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Galectins are innate immune system regulators associated with disease progression in cancer. This paper aims to investigate the correlation between mutated cancer-critical genes and galectin levels in breast cancer patients to determine whether galectins and genetic profiles can be used as biomarkers for disease and potential therapy targets. Prisma Health Cancer Institute's Biorepository provided seventy-one breast cancer samples, including all four stages spanning the major molecular subtypes and histologies. Hotspot mutation statuses of cancer-critical genes were determined using multiplex PCR in tumor samples from the same patients by Precision Genetics and the University of South Carolina Functional Genomics Core Facility. The galectin-1, -3, and -9 levels in patients' sera were analyzed using Enzyme-linked Immunosorbent Assay (ELISA). An analysis was performed using JMP software to compare mean and median serum galectin levels between samples with and without specific cancer-critical genes, including pooled t -test, Wilcoxon Rank Sum Test, ANOVA, and Steel Dwass Test (α=0.05). Our analysis indicates that KIT mutations correlate with elevated serum levels of galectin-9 in patients with breast cancer. In patients with Luminal A subtype, FLT3 mutation correlates with lower serum galectin-1 and -9 levels and TP53 mutations correlate with higher serum galectin-3 levels. Patients with invasive ductal carcinoma had significantly higher serum galectin-3 levels than patients with ductal carcinoma in situ. Patients with both TP53 and PIK3CA mutations exhibit elevated serum galectin-3 levels, while patients with one or neither mutation show no significant difference in serum galectin-3 levels. In addition, metastatic breast cancer samples were more likely to have a KIT or PIK3CA mutation compared to primary breast cancer samples. The relationship between genetic mutations and galectin levels has the potential to identify appropriate candidates for combined therapy, targeting genetic mutations and galectins. Further understanding of the effect of genetic mutations and galectin levels on cancer progression and metastasis could aid in the search for biomarkers for breast cancer diagnosis, disease progression, and prognosis.

Galectins play a pivotal role in lung cancer oncogenic pathways, influencing apoptosis, angiogenesis, and tumor metastasis. Biomarkers that diagnose, prognose, and guide cancer treatment are crucial, with galectins having the biomarker potential for non-small cell lung cancer (NSCLC). Using enzyme-linked immunosorbent assay (ELISA), we assessed serum galectin-1, -3, and -9 levels in NSCLC patients. A retrospective chart review was performed to examine patient demographics, cancer stage, tumor biology, cancer treatment, and patient outcomes. Galectin levels were then compared across these factors. In this exploratory analysis, galectin-3 levels were significantly lower in patients with squamous cell lung cancer ( p = 0.0019) and in patients exposed to chemotherapy ( p = 0.0375). Galectin-1 levels were significantly lower in patients with previous metastasis but had no correlation with future metastasis. Abnormal galectin-1 levels were significantly correlated with decreased overall survival (OS) in NSCLC ( p = 0.0357) and specifically in patients with surgically resectable NSCLC ( p = 0.0112). However, abnormal galectin-1 levels were not found to correlate with decreased OS in multivariable analysis ( p = 0.0513). These findings may have clinical implications as galectin-3 inhibitors are in trials for NSCLC. Additionally, they suggest that galectin-1 has potential as a prognostic marker for surgically resectable NSCLC.

Recent studies have reported several beneficial effects of natural compounds on cancerous cells, highlighting their use for future treatments. These preliminary findings have encouraged experiments with natural substances, such as plant extracts, to examine both cytotoxic and mitogenic effects and find alternative treatments for diseases such as breast cancer. This study examines the effects of microwave-assisted and ethanol maceration of marjoram ( Origanum majorana ) on MCF-7 breast cancer cell lines and normal breast tissue cell lines used as controls. Marjoram extracts displayed a cytotoxic effect on the MCF-7 cell lines and a mitogenic effect on the control cell lines at the MTS test. The metabolic profiles of MCF-7 and control cell lines were also assessed using the Biolog Phenotype Mammalian Metabolic (PM-M) platform and revealed statistically significant differences in the utilization of energy sources, metabolic activity in the presence of certain ionic species, and responses to metabolic effectors, such as stimulant/catabolic compounds and steroid hormones. Exposure to marjoram extracts exerted positive effects on the MCF-7 cells on the abnormal utilization of energy sources and the responses to metabolic effectors, while no major effects were detected on control cells. These effects were compared to the metabolic impact of the chemotherapeutic agent doxorubicin, which showed profound cytotoxic effects on both cancerous and normal breast cells. In conclusion, our in vitro evidence indicates that marjoram extracts are a promising alternative to chemotherapy in breast cancer since they can successfully eliminate cancerous cells by affecting their metabolic capacity to proliferate without inducing noticeable adverse effects on normal breast tissue.

Purpose: Adavosertib may alter exposure to substrates of the cytochrome P450 (CYP) family of enzymes. This study assessed its effect on the pharmacokinetics of a cocktail of probe substrates for CYP3A (midazolam), CYP2C19 (omeprazole), and CYP1A2 (caffeine)., Methods: Period 1: patients with locally advanced or metastatic solid tumors received 'cocktail': caffeine 200 mg, omeprazole 20 mg, and midazolam 2 mg (single dose); period 2: after 7- to 14-day washout, patients received adavosertib 225 mg twice daily on days 1-3 (five doses), with cocktail on day 3. After cocktail alone or in combination with adavosertib administration, 24-h pharmacokinetic sampling occurred for probe substrates and their respective metabolites paraxanthine, 5-hydroxyomeprazole (5-HO), and 1'-hydroxymidazolam (1'-HM). Safety was assessed throughout., Results: Of 33 patients (median age 60.0 years, range 41-83) receiving cocktail, 30 received adavosertib. Adavosertib co-administration increased caffeine, omeprazole, and midazolam exposure by 49%, 80%, and 55% (AUC 0-12 ), respectively; AUC 0-t increased by 61%, 98%, and 55%. Maximum plasma drug concentration (C max ) increased by 4%, 46%, and 39%. Adavosertib co-administration increased 5-HO and 1'-HM exposure by 43% and 54% (AUC 0-12 ) and 49% and 58% (AUC0-t), respectively; paraxanthine exposure was unchanged. Adavosertib co-administration decreased C max for paraxanthine and 5-HO by 19% and 7%; C max increased by 33% for 1'-HM. After receiving adavosertib, 19 (63%) patients had treatment-related adverse events (six [20%] grade ≥ 3)., Conclusion: Adavosertib (225 mg bid) is a weak inhibitor of CYP1A2, CYP2C19, and CYP3A., Clinicaltrials: GOV: NCT03333824., (© 2023. The Author(s).)

Purpose: Adavosertib is a small-molecule, ATP-competitive inhibitor of Wee1 kinase. Molecularly targeted oncology agents have the potential to increase the risk of cardiovascular events, including prolongation of QT interval and associated cardiac arrhythmias. This study investigated the effect of adavosertib on the QTc interval in patients with advanced solid tumors., Methods: Eligible patients were ≥ 18 years of age with advanced solid tumors for which no standard therapy existed. Patients received adavosertib 225 mg twice daily on days 1-2 at 12-h intervals and once on day 3. Patients underwent digital 12-lead electrocardiogram and pharmacokinetic assessments pre-administration and time-matched assessments during the drug administration period. The relationship between maximum plasma drug concentration (C max ) and baseline-adjusted corrected QT interval by Fridericia (QTcF) was estimated using a prespecified linear mixed-effects model., Results: Twenty-one patients received adavosertib. Concentration-QT modeling of ΔQTcF and the upper limit of the 90% confidence interval corresponding to the geometric mean of C max observed on days 1 and 3 were below the threshold for regulatory concern (not > 10 ms). No significant relationship between ΔQTcF (vs baseline) and adavosertib concentration was identified (P = 0.27). Pharmacokinetics and the adverse event (AE) profile were consistent with previous studies at this dose. Eleven (52.4%) patients experienced 17 treatment-related AEs in total, including diarrhea and nausea (both reported in six [28.6%] patients), vomiting (reported in two [9.5%] patients), anemia, decreased appetite, and constipation (all reported in one [4.8%] patient)., Conclusion: Adavosertib does not have a clinically important effect on QTc prolongation., Clinicaltrials: GOV: NCT03333824., (© 2023. The Author(s).)

