A phase I study of AT-101, a BH3 mimetic, in combination with paclitaxel and carboplatin in solid tumors.

Background AT-101 is a BH3 mimetic that inhibits the heterodimerization of Bcl-2, Bcl-xL, Bcl-W, and Mcl-1 with pro-apoptotic proteins, thereby lowering the threshold for apoptosis. This phase I trial investigated the MTD of AT-101 in combination with paclitaxel and carboplatin in patients with advanced solid tumors. Methods Patients were treated with AT-101 (40 mg) every 12 h on days 1, 2 and 3 of each cycle combined with varying dose levels (DL) of paclitaxel and carboplatin [DL1: paclitaxel (150 mg/m2) and carboplatin (AUC 5) on day 1 of each cycle; DL2: paclitaxel (175 mg/m2) and carboplatin (AUC 6) on day 1 of each cycle]. Secondary objectives included characterizing toxicity, efficacy, pharmacokinetics, and pharmacodynamics of the combination. Results Twenty-four patients were treated across two DLs with a planned expansion cohort. The most common tumor type was prostate (N = 11). Two patients experienced DLTs: grade 3 abdominal pain at DL1 and grade 3 ALT increase at DL2; however, the MTD was not determined. Moderate hematologic toxicity was observed. One CR was seen in a patient with esophageal cancer and 4 patients achieved PRs (1 NSCLC, 3 prostate). PD studies did not yield statistically significant decreases in Bcl-2 and caspase 3 protein levels, or increased apoptotic activity induced by AT-101. Conclusion The combination of AT-101 at 40 mg every 12 h on days 1, 2 and 3 combined with paclitaxel and carboplatin was safe and tolerable. Based on the modest clinical efficacy seen in this trial, this combination will not be further investigated. Clinical Trial Registration: NCT00891072, CTEP#: 8016.

Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.

BACKGROUND: Metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment with conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features are associated with the response to PD-1 blockade in other tumour types. Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in patients with dMMR/MSI-H metastatic colorectal cancer. METHODS: In this ongoing, multicentre, open-label, phase 2 trial, we enrolled adults (aged ≥18 years) with histologically confirmed recurrent or metastatic colorectal cancer locally assessed as dMMR/MSI-H from 31 sites (academic centres and hospitals) in eight countries (Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the USA). Eligible patients had progressed on or after, or been intolerant of, at least one previous line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan. Patients were given 3 mg/kg nivolumab every 2 weeks until disease progression, death, unacceptable toxic effects, or withdrawal from study. The primary endpoint was investigator-assessed objective response as per Response Evaluation Criteria in Solid Tumors (version 1.1). All patients who received at least one dose of study drug were included in all analyses. This trial is registered with ClinicalTrials.gov, number NCT02060188. FINDINGS: Of the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, 40 (54%) had received three or more previous treatments. At a median follow-up of 12·0 months (IQR 8·6-18·0), 23 (31·1%, 95% CI 20·8-42·9) of 74 patients achieved an investigator-assessed objective response and 51 (69%, 57-79) patients had disease control for 12 weeks or longer. Median duration of response was not yet reached; all responders were alive, and eight had responses lasting 12 months or longer (Kaplan-Meier 12-month estimate 86%, 95% CI 62-95). The most common grade 3 or 4 drug-related adverse events were increased concentrations of lipase (six [8%]) and amylase (two [3%]). 23 (31%) patients died during the study; none of these deaths were deemed to be treatment related by the investigator. INTERPRETATION: Nivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H metastatic colorectal cancer, and could be a new treatment option for these patients. FUNDING: Bristol-Myers Squibb.

A Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of Pictilisib in Combination with Erlotinib in Patients with Advanced Solid Tumors.

