients with MHI versus NHF. Mean exposure (AUClast, AUCinf) was increased by 45% and 56%, respectively, in patients with MHI without impacting tolerability. In the extension phase (NHF, n = 8; MHI, n = 7), the overall safety profile was consistent with previous trials. In patients with MHI, E-R modeling predicted niraparib 200 mg reduced Grade ≥ 3 thrombocytopenia incidence, whereas a 200/100 mg regimen yielded exposures below efficacy-associated levels in 15% of patients. CONCLUSION: These findings support adjusting the 300 mg niraparib starting dose to 200 mg QD in patients with MHI. TRIAL REGISTRATION: NCT03359850; registered December 2, 2017.

Time-dependent changes in kidney injury biomarkers in patients receiving multiple cycles of cisplatin chemotherapy.

Proteins secreted into urine following tubular injury are being increasingly used as biomarkers of clinical and subclinical nephrotoxicity. In the present study, we sought to characterize the time-dependent urinary excretion of three promising biomarkers, kidney injury molecule-1 (KIM-1), calbindin, and trefoil factor 3 (TFF3), during two different chemotherapy cycles in 27 patients with solid tumors prescribed the anticancer drug cisplatin (≥25 mg/m2). Urinary biomarkers were evaluated at Days 3 and 10 during an initial and a subsequent cycle of cisplatin chemotherapy. Longitudinal analyses compared the mean difference estimations for biomarker concentrations during and across the initial and subsequent cycles of cisplatin treatment. Traditional biomarkers including serum creatinine, estimated glomerular filtration rate, and blood urea nitrogen were unchanged during and across both cycles of cisplatin therapy. In response to the initial cycle, urinary KIM-1 concentrations increased from baseline and remained elevated through a subsequent cycle of cisplatin chemotherapy. By comparison, urinary levels of calbindin were elevated 10 days after the initial cisplatin treatment, but largely unchanged by cisplatin exposure in a subsequent cycle. Early elevations in urinary TFF3 at 3 days after cisplatin administration were observed consistently in both the initial and subsequent cycle of cisplatin treatment. In conclusion, the longitudinal assessment of biomarker performance in the same cohort of oncology patients reveals different patterns of urinary excretion between initial and subsequent cycles of cisplatin-containing chemotherapy. These data add novel cycle-dependent insight to the growing literature addressing the ability of urinary biomarkers to detect subclinical renal injury in patients receiving cisplatin.

Preclinical and Dose-Finding Phase I Trial Results of Combined Treatment with a TORC1/2 Inhibitor (TAK-228) and Aurora A Kinase Inhibitor (Alisertib) in Solid Tumors.

PURPOSE: The purpose of this study was to evaluate the rational combination of TORC1/2 inhibitor TAK-228 and Aurora A kinase inhibitor alisertib in preclinical models of triple-negative breast cancer (TNBC) and to conduct a phase I dose escalation trial in patients with advanced solid tumors. EXPERIMENTAL DESIGN: TNBC cell lines and patient-derived xenograft (PDX) models were treated with alisertib, TAK-228, or the combination and evaluated for changes in proliferation, cell cycle, mTOR pathway modulation, and terminal cellular fate, including apoptosis and senescence. A phase I clinical trial was conducted in patients with advanced solid tumors treated with escalating doses of alisertib and TAK-228 using a 3+3 design to determine the maximum tolerated dose (MTD). RESULTS: The combination of TAK-228 and alisertib resulted in decreased proliferation and cell-cycle arrest in TNBC cell lines. Treatment of TNBC PDX models resulted in significant tumor growth inhibition and increased apoptosis with the combination. In the phase I dose escalation study, 18 patients with refractory solid tumors were enrolled. The MTD was alisertib 30 mg b.i.d. days 1 to 7 of a 21-day cycle and TAK-228 2 mg daily, continuous dosing. The most common treatment-related adverse events were neutropenia, fatigue, nausea, rash, mucositis, and alopecia. CONCLUSIONS: The addition of TAK-228 to alisertib potentiates the antitumor activity of alisertib in vivo, resulting in increased cell death and apoptosis. The combination is tolerable in patients with advanced solid tumors and should be evaluated further in expansion cohorts with additional pharmacodynamic assessment.

A phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas.

PURPOSE: To evaluate the toxicity profile, pharmacologic, and biological properties of 3-pyridylmethyl N-{4-[(2-aminophenyl)carbamoyl]benzyl}carbamate (MS-275), a histone deacetylase inhibitor, when administered orally on three different dosing schedules. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies and lymphomas were treated on three dose schedules: once every other week, twice weekly for 3 weeks every 28 days, and once weekly for 3 weeks every 28 days. First-cycle plasma pharmacokinetics and peripheral blood mononuclear cell histone acetylation were determined. RESULTS: Twenty-seven patients received > or =149 courses of treatment. Hypophosphatemia and asthenia were dose limiting on the weekly and twice-weekly dosing schedules; there was no dose-limiting toxicity on the every other week schedule. Pharmacokinetic variables revealed dose-dependent and dose-proportional increases. Two of 27 patients showed partial remissions, including one patient with metastatic melanoma who had a partial response and has remained on study for >5 years. Six patients showed prolonged disease stabilization. Levels of histone H3 and H4 acetylation in peripheral blood mononuclear cells increased qualitatively but with a high degree of interpatient variation. CONCLUSIONS: MS-275 is well tolerated at doses up to 6 mg/m(2) every other week or 4 mg/m(2) weekly for 3 weeks followed by 1 week of rest and results in biologically relevant plasma concentrations and antitumor activity. Twice-weekly dosing was not tolerable due to asthenia, and further evaluation of this schedule was halted. The recommended dose for further disease-focused studies is 4 mg/m(2) given weekly for 3 weeks every 28 days or 2 to 6 mg/m(2) given once every other week.

A phase I study of gefitinib, capecitabine, and celecoxib in patients with advanced solid tumors.

This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicity profile of the combination of gefitinib, capecitabine, and celecoxib in patients with advanced solid tumors. Patients were treated with escalating doses of gefitinib once daily, capecitabine twice daily (14 of 28 days), and celecoxib twice daily. Plasma samples for biomarkers were obtained at baseline and weekly for the first 2 cycles. Pharmacokinetic variables were correlated with toxicity and presence of biological effect. Tumor biopsies from 5 patients were analyzed for changes in tumor metabolic activity by nuclear magnetic resonance spectroscopy. [18F]fluorodeoxyglucose positron emission tomography was done as a correlate in 6 patients at the MTD. Thirty-nine patients received 168 cycles of therapy. The dose-limiting toxicities observed included nausea, dehydration and nausea, diarrhea, and stomatitis. The MTD was 250 mg/d gefitinib (days 1-14) and 2,000 mg/m2/d capecitabine divided twice daily (days 8-21) every 28 days. Celecoxib was eliminated due to concerns of increased risk for cardiovascular toxicity, although no patients in this study had cardiac events. One patient with cholangiocarcinoma had a confirmed partial response. Fourteen of 39 (36%) patients maintained prolonged stable disease for a median of 4 months (range, 3-24 months). [18F]fluorodeoxyglucose positron emission tomography scan and metabolomic analyses revealed differences in metabolic response to gefitinib versus capecitabine. The combination of gefitinib and capecitabine is well tolerated and appears to have activity against certain advanced solid tumors, providing a rationale for further evaluation in advanced solid malignancies.