Galectins have been shown to have roles in cancer progression via their contributions to angiogenesis, metastasis, cell division, and the evasion of immune destruction. This study analyzes galectin-1, -3, and -9 serum concentrations in breast cancer patients through enzyme-linked immunosorbent assay (ELISA) against the characteristics of the patient and the tumor such as stage, molecular subtype, and receptor expression. Galectin-9 was found to be statistically significantly increased in HER2-enriched tumors and reduced in patients with hormone-receptor-positive tumors. Galectin-1 was found to be statistically significantly increased in the serum of patients who had undergone hormonal, immunotherapy, or chemotherapy. These findings provide insight into the changes in galectin levels during the progress of cancer, the response to treatment, and the molecular phenotype. These findings are valuable in the further understanding of the relationships between galectin and tumor biology and can inform future research on therapeutic targets for galectin inhibitors and the utility of galectin biomarkers.

Immunotherapy response score (IRS) integrates tumor mutation burden (TMB) and quantitative expression biomarkers to predict anti-PD-1/PD-L1 [PD-(L)1] monotherapy benefit. Here, we evaluated IRS in additional cohorts. Patients from an observational trial (NCT03061305) treated with anti-PD-(L)1 monotherapy were included and assigned to IRS-High (-H) versus -Low (-L) groups. Associations with real-world progression-free survival (rwPFS) and overall survival (OS) were determined by Cox proportional hazards (CPH) modeling. Those with available PD-L1 IHC treated with anti-PD-(L)1 with or without chemotherapy were separately assessed. Patients treated with PD-(L)1 and/or chemotherapy (five relevant tumor types) were assigned to three IRS groups [IRS-L divided into IRS-Ultra-Low (-UL) and Intermediate-Low (-IL), and similarly assessed]. In the 352 patient anti-PD-(L)1 monotherapy validation cohort (31 tumor types), IRS-H versus IRS-L patients had significantly longer rwPFS and OS. IRS significantly improved CPH associations with rwPFS and OS beyond microsatellite instability (MSI)/TMB alone. In a 189 patient (10 tumor types) PD-L1 IHC comparison cohort, IRS, but not PD-L1 IHC nor TMB, was significantly associated with anti-PD-L1 rwPFS. In a 1,103-patient cohort (from five relevant tumor types), rwPFS did not significantly differ in IRS-UL patients treated with chemotherapy versus chemotherapy plus anti-PD-(L)1, nor in IRS-H patients treated with anti-PD-(L)1 versus anti-PD-(L)1 + chemotherapy. IRS associations were consistent across subgroups, including both Europeans and non-Europeans. These results confirm the utility of IRS utility for predicting pan-solid tumor PD-(L)1 monotherapy benefit beyond available biomarkers and demonstrate utility for informing on anti-PD-(L)1 and/or chemotherapy treatment., Significance: This study confirms the utility of the integrative IRS biomarker for predicting anti-PD-L1/PD-1 benefit. IRS significantly improved upon currently available biomarkers, including PD-L1 IHC, TMB, and MSI status. Additional utility for informing on chemotherapy, anti-PD-L1/PD-1, and anti-PD-L1/PD-1 plus chemotherapy treatments decisions is shown., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Background: Anti-PD-1 and PD-L1 (collectively PD-[L]1) therapies are approved for many advanced solid tumors. Biomarkers beyond PD-L1 immunohistochemistry, microsatellite instability, and tumor mutation burden (TMB) may improve benefit prediction., Methods: Using treatment data and genomic and transcriptomic tumor tissue profiling from an observational trial (NCT03061305), we developed Immunotherapy Response Score (IRS), a pan-tumor predictive model of PD-(L)1 benefit. IRS real-world progression free survival (rwPFS) and overall survival (OS) prediction was validated in an independent cohort of trial patients., Results: Here, by Cox modeling, we develop IRS-which combines TMB with CD274, PDCD1, ADAM12 and TOP2A quantitative expression-to predict pembrolizumab rwPFS (648 patients; 26 tumor types; IRS-High or -Low groups). In the 248 patient validation cohort (248 patients; 24 tumor types; non-pembrolizumab PD-[L]1 monotherapy treatment), median rwPFS and OS are significantly longer in IRS-High vs. IRS-Low patients (rwPFS adjusted hazard ratio [aHR] 0.52, p = 0.003; OS aHR 0.49, p = 0.005); TMB alone does not significantly predict PD-(L)1 rwPFS nor OS. In 146 patients treated with systemic therapy prior to pembrolizumab monotherapy, pembrolizumab rwPFS is only significantly longer than immediately preceding therapy rwPFS in IRS-High patients (interaction test p = 0.001). In propensity matched lung cancer patients treated with first-line pembrolizumab monotherapy or pembrolizumab+chemotherapy, monotherapy rwPFS is significantly shorter in IRS-Low patients, but is not significantly different in IRS-High patients. Across 24,463 molecularly-evaluable trial patients, 7.6% of patients outside of monotherapy PD-(L)1 approved tumor types are IRS-High/TMB-Low., Conclusions: The validated, predictive, pan-tumor IRS model can expand PD-(L)1 monotherapy benefit outside currently approved indications., (© 2023. The Author(s).)

Background: The Janus kinase (JAK)/signal transducers and activators of transcription pathway has been implicated in the pathogenesis and progression of various hematologic malignancies. JAK1-regulated cytokines stimulate proliferation and growth of malignant cells and resistance to certain therapies., Patients and Methods: This phase 1/2 study evaluated 2 oral, novel JAK1 inhibitors (INCB052793 and itacitinib) in advanced hematologic malignancies. Phase 1a assessed dose escalation and expansion of INCB052793 monotherapy. Phase 1b evaluated INCB052793 plus standard therapy in relapsed/refractory multiple myeloma, acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS). Phase 2 evaluated INCB052793 or itacitinib plus azacitidine in DNA methyltransferase inhibitor (DNMTi)-refractory AML or MDS. Primary endpoints included safety and tolerability for phase 1, and objective response rate for phase 2., Results: Fifty-eight patients were enrolled, all received study treatment and discontinued either treatment or participation in the study. The most common reasons for treatment discontinuation were progressive disease (35.4% and 50.0%) and adverse events (22.9% and 20.0%) for INCB052793 and itacitinib plus azacitidine, respectively. In phase 1, 12 of 39 patients (31%) achieved an objective response; 35 mg once daily was selected as the phase 2 dose. Two patients with DNMTi-refractory disease had an objective response in phase 2. The study was terminated for lack of efficacy., Conclusion: Inhibition of JAK1 with INCB052793 (monotherapy or combination therapy) or itacitinib plus azacitidine did not demonstrate clinically meaningful responses in these patients with hematopoietic malignancies., (Copyright © 2022. Published by Elsevier Inc.)

To investigate a potential role for galectins as biomarkers that enable diagnosis or prognostication of breast or non-small cell lung cancer, the serum levels of galectins -1, -3, -7, -8, and -9 of cancer patients determined by ELISA assays were compared to the mutation status of 50 known cancer-critical genes, which were determined using multiplex PCR in tumors of the same patients. Mutations in the KIT proto-oncogene, which codes for the c-Kit protein, a receptor tyrosine kinase, correlated with higher levels of galectins -1, -3, -8, and -9 in breast cancer patients and galectin-1 in non-small cell lung cancer patients. Mutations in the KIT gene were more likely found in brain metastases from both of these primary cancers. The most common KIT mutation in our panel was p.M541L, a missense mutation in the transmembrane domain of the c-Kit protein. These results demonstrate an association between KIT oncogenic signaling and elevated serum galectins in patients with metastatic disease. Changes in protein trafficking and the glycocalyx composition of cancer cells may explain the observed alterations in galectin expression. This study can be useful for the targeted selection of receptor tyrosine kinase and galectin inhibitor anti-cancer treatments.