BACKGROUND: Epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K) are involved in the proliferation and survival of many cancer types. Enhanced antitumor activity may be achieved through combined inhibition of these pathways. We report results for pictilisib (GDC-0941, a class I pan-PI3K inhibitor) plus erlotinib (an EGFR tyrosine kinase inhibitor) in patients with advanced solid tumors. MATERIALS AND METHODS: A 3 + 3 dose-escalation study was carried out at a starting daily dose of 60 mg pictilisib on days 1-21 of a 28-day cycle and 150 mg erlotinib from day 2 of cycle 1. The primary objectives of the study were to assess safety and tolerability, identify dose-limiting toxicities (DLTs), estimate the maximum tolerated dose, and identify the recommended phase II dose (RP2D). Evaluation of a dose-expansion cohort at the RP2D was performed. RESULTS: Fifty-seven patients were treated in the study. All patients experienced at least one adverse event (AE). Grade ≥3 AEs, serious AEs, and deaths were reported in 38 (66.7%), 19 (33.3%), and 4 (7.0%) patients, respectively. DLTs occurred in nine patients across eight cohorts and the RP2D was determined to be 340 mg pictilisib on a "5 days on, 2 days off" schedule plus 100 mg erlotinib. Two patients (3.5%) experienced partial response and 19 (33.3%) had stable disease. CONCLUSION: Combining pictilisib with erlotinib in patients with advanced solid tumors is feasible; however, antitumor activity is limited. Additional studies may identify patients likely to benefit from combined inhibition of EGFR and PI3K pathways. IMPLICATIONS FOR PRACTICE: Combining drugs targeting different signaling pathways in cancer growth and survival could overcome drug resistance and improve antitumor activity. In this first-in-human study for the combination, addition of the PI3K inhibitor pictilisib to the EGFR tyrosine kinase inhibitor erlotinib resulted in toxicity that led to dose and schedule modifications to identify a tolerable recommended phase II dose of 340 mg pictilisib on a "5 days on, 2 days off" schedule plus 100 mg erlotinib daily. The limited antitumor activity observed, however, suggests that additional studies are needed to identify patients most likely to benefit from combined EGFR and PI3K inhibition.

Clinical Actionability of Comprehensive Genomic Profiling for Management of Rare or Refractory Cancers.

BACKGROUND: The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. METHODS: A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. RESULTS: Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0-10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. CONCLUSION: Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability. IMPLICATIONS FOR PRACTICE: Identification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next-generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents.

Increasing mortality in the United States from cholangiocarcinoma: an analysis of the National Center for Health Statistics Database.

BACKGROUND: While mortality in the United States has decreased for most cancers, mortality from combined hepatocellular liver cancer and intrahepatic cholangiocarcinoma (ICC) has increased and ranked 1st in annual percent increase among cancer sites. Because reported statistics combine ICC with other liver cancers, mortality rates of cholangiocarcinoma (CCA) remain unknown. This study is to determine CCA mortality trends and variation based on national data. METHODS: This nation-wide study was based on the underlying cause of death data collected by the National Center for Health Statistics (NCHS) between 1999 and 2014. The Center for Disease Control (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) system was used to obtain data. ICC and extra-hepatic CCA (ECC) were defined by ICD-10 diagnosis codes. Age-adjusted mortality rate was standardized to the US population in 2000. RESULTS: There were more than 7000 CCA deaths each year in the US after 2013. CCA mortality for those aged 25+ increased 36 % between 1999 and 2014, from 2.2 per 100,000 (95 % confidence interval [CI] 2.1-2.3) to 3.0 per 100,000 (95 % CI, 2.9-3.1). Mortality rates were lower among females compared with males (risk ratio [RR] 0.78, 95 % CI 0.77-0.79). Asians had the highest mortality. Between 2004 and 2014, the increase in CCA mortality was highest among African Americans (45 %) followed by Asians (22 %), and whites (20 %). CONCLUSION: Based on the most recent national data, CCA mortality rates have increased substantially in the past decade. Among different race/ethnic groups, African Americans have the highest increase in CCA mortality.

Structure-guided design of a selective BCL-X(L) inhibitor.

The prosurvival BCL-2 family protein BCL-X(L) is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-X(L) will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-X(L)-selective inhibitor would be expected to minimize the toxicity to normal tissues. We describe the use of a high-throughput screen to discover a new series of small molecules targeting BCL-X(L) and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-X(L) and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-X(L) from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-X(L) for their sustained growth.