Galectins are proteins with high-affinity β-galactoside-binding sites that function in a variety of signaling pathways through interactions with glycoproteins. The known contributions of galectins-1, -3, -7, -8, and -9 to angiogenesis, metastasis, cell division, and evasion of immune destruction led us to investigate the circulating levels of these galectins in cancer patients. This study compares galectin concentrations by enzyme-linked immunosorbent assay (ELISA) from each stage of breast, lung, and colon cancer. Galectins-1 and -7, which share a prototype structure, were found to have statistically significant increases in breast and lung cancer. Of the tandem-repeat galectins, galectin-8 showed no statistically significant change in these cancer types, but galectin-9 was increased in colon and lung cancer. Galectin-3 is the only chimera-type galectin and was increased in all stages of breast, colon, and lung cancer. In conclusion, there were significant differences in the galectin levels in patients with these cancers compared with healthy controls, and galectin levels did not significantly change from stage to stage. These findings suggest that further research on the roles of galectins early in disease pathogenesis may lead to novel indications for galectin inhibitors.

Lessons Learned: Disease control with signals of response were demonstrated, which should lead to future validating clinical trials using checkpoint inhibitors in this underserved rare malignancy population. Although the study of single types of rare cancers is practically challenging, clinical trial designs that aggregate such patients into cohorts treated similarly are feasible, even in the community setting., Background: Patients with rare cancers are an underserved population with limited access to clinical trials aside from phase I trials in the refractory setting. Treatment of these patients is often based on collections of anecdotes and small denominator review articles. Despite broad evidence of efficacy of combined immune checkpoint blockade across multiple tumor types, patients with rare tumors have not been afforded the opportunity for these therapies., Methods: A phase II, investigator-initiated, single institution trial using durvalumab (1,500 mg every [Q]4 weeks × 13) and tremelimumab (75 mg Q4 weeks × 7, then Q12 weeks × 2) is reported. The population included 50 patients with advanced rare solid tumors (incidence <6/100,000 per year). The phase II dose and safety profile were defined in prior phase I trials. All patients had exhausted standard therapy options and all had received at least one prior line of systemic therapy (n = 49) unless a standard treatment option did not exist (n = 1)., Results: A complete response was demonstrated in one patient with anal cancer. Striking partial responses were seen in four patients. Prolonged disease stability was noted in 18 patients. Thirteen patients experienced disease progression. Patients were considered unevaluable if unable to initiate therapy (n = 6) or unable to complete two cycles of therapy (n = 8). In all cases, patients were unevaluable because of clinical deterioration. The toxicity profile paralleled prior published studies. Toxicities were manageable and without new signals. There were two events of grade 4 immune-mediated hepatitis and one death from pneumonitis., Conclusion: This single-cohort basket trial demonstrated clinical activity from combined checkpoint blockade in 23 of the 36 evaluable patients. Patients with rare cancers, not eligible for immunotherapy via conventional clinical trial mechanisms, should be considered for this therapy through compassionate use, further clinical trials, and national registry programs., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Purpose: Tissue-based comprehensive genomic profiling (CGP) is increasingly used for treatment selection in patients with advanced cancer; however, tissue availability may limit widespread implementation. Here, we established real-world CGP tissue availability and assessed CGP performance on consecutively received samples., Materials and Methods: We conducted a post hoc, nonprespecified analysis of 32,048 consecutive tumor tissue samples received for StrataNGS, a multiplex polymerase chain reaction (PCR)-based comprehensive genomic profiling (PCR-CGP) test, as part of an ongoing observational trial (NCT03061305). Sample characteristics and PCR-CGP performance were assessed across all tested samples, including exception samples not meeting minimum input quality control (QC) requirements (< 20% tumor content [TC], < 2 mm 2 tumor surface area [TSA], DNA or RNA yield < 1 ng/µL, or specimen age > 5 years). Tests reporting ≥ 1 prioritized alteration or meeting TC and sequencing QC were considered successful. For prostate carcinoma and lung adenocarcinoma, tests reporting ≥ 1 actionable or informative alteration or meeting TC and sequencing QC were considered actionable., Results: Among 31,165 (97.2%) samples where PCR-CGP was attempted, 10.7% had < 20% TC and 59.2% were small (< 25 mm 2 tumor surface area). Of 31,101 samples evaluable for input requirements, 8,089 (26.0%) were exceptions not meeting requirements. However, 94.2% of the 31,101 tested samples were successfully reported, including 80.5% of exception samples. Positive predictive value of PCR-CGP for ERBB2 amplification in exceptions and/or sequencing QC-failure breast cancer samples was 96.7%. Importantly, 84.0% of tested prostate carcinomas and 87.9% of lung adenocarcinomas yielded results informing treatment selection., Conclusion: Most real-world tissue samples from patients with advanced cancer desiring CGP are limited, requiring optimized CGP approaches to produce meaningful results. An optimized PCR-CGP test, coupled with an inclusive exception testing policy, delivered reportable results for > 94% of samples, potentially expanding the proportion of CGP-testable patients and impact of biomarker-guided therapies., Competing Interests: Scott A. Tomlins Employment: Strata Oncology Leadership: Strata Oncology Stock and Other Ownership Interests: Strata Oncology, Javelin Oncology Consulting or Advisory Role: Janssen, Astellas Medivation, Strata Oncology Research Funding: Astellas Medivation Patents, Royalties, Other Intellectual Property: I am a coinventor on a patent issued to the University of Michigan on ETS gene fusions in prostate and am included in the royalty stream. The diagnostic field of use was licensed to Hologic/Gen-Probe (who sublicensed some rights to Ventana/Roche) and is licensed to LynxDx. I am a coinventor on a patent issued to Strata Oncology related to MSI determination and checkpoint inhibitor benefit Travel, Accommodations, Expenses: Strata Oncology, Genzyme Daniel H. Hovelson Employment: Strata Oncology Elizabeth C. Dees Consulting or Advisory Role: Novartis, Strata Oncology, G1 Therapeutics Research Funding: Novartis, Genentech/Roche, Pfizer, Merck, H3 Biomedicine, Meryx Pharmaceuticals Travel, Accommodations, Expenses: G1 Therapeutics Mark E. Burkard Consulting or Advisory Role: Pointcare genomics, Strata Oncology, Novartis Research Funding: AbbVie, Strata Oncology, Puma Biotechnology, Loxo, Merck, Arcus Ventures, Apollomics, Elevation Oncology, Genentech Patents, Royalties, Other Intellectual Property: I have a patent for implantable/localized drug delivery device that can sample the tumor microenvironment and deliver drug, I have a patent for a method to detect recombination events with CRISPR-mediated editing, and I have a patent for conducting expansion microscopy without specialized equipment Michael Guarino Stock and Other Ownership Interests: Johnson and Johnson, Johnson and Johnson Travel, Accommodations, Expenses: McKesson, ARMO BioSciences, AstraZeneca, BMS, De Novo Pharmaceuticals Marc R. Matrana Consulting or Advisory Role: Strata Oncology Speakers' Bureau: Bristol Myers Squibb, AstraZeneca, Merck, Eisai, Genentech, Janssen, Exelixis Eddy S. Yang Consulting or Advisory Role: Strata Oncology, AstraZeneca, Bayer, Clovis Oncology, Lilly Research Funding: Lilly, Novartis, Clovis Oncology, Puma Biotechnology Benjamin M. Parsons Consulting or Advisory Role: Celgene, Amgen, AstraZeneca Speakers' Bureau: Amgen, Celgene, AstraZeneca Open Payments Link: https://openpaymentsdata.cms.gov/physician/795031 Michael A. Thompson Stock and Other Ownership Interests: Doximity Consulting or Advisory Role: Celgene, VIA Oncology, Takeda, GlaxoSmithKline, Strata Oncology, Syapse, Adaptive Biotechnologies, AbbVie, GRAIL, Epizyme, Janssen Oncology Research Funding: Takeda, Bristol Myers Squibb, TG Therapeutics, Cancer Research and Biostatistics, AbbVie, PrECOG, Strata Oncology, Lynx Biosciences, Denovo Biopharma, ARMO BioSciences, GlaxoSmithKline, Amgen Patents, Royalties, Other Intellectual Property: UpToDate, Peer Review for Plasma Cell Dyscrasias (Editor: Robert Kyle) Travel, Accommodations, Expenses: Takeda, GlaxoSmithKline, Syapse Other Relationship: Doximity Open Payments Link: https://openpaymentsdata.cms.gov/physician/192826/summary William J. Edenfield Consulting or Advisory Role: Chimerix Suresh Nair Stock and Other Ownership Interests: Moderna Therapeutics, Novavax, Biontech, Gilead Sciences Research Funding: Bristol Myers Squibb, Merck, Nektar Adedayo Onitilo Consulting or Advisory Role: Kite, a Gilead company, Envision Communications Speakers' Bureau: GlaxoSmithKline, Puma Biotechnology, Kite/Gilead, AbbVie Robert Siegel Research Funding: Merck, Mirati Therapeutics, GRAIL, Altor BioScience, Galera Therapeutics, Apollomics, Strata Oncology, Arcus Biosciences, Bristol Myers Squibb, Cancer Insight, Puma Biotechnology, Conjupro Biotherapeutics, Razor Genomics, Sanofi, Seattle Genetics Other Relationship: American Board of Internal Medicine (ABIM) William J. Irvin Research Funding: Merck, Altor BioScience, Odonate Therapeutics, Boston Biomedical, Novartis, Pfizer, Seattle Genetics, Altor BioScience, AstraZeneca Arvinda Padmanabhan Speakers' Bureau: Clovis Oncology, Roche Anneliese Gonzalez Research Funding: Novartis, Radius Health, Astellas Pharma Paul Harms Research Funding: Q32 Bio Jennifer Hipp Employment: Strata Oncology Stock and Other Ownership Interests: Strata Oncology Consulting or Advisory Role: PathAI Kat Kwiatkowski Employment: Strata Oncology Stock and Other Ownership Interests: Strata Oncology, Epizyme, Loxo, Editas Medicine, Intuitive Surgical Khalis Mitchell Employment: Strata Oncology Stock and Other Ownership Interests: Mirati Therapeutics Javed Siddiqui Consulting or Advisory Role: Strata Oncology, LynxDx Hana Vakil Employment: Strata Oncology Stock and Other Ownership Interests: Strata Oncology D. Bryan Johnson Employment: Strata Oncology Stock and Other Ownership Interests: Strata Oncology Daniel R. Rhodes Employment: Strata Oncology, Javelin Oncology Leadership: Strata Oncology, Javelin Oncology Stock and Other Ownership Interests: Strata Oncology, Javelin Oncology Patents, Royalties, Other Intellectual Property: I am paid royalties from the University of Michigan on license revenues related to a patent on prostate cancer gene fusions No other potential conflicts of interest were reported. Scott A. Tomlins Employment: Strata Oncology Leadership: Strata Oncology Stock and Other Ownership Interests: Strata Oncology, Javelin Oncology Consulting or Advisory Role: Janssen, Astellas Medivation, Strata Oncology Research Funding: Astellas Medivation Patents, Royalties, Other Intellectual Property: I am a coinventor on a patent issued to the University of Michigan on ETS gene fusions in prostate and am included in the royalty stream. The diagnostic field of use was licensed to Hologic/Gen-Probe (who sublicensed some rights to Ventana/Roche) and is licensed to LynxDx. I am a coinventor on a patent issued to Strata Oncology related to MSI determination and checkpoint inhibitor benefit Travel, Accommodations, Expenses: Strata Oncology, Genzyme Daniel H. Hovelson Employment: Strata Oncology Elizabeth C. Dees Consulting or Advisory Role: Novartis, Strata Oncology, G1 Therapeutics Research Funding: Novartis, Genentech/Roche, Pfizer, Merck, H3 Biomedicine, Meryx Pharmaceuticals Travel, Accommodations, Expenses: G1 Therapeutics Mark E. Burkard Consulting or Advisory Role: Pointcare genomics, Strata Oncology, Novartis Research Funding: AbbVie, Strata Oncology, Puma Biotechnology, Loxo, Merck, Arcus Ventures, Apollomics, Elevation Oncology, Genentech Patents, Royalties, Other Intellectual Property: I have a patent for implantable/localized drug delivery device that can sample the tumor microenvironment and deliver drug, I have a patent for a method to detect recombination events with CRISPR-mediated editing, and I have a patent for conducting expansion microscopy without specialized equipment Michael Guarino Stock and Other Ownership Interests: Johnson and Johnson, Johnson and Johnson Travel, Accommodations, Expenses: McKesson, ARMO BioSciences, AstraZeneca, BMS, De Novo Pharmaceuticals Marc R. Matrana Consulting or Advisory Role: Strata Oncology Speakers' Bureau: Bristol Myers Squibb, AstraZeneca, Merck, Eisai, Genentech, Janssen, Exelixis Eddy S. Yang Consulting or Advisory Role: Strata Oncology, AstraZeneca, Bayer, Clovis Oncology, Lilly Research Funding: Lilly, Novartis, Clovis Oncology, Puma Biotechnology Benjamin M. Parsons Consulting or Advisory Role: Celgene, Amgen, AstraZeneca Speakers' Bureau: Amgen, Celgene, AstraZeneca Open Payments Link: https://openpaymentsdata.cms.gov/physician/795031 Michael A. Thompson Stock and Other Ownership Interests: Doximity Consulting or Advisory Role: Celgene, VIA Oncology, Takeda, GlaxoSmithKline, Strata Oncology, Syapse, Adaptive Biotechnologies, AbbVie, GRAIL, Epizyme, Janssen Oncology Research Funding: Takeda, Bristol Myers Squibb, TG Therapeutics, Cancer Research and Biostatistics, AbbVie, PrECOG, Strata Oncology, Lynx Biosciences, Denovo Biopharma, ARMO BioSciences, GlaxoSmithKline, Amgen Patents, Royalties, Other Intellectual Property: UpToDate, Peer Review for Plasma Cell Dyscrasias (Editor: Robert Kyle) Travel, Accommodations, Expenses: Takeda, GlaxoSmithKline, Syapse Other Relationship: Doximity Open Payments Link: https://openpaymentsdata.cms.gov/physician/192826/summary William J. Edenfield Consulting or Advisory Role: Chimerix Suresh Nair Stock and Other Ownership Interests: Moderna Therapeutics, Novavax, Biontech, Gilead Sciences Research Funding: Bristol Myers Squibb, Merck, Nektar Adedayo Onitilo Consulting or Advisory Role: Kite, a Gilead company, Envision Communications Speakers' Bureau: GlaxoSmithKline, Puma Biotechnology, Kite/Gilead, AbbVie Robert Siegel Research Funding: Merck, Mirati Therapeutics, GRAIL, Altor BioScience, Galera Therapeutics, Apollomics, Strata Oncology, Arcus Biosciences, Bristol Myers Squibb, Cancer Insight, Puma Biotechnology, Conjupro Biotherapeutics, Razor Genomics, Sanofi, Seattle Genetics Other Relationship: American Board of Internal Medicine (ABIM) William J. Irvin Research Funding: Merck, Altor BioScience, Odonate Therapeutics, Boston Biomedical, Novartis, Pfizer, Seattle Genetics, Altor BioScience, AstraZeneca Arvinda Padmanabhan Speakers' Bureau: Clovis Oncology, Roche Anneliese Gonzalez Research Funding: Novartis, Radius Health, Astellas Pharma Paul Harms Research Funding: Q32 Bio Jennifer Hipp Employment: Strata Oncology Stock and Other Ownership Interests: Strata Oncology Consulting or Advisory Role: PathAI Kat Kwiatkowski Employment: Strata Oncology Stock and Other Ownership Interests: Strata Oncology, Epizyme, Loxo, Editas Medicine, Intuitive Surgical Khalis Mitchell Employment: Strata Oncology Stock and Other Ownership Interests: Mirati Therapeutics Javed Siddiqui Consulting or Advisory Role: Strata Oncology, LynxDx Hana Vakil Employment: Strata Oncology Stock and Other Ownership Interests: Strata Oncology D. Bryan Johnson Employment: Strata Oncology Stock and Other Ownership Interests: Strata Oncology Daniel R. Rhodes Employment: Strata Oncology, Javelin Oncology Leadership: Strata Oncology, Javelin Oncology Stock and Other Ownership Interests: Strata Oncology, Javelin Oncology Patents, Royalties, Other Intellectual Property: I am paid royalties from the University of Michigan on license revenues related to a patent on prostate cancer gene fusions No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Purpose: Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC)., Methods: A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 bone marrow arrest in a first-in-human Phase I study (G1T28-1-01). PK, PD, safety, and efficacy data from G1T28-1-01 and two Phase Ib/IIa studies (G1T28-02/-03) in ES-SCLC were analyzed to support RP2D selection., Results: Model simulation of bone marrow arrest based on preclinical data predicted that a ≥ 192 mg/m 2 dose would induce a 40-50% decrease in total bone marrow proliferation in humans and almost 100% cell cycle arrest of cycling HSPCs. Consistent with this model, analysis of bone marrow aspirates in healthy volunteers after trilaciclib 192 mg/m 2 administration demonstrated almost 100% G1 arrest in HSPCs and 40% decrease in total bone marrow proliferation, with minimal toxicity. G1T28-02/-03 reported similar PK parameters with trilaciclib 200 mg/m 2 but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m 2 doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m 2 was selected as the RP2D, which was also favored by myelopreservation endpoints in G1T28-02/-03., Conclusion: Integrated PK/PD, safety, and efficacy data support 240 mg/m 2 as the RP2D for trilaciclib. CLINICALTRIALS., Gov Identifiers: NCT02243150; NCT02499770; NCT02514447.