Engagement as an Element of Safe Inpatient Psychiatric Environments.

BACKGROUND: The American Psychiatric Nurses Association (APNA) Institute for Safe Environments (ISE) has focused on key elements that affect safety in psychiatric treatment environments; one of these key elements is patient engagement. An ISE workgroup discussed and reviewed the literature on engagement and safety in inpatient psychiatric settings. This article presents what we have learned about the role that engagement plays in inpatient treatment of severely mentally ill individuals and evidence that links nurse-patient engagement to safety. OBJECTIVES: To describe, using supporting literature, the role that nurse-patient engagement plays in creating safe, therapeutic environments for individuals with severe mental illness. DESIGN: (1) Define engagement and describe why it is an important element of safe treatment environments; (2) identify what helps and what hinders patients in their engagement with nurses, and nurses in their engagement with patients; (3) describe how engagement may improve unit safety; and (4) propose recommendations and set future directions for practice, research, and education. CONCLUSION: Engagement may provide the foundation for safe, therapeutic, and recovery-oriented treatment. In the future, APNA's ISE plans to build upon this foundation by developing a clinical model of nurse-patient engagement and safety by drawing together emerging research and practice models.

The power of genes: a case of unusually severe systemic toxicity after localized hepatic chemoembolization with irinotecan-eluted microspheres for metastatic colon cancer.

OBJECTIVE: To report a case of systemic irinotecan toxicity following regional transarterial chemoembolization with drug-eluting beads loaded with irinotecan (DEBIRI-TACE) in a patient later found to have a homozygous mutation for UGT1A1*28. CASE SUMMARY: An 80-year-old woman presented with a cecal colon cancer with synchronous metastases to the liver. After resection of the primary tumor, the patient underwent DEBIRI-TACE with 100 mg of irinotecan to treat the residual disease in the liver. A week after this procedure, the patient developed grade 4 neutropenia, and later, alopecia. Eventually, it was found that the patient had a mutation of UDP glucuronosyltransferase 1 family polypeptide A1 (UGT1A1), which provided a reasonable explanation for the observed reaction. DISCUSSION: The toxic effects of irinotecan are well understood. Patients with genetic polymorphisms of the genes encoding for the enzyme UGT1A1 may have increased incidence of irinotecan-associated toxicities because of decreased clearance of the active metabolite SN38 via the glucuronidation pathway. To date, there have been limited publications describing systemic adverse events following TACE or DEBIRI-TACE and, based on a thorough literature search, none following these procedures in patients with UGT1A1 polymorphisms. Based on the scoring results of the Naranjo algorithm (7), we are confident in attributing the observed reaction to the patient's genetic polymorphism. CONCLUSION: Although genetic testing prior to the initiation of irinotecan therapy is not currently recommended, assessment of UGT1A1 polymorphism is warranted when severe adverse events typical of systemic therapy manifest following DEBIRI-TACE.

Treatment of multiple endocrine neoplasia 1/2 tumors: case report and review of the literature.

BACKGROUND: Neuroendocrine tumors are uncommon tumors that are histopathologically and biologically heterogeneous and include the multiple endocrine neoplasia (MEN) 1 and 2 syndromes. The morbidity of MEN-1 and MEN-2 is often due to the symptomatology of the endocrine hormones produced, and the mortality mainly occurs from hepatic dysfunction incurred by liver metastases. At present, there is essentially no effective cure once the tumor has metastasized to the liver. PATIENT: We present a patient with progressive, metastatic MEN-1 with the classic '3 P's' triad of neuroendocrine tumor of the pancreas, parathyroid adenoma and a pituitary adenoma. RESULTS: After progression on high-dose Sandostatin LAR (60 mg/month) and multiple surgeries, the patient had a partial response (40% decrease) to a novel regimen of capecitabine and temozolomide (CAPTEM) and progression-free survival of 18 months. He had minor grade 1 toxicities and no grade 2, 3 or 4 toxicities. DISCUSSION: The history and treatment options for MEN-1/2 cancers are reviewed, as well as the data behind our novel regimen, CAPTEM. CONCLUSION: The CAPTEM regimen is a tolerable, safe, easy to administer oral regimen with possible efficacy for MEN-1 tumors.

Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors.

Immunotherapy is the standard of care for several cancers and the field continues to advance at a rapid pace, with novel combinations leading to indications in an increasing number of disease settings. Durable responses and long-term survival with immunotherapy have been demonstrated in some patients, though lack of initial benefit and recurrence after extended disease control remain major hurdles for the field. Many new combination regimens are in development for patients whose disease progressed on initial immunotherapy. To guide clinical trial design and support analyses of emerging molecular and cellular data surrounding mechanisms of resistance, the Society for Immunotherapy of Cancer (SITC) previously generated consensus clinical definitions for resistance to single-agent anti-PD-1 immune checkpoint inhibitors (ICIs) in three distinct scenarios: primary resistance, secondary resistance, and progression after treatment discontinuation. An unmet need still exists, however, for definitions of resistance to ICI-based combinations, which represent an expanding frontier in the immunotherapy treatment landscape. In 2021, SITC convened a workshop including stakeholders from academia, industry, and government to develop consensus definitions for resistance to ICI-based combination regimens for improved outcome assessment, trial design and drug development. This manuscript reports the minimum drug exposure requirements and time frame for progression that define resistance in both the metastatic setting and the perioperative setting, as well as key caveats and areas for future research with ICI/ICI combinations. Definitions for resistance to ICIs in combination with chemotherapy and targeted therapy will be published in companion volumes to this paper.

Phase I study of gemcitabine, docetaxel and imatinib in refractory and relapsed solid tumors.

PURPOSE: In a phase I study, the combination of gemcitabine and imatinib was well tolerated with broad anticancer activity. This phase I trial evaluated the triplet of docetaxel, gemcitabine and imatinib. EXPERIMENTAL DESIGN: Imatinib was administered at 400 mg daily on days 1-5, 8-12 and 15-19. Gemcitabine was started at 600 mg/m(2) at a rate of 10 mg/min on days 3 and 10 and docetaxel at 30 mg/m(2) on day 10, on a 21-day cycle. Diffusion and dynamic contrast-enhanced perfusion MRI was performed in selected patients. RESULTS: Twenty patients with relapsed/refractory solid tumors were enrolled in this IRB-approved study. The mean age was 64, and mean ECOG PS was 1. Two patients were evaluated by diffusion/perfusion MRI. After two grade 3 hematological toxicities at dose level 1, the protocol was amended to reduce the dose of imatinib. MTDs were 600 mg/ m(2) on days 3 and 10 for gemcitabine, 30 mg/ m(2) on day 10 for docetaxel, and 400 mg daily on days 1-5 and 8-12 for imatinib. Dose limiting toxicities after one cycle were neutropenic fever, and pleural and pericardial effusions. The best response achieved was stable disease, for six cycles, in one patient each with mesothelioma and non small cell lung cancer (NSCLC) at the MTD. Two patients with NSCLC had stable disease for four cycles. DISCUSSION: An unexpectedly low MTD for this triplet was identified. Our results suggest drug-drug interactions that amplify toxicities with little evidence of improved tumor control.

A phase I study of veliparib with cyclophosphamide and veliparib combined with doxorubicin and cyclophosphamide in advanced malignancies.

PURPOSE: Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models. We conducted a phase I trial of V with iv cyclophosphamide (C) and V plus iv doxorubicin (A) and C. METHODS: Objectives were to establish the maximum tolerated dose (MTD) of the combinations, characterize V pharmacokinetics (PK) in the presence and absence of C, measure PAR in peripheral blood mononuclear cells (PBMCs) and γH2AX in circulating tumor cells (CTCs). In Group 1, dose escalations of V from 10 to 50 mg every 12 h Days 1-4 plus C 450 to 750 mg/m2 Day 3 in 21-day cycles were evaluated. In Group 2, V doses ranged from 50 to 150 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 in 21-day cycles. In Group 3, patients received AC Day 1 plus V Days 1-7, and in Group 4, AC Day 1 plus V Days 1-14 was given in 21-day cycles to evaluate effects on γH2AX foci. RESULTS: Eighty patients were enrolled. MTD was not reached for V and C. MTD for V and AC was V 100 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 every 21 days. V PK appears to be dose-dependent and has no effect on the PK of C. Overall, neutropenia and anemia were the most common adverse events. Objective response in V and AC treated groups was 22% (11/49). Overall clinical benefit rate was 31% (25/80). PAR decreased in PBMCs. Percentage of γH2AX-positive CTCs increased after treatment with V and AC. CONCLUSION: V and AC can be safely combined. Activity was observed in patients with metastatic breast cancer.