Objectives: Cytokine release syndrome (CRS) is a potentially severe complication of COVID-19 most commonly resulting in respiratory failure. This ten-patient study was designed to determine the efficacy of therapeutic plasma exchange (TPE) in improving oxygenation and in reducing the cytokine load in a critically ill subset of patients., Methods: Five single volume plasma exchanges over eight days within a 14-day study period. In mechanically ventilated patients, oxygenation was measured via the PaO2/FiO2 (P/F) ratio and the oxygenation index (OI) daily for 14 days. Supplemental oxygen requirements were tracked daily for non-ventilated patients., Results: Non-ventilated patients were liberated from supplemental oxygen after TPE. The response was rapid with an 87% average reduction in oxygenation requirements following and average time to return to room air of 5.25 days. All mechanically ventilated patients demonstrated improvement in oxygenation with a 78% average improvement in the P/F ratio and a 43% improvement in OI. C-reactive protein (CRP) and serum levels of IL-6, IL-8, IL-10, TNFα, IFNγ and GM-CSF, were measured daily with immediate post TPE levels drawn on days 1, 2, 4, 6 and 8. All patients demonstrated significant reductions in CRP, IL-6, IL-10 and TNFα., Conclusions: In the majority of patients with Penn class 3 and 4 CRS complicating COVID-19, TPE demonstrated a prompt improvement in oxygenation and reduction in cytokine load without compromising patient safety. As this pilot study was envisioned to be hypothesis generating, expanded trials using TPE alone and in conjunction with novel pharmacologic agents are warranted., Registration: ClinicalTrials.gov NCT04374149., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Nonadherence to aromatase inhibitors (AIs) for breast cancer is common and increases the risk of recurrence. Text messaging increases adherence to medications for chronic conditions., Methods: We conducted a randomized clinical trial of text messaging (TM) versus no text messaging (No-TM) at 40 sites in the United States. Eligible patients were postmenopausal women with early-stage breast cancer taking an AI for > 30 days with a planned duration of ≥ 36 months. Test messages were sent twice a week over 36 months. Content themes focused on overcoming barriers to medication adherence and included cues to action, statements related to medication efficacy, and reinforcements of the recommendation to take AIs. Both groups were assessed every 3 months. The primary outcome was time to adherence failure (AF), where AF was defined as urine AI metabolite assay results satisfying one of the following: < 10 ng/mL, undetectable, or no submitted specimen. A stratified log-rank test was conducted. Multiple sensitivity analyses were performed., Results: In total, 724 patients were registered between May 2012 and September 2013, among whom,702 patients (348 in the text-messaging arm and 354 in the no-text-messaging arm) were eligible at baseline. Observed adherence at 36 months was 55.5% for TM and 55.4% for No-TM. The primary analysis showed no difference in time to AF by arm (3-year AF: 81.9% TM v 85.6% No-TM; HR, 0.89 [95% CI, 0.76 to 1.05]; P = .18). Multiple time to AF sensitivity analyses showed similar nonsignificant results. Three-year self-reported time to AF (10.4% v 10.3%; HR, 1.16 [95% CI, 0.69 to 1.98]; P = .57) and site-reported time to AF (21.9% v 18.9%; HR, 1.31 [95% CI, 0.86 to 2.01]; P = .21) also did not differ by arm., Conclusion: To our knowledge, this was the first large, long-term, randomized trial of an intervention directed at improving AI adherence. We found high rates of AI AF. Twice-weekly text reminders did not improve adherence to AIs. Improving long-term adherence will likely require personalized and sustained behavioral interventions., Competing Interests: The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

This phase 1/2 study assessed parsaclisib (INCB050465), a next-generation, potent, and highly selective phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor, in patients with relapsed or refractory B-cell malignancies, alone or in combination with a Janus kinase 1 inhibitor (itacitinib) or chemotherapy (rituximab, ifosfamide, carboplatin, and etoposide). Seventy-two patients received parsaclisib monotherapy (5-45 mg once daily). Expansion doses were 20 and 30 mg once daily; intermittent dosing at 20 mg (once daily for 9 weeks, then once weekly) was explored. No dose-limiting toxicities were identified, and maximum tolerated dose was not reached. Most common nonhematologic treatment-emergent adverse events (TEAEs) were diarrhea/colitis (36%), nausea (36%), fatigue (31%), and rash (31%). Grade 3/4 neutropenia occurred in 19% of patients. Serious TEAEs (>2 patients) were diarrhea/colitis (n = 9), pyrexia (n = 4), hypotension (n = 3), and sepsis (n = 3). Aspartate and alanine transaminase elevations occurring before treatment discontinuation were grade 1, except 1 grade 3 event each, secondary to sepsis. Two patients experienced 3 fatal parsaclisib-unrelated TEAEs (respiratory failure; respiratory failure and sepsis). In non-Hodgkin lymphoma (NHL), objective response rates to monotherapy were 71% in follicular lymphoma, 78% in marginal zone lymphoma, 67% in mantle cell lymphoma, and 30% in diffuse large B-cell lymphoma; 93% of responses occurred at first assessment (∼9 weeks). Parsaclisib has demonstrated antitumor activity in relapsed or refractory B-cell NHL with the potential for improved long-term patient outcomes. Phase 2 studies in relapsed or refractory B-cell NHL subtypes are ongoing. This trial was registered at www.clinicaltrials.gov as #NCT02018861., (© 2019 by The American Society of Hematology.)

Purpose: This large two-part, three-arm phase I study examined the safety and tolerability of CC-486 (an oral formulation of azacitidine, a hypomethylating agent) alone or in combination with the cytotoxic agents, carboplatin or nab-paclitaxel, in patients with advanced unresectable solid tumors. Patients and Methods: Part 1 ( n = 57) was a dose escalation of CC-486 alone (arm C) or with carboplatin (arm A) or nab-paclitaxel (arm B). The primary endpoint was safety, MTD, and recommended part 2 dose (RP2D) of CC-486. In part 2 ( n = 112), the primary endpoint was the safety and tolerability of CC-486 administered at the RP2D for each treatment arm, in tumor-specific expansion cohorts. Secondary endpoints included pharmacokinetics, pharmacodynamics, and antitumor activity of CC-486. Results: At pharmacologically active doses CC-486 in combination with carboplatin or nab-paclitaxel had a tolerable safety profile and no drug-drug interactions. The CC-486 RP2D was determined as 300 mg (every day, days 1-14/21) in combination with carboplatin (arm A) or as monotherapy (arm C); and 200 mg in the same dosing regimen in combination with nab-paclitaxel (arm B). Albeit limited by the small sample size, CC-486 monotherapy resulted in partial responses (three/eight) and stable disease (four/eight) in patients with nasopharyngeal cancer. Three of the stable disease responses lasted more than 150 days. Conclusions: CC-486 is well tolerated alone or in combination with carboplatin or nab-paclitaxel. Exploratory analyses suggest clinical activity of CC-486 monotherapy in nasopharyngeal cancer and provided the basis for an ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT02269943). Clin Cancer Res; 24(17); 4072-80. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Purpose: Phase Ib study evaluating the effect of apalutamide, at therapeutic exposure, on ventricular repolarization by applying time-matched pharmacokinetics and electrocardiography (ECG) in patients with castration-resistant prostate cancer. Safety of daily apalutamide was also assessed., Methods: Patients received 240 mg oral apalutamide daily. Time-matched ECGs were collected via continuous 12-lead Holter recording before apalutamide (Day - 1) and on Days 1 and 57 (Cycle 3 Day 1). Pharmacokinetics of apalutamide were assessed on Days 1 and 57 at matched time points of ECG collection. QT interval was corrected for heart rate using Fridericia correction (QTcF). The primary endpoint was the maximum mean change in QTcF (ΔQTcF) from baseline to Cycle 3 Day 1 (steady state). Secondary endpoints were the effect of apalutamide on other ECG parameters, pharmacokinetics of apalutamide and its active metabolite, relationship between plasma concentrations of apalutamide and QTcF, and safety., Results: Forty-five men were enrolled; 82% received treatment for ≥ 3 months. At steady state, the maximum ΔQTcF was 12.4 ms and the upper bound of its associated 90% CI was 16.0 ms. No clinically meaningful effects of apalutamide were reported for heart rate or other ECG parameters. A concentration-dependent increase in QTcF was observed for apalutamide. Most adverse events (AEs) (73%) were grade 1-2 in severity. No patients discontinued due to QTc prolongation or AEs., Conclusion: The effect of apalutamide on QTc prolongation was modest and does not produce a clinically meaningful effect on ventricular repolarization. The AE profile was consistent with other studies of apalutamide.

Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), MET, and ROS1, is approved for treatment of patients with ALK-positive or ROS1-positive advanced non-small-cell lung cancer (NSCLC). However, ALK rearrangements are also implicated in other malignancies, including anaplastic large-cell lymphoma and inflammatory myofibroblastic tumors (IMTs). In this ongoing, multicenter, single-arm, open-label phase 1b study (PROFILE 1013; NCT01121588), patients with ALK-positive advanced malignancies other than NSCLC were to receive a starting dose of crizotinib 250 mg twice daily. Primary endpoints were safety and objective responses based on Response Evaluation Criteria in Solid Tumors version 1.1 or National Cancer Institute International Response Criteria. Forty-four patients were enrolled (lymphoma, n = 18; IMT, n = 9; other tumors, n = 17). The objective response rate was 53% (95% confidence interval [CI], 28-77) for lymphoma, with 8 complete responses (CRs) and 1 partial response (PR); 67% (95% CI, 30-93) for IMTs, with 1 CR and 5 PRs; and 12% (95% CI, 2-36) for other tumors, with 2 PRs in patients affected by colon carcinoma and medullary thyroid cancer, respectively. The median duration of treatment was almost 3 years for patients with lymphoma and IMTs, with 2-year progression-free survival of 63% and 67%, respectively. The most common treatment-related adverse events were diarrhea (45.5%) and vision disorders (45.5%), mostly grade 1. These findings indicate strong and durable activity of crizotinib in ALK-positive lymphomas and IMTs. The safety profile was consistent with the known safety profile of crizotinib even with long-term treatment., (© 2018 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc.)

Bendamustine hydrochloride (BDM) is approved in the United States to treat chronic lymphocytic leukemia and relapsed indolent B-cell non-Hodgkin lymphoma. The first formulation marketed in the United States (original BDM) was a lyophilized product requiring reconstitution prior to dilution to the final admixture. A liquid formulation of BDM was subsequently introduced that did not require reconstitution before dilution. Both formulations are administered as a 500 mL admixture with a recommended infusion time of 30 or 60 minutes for chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma, respectively. A newer liquid BDM formulation (rapid BDM) is a ready-to-dilute solution not requiring reconstitution that dilutes into an admixture of only 50 mL and can be safely administered in a shorter infusion time (10 minutes). Rapid BDM admixture also has longer stability at room temperature than both lyophilized and liquid BDM formulations (6 vs 2 to 3 hours). This phase 1, open-label, randomized, crossover (3-period, partially replicated) study, conducted in "end-of-life" cancer patients at 10 oncology centers in the United States, demonstrates that rapid BDM is bioequivalent to original BDM as determined by area under the curve. Expected differences in maximum plasma concentration and time to maximum plasma concentration were observed between study treatments, given the substantially shorter infusion time of rapid BDM. No clinically relevant differences in other evaluated pharmacokinetic parameters were found. Rapid BDM infusions were safe and tolerable for cancer patients in this study. The overall safety profiles of the 2 BDM formulations were comparable, with no new safety signals identified and no differences in infusion-related adverse events., (© 2017, The American College of Clinical Pharmacology.)

Background: Avelumab, a human Ig-G1 monoclonal antibody targeting PD-L1 and approved in the USA for the treatment of metastatic Merkel cell carcinoma, has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours in a dose-escalation phase 1a trial. In this dose-expansion cohort of that trial, we assess avelumab treatment in a cohort of patients with advanced, platinum-treated non-small-cell lung cancer (NSCLC)., Methods: In this dose-expansion cohort of a multicentre, open-label, phase 1 study, patients with progressive or platinum-resistant metastatic or recurrent NSCLC were enrolled at 58 cancer treatment centres and academic hospitals in the USA. Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or non-squamous histology, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), tumour biopsy or archival sample for biomarker assessment, and Eastern Cooperative Oncology Group performance status 0 or 1, among other criteria. Patient selection was not based on PD-L1 expression or expression of other biomarkers, including EGFR or KRAS mutation or ALK translocation status. Patients received infusional avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity. The primary objective was to assess safety and tolerability. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort is closed and the trial is ongoing., Findings: Between Sept 10, 2013, and June 24, 2014, 184 patients were enrolled and initiated treatment with avelumab. Median follow-up duration was 8·8 months (IQR 7·2-11·9). The most common treatment-related adverse events of any grade were fatigue (46 [25%] of 184 patients), infusion-related reaction (38 [21%]), and nausea (23 [13%]). Grade 3 or worse treatment-related adverse events occurred in 23 (13%) of 184 patients; the most common (occurring in more than two patients) were infusion-related reaction (four [2%] patients) and increased lipase level (three [2%]). 16 (9%) of 184 patients had a serious adverse event related to treatment with avelumab, with infusion-related reaction (in four [2%] patients) and dyspnoea (in two [1%]) occurring in more than one patient. Serious adverse events irrespective of cause occurred in 80 (44%) of 184 patients. Those occurring in more than five patients (≥3%) were dyspnoea (ten patients [5%]), pneumonia (nine [5%]), and chronic obstructive pulmonary disease (six [3%]). Immune-related treatment-related events occurred in 22 patients (12%). Of 184 patients, 22 (12% [95% CI 8-18]) achieved a confirmed objective response, including one complete response and 21 partial responses. 70 (38%) had stable disease. Overall, 92 (50%) of 184 patients achieved disease control (they had a confirmed response or stable disease as their best overall response). One patient was initially thought to have died from grade 5 radiation pneumonitis during the study; however, this adverse event was subsequently regraded to grade 3 and the death was attributed to disease progression., Interpretation: Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or treatment-resistant NSCLC, providing a rationale for further studies of avelumab in this disease setting., Funding: Merck KGaA and Pfizer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Irinotecan-induced dysarthria has been reported in the literature, but the underlying mechanism of this neurotoxicity remains unclear. Here, we present a 35-year-old female with metastatic colon cancer who experienced dysarthria during irinotecan infusion. Her symptoms were decreased and eventually eliminated with subsequent increases in infusion time. When the patient returned to original 90 min infusion time, symptoms were significantly reduced in both severity and duration as compared to the first infusion. We suggest infusion time as a potential intervention for patients experiencing dysarthria, and we review the existing literature, explore treatment options, and discuss proposed mechanisms surrounding this unusual adverse drug reaction.