Belowground productivity varies by assessment technique, vegetation type, and nutrient availability in tidal freshwater forested wetlands transitioning to marsh.

Wetlands along upper estuaries are characterized by dynamic transitions between forested and herbaceous communities (marsh) as salinity, hydroperiod, and nutrients change. The importance of belowground net primary productivity (BNPP) associated with fine and coarse root growth also changes but remains the dominant component of overall productivity in these important blue carbon wetlands. Appropriate BNPP assessment techniques to use in various tidal wetlands are not well-defined, and could make a difference in BNPP estimation. We hypothesized that different BNPP techniques applied among tidal wetlands differ in estimation of BNPP and possibly also correlate differently with porewater nutrient concentrations. We compare 6-month and 12-month root ingrowth, serial soil coring techniques utilizing two different calculations, and a mass balance approach (TBCA, Total Belowground Carbon Allocation) among four tidal wetland types along each of two river systems transitioning from freshwater forest to marsh. Median values of BNPP were 266 to 2946 g/m2/year among all techniques used, with lower BNPP estimation from root ingrowth cores and TBCA (266-416 g/m2/year), and higher BNPP estimation from serial coring of standing crop root biomass (using Smalley and Max-Min calculation methods) (2336-2946 g/m2/year). Root turnover (or longevity) to a soil depth of 30 cm was 2.2/year (1.3 years), 2.7/year (1.1 years), 4.5/year (0.9 years), and 1.2/year (2.6 years), respectively, for Upper Forest, Middle Forest, Lower Forest, and Marsh. Marsh had greater root biomass and BNPP, with slower root turnover (greater root longevity) versus forested wetlands. Soil porewater concentrations of NH3 and reactive phosphorus stimulated BNPP in the marsh when assessed with short-deployment BNPP techniques, indicating that pulses of mineralized nutrients may stimulate BNPP to facilitate marsh replacement of forested wetlands. Overall, ingrowth techniques appeared to represent forested wetland BNPP adequately, while serial coring may be necessary to represent herbaceous plant BNPP from rhizomes as marshes replace forested wetlands.

Neoadjuvant Therapy for Melanoma: A U.S. Food and Drug Administration-Melanoma Research Alliance Public Workshop.

Tremendous progress has been made in treating patients with metastatic melanoma over the past decade. In that timeframe, the FDA has approved 12 novel treatments for patients with advanced unresectable melanoma, comprising both kinase-targeted therapies and immune checkpoint inhibitors (ICI), and five treatments for adjuvant (postoperative) use in patients with high-risk resectable stage III melanoma. It is not known whether outcomes can be further improved by administering kinase inhibitors or ICI in the neoadjuvant (presurgical) setting in patients with high-risk resectable melanomas. Noting research community interest in exploring the neoadjuvant approach for treating melanoma and recognizing that early harmonization of methodologies may expedite the development of therapeutics in this space, the FDA and Melanoma Research Alliance convened a public workshop on November 6, 2019, in National Harbor, Maryland, to discuss key issues. The workshop consisted of 23 faculty and included more than 250 live participants. Topics discussed included opportunities for advancing novel endpoints for regulatory purposes as well as translational research, clinical trial design considerations, and strategies for optimizing patient selection while mitigating risk.

Effects of nutrient pre-exposure on atrazine toxicity to Vallisneria americana Michx. (wild celery).

Accelerated eutrophication is common to many freshwater and marine environments and often co-occurs with the presence of anthropogenic chemicals. However, the toxic effects of common chemical stressors such as herbicides in the presence of elevated nutrients are not well understood for most aquatic flora, particularly vascular species. To provide insight, field-collected Vallisneria americana Michx. (wild celery) were sequentially exposed to three nutrient concentrations for 3 months and then to nominal 11 and 110 microg L(-1) atrazine for 96 h. Nutrient concentrations (combined NH(4)(+), NO(2)(-), NO(3)(-), PO(4)(-)) were based on ambient concentrations in the St. Johns River (FL) and ranged from 0.013 to 0.668 mg L(-1). Nutrient pretreatment potentiated the toxicity of atrazine as determined by chlorophyll fluorescence activity. Electron transport rates (ETR) were significantly less (48-59%) for plants pretreated with low and ambient nutrient levels in the presence of an average of 107.5-128.1 microg L(-1) atrazine. Significant ETR reductions were also observed for plants exposed to an average of 11.4 microg L(-1) atrazine after exposure to nutrients three times the ambient concentration in the St. Johns River. The results indicate the importance of considering the presence of nutrients in chemical hazard assessments, particularly for phytotoxicants and nontarget vascular plants.

A Machine-Learning Approach to Identify a Prognostic Cytokine Signature That Is Associated With Nivolumab Clearance in Patients With Advanced Melanoma.

Lower clearance of immune checkpoint inhibitors is a predictor of improved overall survival (OS) in patients with advanced cancer. We investigated a novel approach using machine learning to identify a baseline composite cytokine signature via clearance, which, in turn, could be associated with OS in advanced melanoma. Peripheral nivolumab clearance and cytokine data from patients treated with nivolumab in two phase III studies (n = 468 (pooled)) and another phase III study (n = 158) were used for machine-learning model development and validation, respectively. Random forest (Boruta) algorithm was used for feature selection and classification of nivolumab clearance. The 16 top-ranking baseline inflammatory cytokines reflecting immune-cell modulation were selected as a composite signature to predict nivolumab clearance (area under the curve (AUC) = 0.75; accuracy = 0.7). Predicted clearance (high vs. low) via the cytokine signature was significantly associated with OS across all three studies (P < 0.01), regardless of treatment (nivolumab vs. chemotherapy).

A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors.

PURPOSE: Given the evidence that coordinate inhibition of AKT induces autophagy, we studied the combination of the AKT inhibitor, MK-2206 with hydroxychloroquine (HCQ) in patients with advanced solid tumors. METHODS: Patients were treated with weekly MK-2206 (135 mg or 200 mg) plus HCQ (200 mg, 400 mg or 600 mg BID). RESULTS: Thirty-five patients were enrolled across 5 dose levels. Two DLTs of grade 3 maculo-papular rash were observed at dose level 2 (MK-2206 200 mg weekly plus HCQ at 400 mg BID) and 1 DLT of grade 3 fatigue at dose level 2B (MK-2206 135 mg weekly plus HCQ 600 mg BID). The maximum tolerated dose (MTD) was declared as dose level 2B. The most common adverse events attributed to MK-2206 were hyperglycemia (N = 18; 51%), fatigue (N = 17; 49%), maculo-papular rash (N = 16; 46%), diarrhea (N = 12; 34%), anorexia (N = 11; 31%), and nausea (N = 11; 31%). Patients experiencing adverse events attributed to HCQ were small in number (N = 13) and primarily included fatigue (N = 5; 14%) and maculo-papular rashes (N = 3; 9%). Statistically significant effects on the pharmacokinetic properties of MK-2206 were observed in combination with HCQ. In addition, the plasma concentrations of HCQ in the combination with MK-2206 were significantly higher than the plasma levels of HCQ as monotherapy in prior studies. The best overall response of stable disease was observed in 5/34 (15%) patients. CONCLUSION: The combination of MK-2206 and hydroxychloroquine was tolerable, but with substantial number of drug-related AEs and minimal evidence of antitumor activity.

Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer.