Introduction: Metaplastic breast carcinoma (MBC) is a rare and aggressive histologic subtype of breast cancer comprising approximately 0.5% to 5.0% of all invasive breast cancers with a poor prognosis and limited therapeutic options., Patients and Methods: We investigated MBC at our institution to evaluate outcomes and investigate the molecular profile of our cohort to determine the presence of mutations for which there are targeted therapies., Results: We found our cohort to consist mainly of the matrix-producing variant (72%) with 48% having the stereotypical estrogen receptor-negative/progesterone receptor-negative/human epidermal growth factor receptor-2-negative phenotype. While the overall survival of our cohort was an average of 1679 days (4.6 years), we had a surprising number of patients with second primaries (40%) and distant metastases (40%), yet few recurrences (12%). Molecular analysis of the tumors indicated that one gene mutation, CSFIR, was significantly associated with outcome (P = .021); however, the cohort was defined by frequent mutations in ERBB4 (36%), PIK3CA (48%), and FLT3 (60%), for which there are now targeted therapies., Conclusion: While surgery is the appropriate first step in the management of this aggressive malignancy, the collection of data pertaining to the use of targeted agents, although anecdotal, may provide clues to better treatment for these patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half-life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300 mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31-87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2-24) for the 14-day dosing schedule and 6 (1-24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC-486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS.

Purpose: Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study., Experimental Design: In ARMOR1, 49 patients received increasing doses (650-2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700-3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed., Results: In ARMOR1, across all doses, 49.0% (24/49) achieved a ≥30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a ≥50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events., Conclusions: The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition., (©2015 American Association for Cancer Research.)

Purpose: Neurotoxic effects of brain irradiation include cognitive impairment in 50% to 90% of patients. Prior studies have suggested that donepezil, a neurotransmitter modulator, may improve cognitive function., Patients and Methods: A total of 198 adult brain tumor survivors ≥ 6 months after partial- or whole-brain irradiation were randomly assigned to receive a single daily dose (5 mg for 6 weeks, 10 mg for 18 weeks) of donepezil or placebo. A cognitive test battery assessing memory, attention, language, visuomotor, verbal fluency, and executive functions was administered before random assignment and at 12 and 24 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated., Results: Of this mostly middle-age, married, non-Hispanic white sample, 66% had primary brain tumors, 27% had brain metastases, and 8% underwent prophylactic cranial irradiation. After 24 weeks of treatment, the composite scores did not differ significantly between groups (P = .48); however, significant differences favoring donepezil were observed for memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016). Significant interactions between pretreatment cognitive function and treatment were found for cognitive composite (P = .01), immediate recall (P = .05), delayed recall (P = .004), attention (P = .01), visuomotor skills (P = .02), and motor speed and dexterity (P < .001), with the benefits of donepezil greater for those who were more cognitively impaired before study treatment., Conclusion: Treatment with donepezil did not significantly improve the overall composite score, but it did result in modest improvements in several cognitive functions, especially among patients with greater pretreatment impairments., (© 2015 by American Society of Clinical Oncology.)

Background: In this multicenter, open-label, randomized phase 2 trial, the authors evaluated the vascular endothelial growth factor receptor inhibitor axitinib, bevacizumab, or both in combination with chemotherapy as first-line treatment of metastatic colorectal cancer (mCRC)., Methods: Patients with previously untreated mCRC were randomized 1:1:1 to receive continuous axitinib 5 mg twice daily, bevacizumab 5 mg/kg every 2 weeks, or axitinib 5 mg twice daily plus bevacizumab 2 mg/kg every 2 weeks, each in combination with modified 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX-6). The primary endpoint was the objective response rate (ORR)., Results: In all, 126 patients were enrolled from August 2007 to September 2008. The ORR was numerically inferior in the axitinib arm (n = 42) versus the bevacizumab arm (n = 43; 28.6% vs 48.8%; 1-sided P = .97). Progression-free survival (PFS) (11.0 months vs 15.9 months; 1-sided P = .57) and overall survival (OS) (18.1 months vs 21.6 months; 1-sided P = .69) also were numerically inferior in the axitinib arm. Similarly, efficacy endpoints for the axitinib/bevacizumab arm (n = 41) were numerically inferior (ORR, 39%; PFS, 12.5 months; OS, 19.7 months). The patients who received axitinib had fewer treatment cycles compared with other arms. Common all-grade adverse events across all 3 treatment arms were fatigue, diarrhea, and nausea (all ≥49%). Hypertension and headache were more frequent in the patients who received axitinib. Patients in the bevacizumab arm had the longest treatment exposures and the highest rates of peripheral neuropathy., Conclusions: Neither the addition of continuous axitinib nor the axitinib/bevacizumab combination to FOLFOX-6 improved ORR, PFS, or OS compared with bevacizumab as first-line treatment of mCRC., (© 2013 American Cancer Society.)

Purpose: Sunitinib has shown antitumor activity with a manageable safety profile as metastatic renal cell carcinoma (RCC) treatment, when given by the standard intermittent schedule as well as a continuous daily dosing (CDD) schedule. A trial was conducted to compare the schedules., Patients and Methods: Patients with treatment-naive, clear cell advanced RCC were randomly assigned 1:1 to receive sunitinib 50 mg/d for 4 weeks followed by 2 weeks off treatment (schedule 4/2; n = 146) or 37.5 mg/d on the CDD schedule (n = 146) for up to 2 years. The primary end point was time to tumor progression., Results: Median time to tumor progression was 9.9 months for schedule 4/2 and 7.1 months for the CDD schedule (hazard ratio, 0.77; 95% CI, 0.57 to 1.04; P = .090). No significant difference was observed in overall survival (23.1 v 23.5 months; P = .615), commonly reported adverse events, or patient-reported kidney cancer symptoms. Schedule 4/2 was statistically superior to CDD in time to deterioration, a composite end point of death, progression, and disease-related symptoms (P = .034). CONCLUSION; There was no benefit in efficacy or safety for continuous dosing of sunitinib compared with the approved 50 mg/d dose on schedule 4/2. Given the numerically longer time to tumor progression with the approved 50 mg/d dose on schedule 4/2, adherence to this dose and schedule remains the treatment goal for patients with advanced RCC.

Given the favorable immunologic effects of IL-2 post transplant, we conducted a feasibility study examining rIL-2 1.0x106 IU/m2/day (SQ) beginning on D+14 post-transplant and continuing for 90 days in 12 patients with low-grade lymphoproliferative disorders. Prior to high-dose chemotherapy and autologous peripheral blood stem cell transplantation (HDCT), 11 patients underwent cytoreduction with fludarabine and cyclophosphamide (Flu/Cy); 11 were in complete remission (CR) and one was in partial remission at the time of HDCT. All 12 patients were in CR 90 days post-HDCT. At a median follow-up of 30 (range 3-44) months, seven patients (58%) remain in remission, four are alive with disease, and one has died of disease progression, resulting in an overall survival of 92%. Kaplan-Meier estimates of progression-free survival (PFS) for the group demonstrate a median of 31 (range 3-43) months. Five patients required rIL-2 cessation at 8-58 days after starting the therapy due to hematologic toxicity. These results are comparable to those achieved in other published bone marrow and peripheral blood stem cell transplantion (PBSCT) series without the addition of rIL-2. Furthermore, rIL-2 using this schedule following fludarabine-based cytoreduction was associated with excessive hematologic toxicity.

Background: Survival rates from mechanical ventilation (MV) in allogeneic bone marrow transplantation are poor, but little is known about the need for and outcomes from MV in patients who undergo autologous hematopoietic stem cell transplantation (AHSCT)., Study Objective: To determine the frequency of and risk factors for the use of MV in recipients of AHSCT and to identify predictors of survival in mechanically ventilated AHSCT patients., Design: Retrospective, cohort analysis, Setting: Tertiary-care, university-affiliated medical center., Patients: One hundred fifty-nine consecutive patients who underwent AHSCT., Interventions: Patient surveillance and data collection., Measurements and Results: The primary outcome measure was the need for MV, and the secondary end point was survival after MV. Of 159 patients, 17 required MV (10. 7%). Three variables were associated with the need for MV: increasing age, use of total body irradiation in the conditioning regimen, and treatment with amphotericin B. As a screening test to predict the need for MV, no risk factor had a sensitivity or specificity > 82%. Three of the 17 mechanically ventilated patients (17.6%) survived to discharge. Only the mean APACHE (acute physiology and chronic health evaluation) II score separated survivors from nonsurvivors (21.7 vs 31.4; p = 0.029). Both the duration of MV and the length of stay in the ICU were similar in survivors and nonsurvivors., Conclusions: We conclude that MV is infrequently needed following AHSCT. Although survival after MV in these patients is limited, clinical variables do not reliably allow clinicians to prospectively identify patients destined to die.

Allogeneic (alloBMT) and autologous bone marrow transplantation (ABMT) have become standard approaches for the management of adults with acute myeloid leukemia (AML). The indications for transplantation remain controversial as parallel improvements in intensive chemotherapy have resulted in excellent outcomes for many patients. AlloBMT is the therapy of choice for patients who fail to respond to induction chemotherapy. For those patients in first remission (CRI), a policy of intensive postremission chemotherapy with transplantation upon relapse appears to be optimal. There are no data to support transplantation in CRI, allogeneic or autologous, for those patients with leukemia characterized by favorable cytogenetic abnormalities [ie, core-binding factor type or t(15;17)], as these patients do well with nonmyeloablative strategies. Patients with relapsed disease appear to be best served with allogeneic transplantation from a human leukocyte antigen (HLA)-matched sibling or one-antigen-mismatched family member, whereas for those patients lacking a related donor, unrelated donor alloBMT or ABMT provides similar long-term overall survival. Randomized studies for the optimal management of relapsed disease are lacking but are needed. The objective of this review is to discuss the data supporting the use of alloBMT or ABMT at various points during the course of de novo adult AML.

Purpose: Blast expression of CD56 is frequent in patients with t(8;21)(q22;q22) acute myeloid leukemia and is associated with an inferior outcome. The expression of CD56 has rarely been reported in acute promyelocytic leukemia (APL) and has not been clinically characterized. Therefore, we examined the prognostic significance of CD56 expression in APL., Patients and Methods: We identified all reported cases of CD56+ APL in the medical literature and collected clinical, biologic, and therapeutic details., Results: Data were obtained for 12 patients with CD56+ APL (> 20% blast expression of CD56), including four cases from a single institution with a total of 42 APL patients. All of the CD56+ APL patients had documented cytogenetic presence of t(15;17), and of the nine reported isotypes, eight (89%) were S-isoform. Only six CD56+ patients (50%) attained complete remission (CR); the other six individuals died within 35 days of presentation. Of the six patients who attained a CR, three (50%) relapsed at 111, 121, and 155 weeks, whereas three remained in continuous CR at 19, 90, and 109 weeks. Comparison of the control CD56- to CD56+ APL patients demonstrated that the latter group had a significantly lower fibrinogen level (P = .007), and among patients for whom data were available, there was a higher frequency of the S-isoform (P = .006). Additionally, the CR rate (50% v 84%, P = .025) and overall median survival (5 v 232 weeks; P = .019) were significantly inferior for CD56+ APL patients., Conclusion: CD56+ acute promyelocytic leukemia is infrequent, seems to occur more frequently with the S-isoform subtype, and may be associated with a lower CR rate and inferior overall survival.

The purpose of this report is to record a patient with myelodysplastic syndrome (MDS) associated acute myelogenous leukemia (AML) and leukemia cutis who had blast expression of the neural cell adhesion molecule (NCAM) and to review the world literature on prognostic implications of extramedullary myeloid cell tumors (granulocytic sarcoma, myeloblastoma, chloroma and leukemia cutis) in MDS and MDS associated AML. Case report and world literature from January 1965-January 1994 for all cases of MDS-associated extramedullary myeloid cell tumors (EMT) is reviewed, and the first patient with EMT, MDS associated AML and blast expression of NCAM is described. There have been 46 cases of MDS associated EMT previously reported. 32 cases occurred in the absence of AML. AML developed in 47% of these patients at a mean of 38 weeks from initial EMT. Of the patients not developing AML, median survival from initial EMT was 11 weeks. Nine patients received chemotherapy at the time of EMT and had a median survival of 36 weeks. The median survival for patients receiving conservative therapy for EMT was 48 weeks. Patients (n = 15) with EMT and MDS associated AML had a poor outcome regardless of therapy with a median survival of 11 weeks. Unlike other forms of isolated EMT, MDS associated EMT is not always a forerunner of AML. Premature induction therapy for MDS associated EMT does not appear to prolong survival. EMT in the setting of MDS associated AML is associated with a poor prognosis despite aggressive chemotherapy. Blast expression of NCAM may prove to be a risk factor for EMT in MDS associated AML.

Purpose: To discuss the predisposing risk factor for all forms of extramedullary leukemia (EML) and to review the clinical features, prognostic significance, and treatment strategies for primary EML and leukemia cutis (LC)/granulocytic sarcomas (GS) in the setting of acute nonlymphocytic leukemia (ANLL)., Methods: A review of all reports published since 1965 related to all forms of extramedullary leukemia (LC, GS, gingival hypertrophy, and meningeal leukemia [ML])., Results: Several factors, including chromosomal abnormalities [t(8;21), inv(16)], cell-surface markers (CD56, CD2, CD4, CD7), French-American-British (FAB) subtype (M2, M4, M5), blast differentiation and maturation, patient nutritional status, age, cellular immune dysfunction, high presenting leukocyte count, and decreased blast Auer rods, have been associated with a higher incidence of EML. Of 154 published cases of primary EML identified, 71 (46%) were initially misdiagnosed. The addition of immunohistochemical stains can assist in preventing such misdiagnoses and should be included in all atypical lymphoma/carcinoma cases. Only one of the patients (3%) with primary EML did not progress to ANLL in the absence of chemotherapy. In contrast, 66% of patients who received chemotherapy for the primary EML never developed ANLL. The prognostic significance of EML at presentation and medullary relapse of ANLL is uncertain. Isolated extramedullary recurrence of ANLL always heralds bone marrow relapse and should be treated with reinduction chemotherapy. Close clinical follow-up observation is necessary to insure resolution of EML. Radiation therapy is an effective local treatment for resistant or symptomatic EML., Conclusion: Many advances in diagnoses and treatment of EML have been made. Future investigations are needed to define the clinical significance of EML in patients with ANLL treated with modern chemotherapy or bone marrow transplantation.