Purpose Nivolumab provides clinical benefit (objective response rate [ORR], 31%; 95% CI, 20.8 to 42.9; disease control rate, 69%; 12-month overall survival [OS], 73%) in previously treated patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC); nivolumab plus ipilimumab may improve these outcomes. Efficacy and safety results for the nivolumab plus ipilimumab cohort of CheckMate-142, the largest single-study report of an immunotherapy combination in dMMR/MSI-H mCRC, are reported. Patients and Methods Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks. Primary end point was investigator-assessed ORR. Results Of 119 patients, 76% had received ≥ two prior systemic therapies. At median follow-up of 13.4 months, investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control rate for ≥ 12 weeks was 80%. Median duration of response was not reached; most responses (94%) were ongoing at data cutoff. Progression-free survival rates were 76% (9 months) and 71% (12 months); respective OS rates were 87% and 85%. Statistically significant and clinically meaningful improvements were observed in patient-reported outcomes, including functioning, symptoms, and quality of life. Grade 3 to 4 treatment-related adverse events (AEs) occurred in 32% of patients and were manageable. Patients (13%) who discontinued treatment because of study drug-related AEs had an ORR (63%) consistent with that of the overall population. Conclusion Nivolumab plus ipilimumab demonstrated high response rates, encouraging progression-free survival and OS at 12 months, manageable safety, and meaningful improvements in key patient-reported outcomes. Indirect comparisons suggest combination therapy provides improved efficacy relative to anti-programmed death-1 monotherapy and has a favorable benefit-risk profile. Nivolumab plus ipilimumab provides a promising new treatment option for patients with dMMR/MSI-H mCRC.

Neoadjuvant Chemotherapy and Adjuvant Chemoradiation Therapy in the Treatment of Resected Gastric Adenocarcinoma: A Case Series.

The treatment of gastric cancer requires a multimodal approach to decrease the risk of locoregional and distant recurrence. The optimal timing of chemotherapy, surgery, and radiation therapy continues to be explored in ongoing trials. In the United States, surgical resection is often followed by adjuvant chemoradiation therapy or by a combination of neoadjuvant and adjuvant chemotherapy. Here we report on 4 patients with resected gastric adenocarcinoma who were treated with a combination of these 2 approaches, receiving neoadjuvant chemotherapy followed by adjuvant chemoradiation therapy.

Bone marrow tolerance during postoperative chemotherapy in colorectal carcinomas.

BACKGROUND: This study seeks to quantify and compare bone marrow tolerance during postoperative chemotherapy therapy between rectal cancer vs. colon cancer patients. During rectal cancer treatment, patients receive neoadjuvant chemoradiation (CRT) irradiation which can exacerbate the hematologic toxicity (HT) via incidental irradiation of the pelvic bone marrow (PBM) during myelosuppressive postoperative chemotherapy. In contrast, colon cancer patients receive the same postoperative myelosuppressive chemotherapy but do not routinely receive preoperative chemoradiation therapy. This comparison will help elucidate the lasting myelosuppressive effects of incidental pelvic bone marrow (PBM) irradiation on rectal cancer patients during neoadjuvant preoperative chemoradiation therapy. METHODS: Rectal cancer patients treated with preoperative CRT followed by postoperative 5-Fluorouracil and oxaliplatin (OxF) chemotherapy (n=35) were compared to colon cancer patients who received only postoperative OxF chemotherapy (n=42). End points were ≥ grade 3 hematologic toxicity (HT3) or hematologic event (HE) defined as ≥ grade 2 HT and a dose reduction in OxF. Wilcoxon rank sum test tested continuous variables and Chi-squared test measured differences in categorical variables. HT3 and HE probability during postoperative chemotherapy was estimated with Kaplan-Meier curves and Cox regression analysis. RESULTS: During OxF chemotherapy, 40.0% (n=14) of rectal cancer patients experienced HT3 compared to 26.1% (n=11) of colon cancer patients (P=0.4). HE was experienced by 48% (n=17) of rectal cancer patients compared to 36% (n=15) of colon cancer patients (P=0.36). Rectal cancer patients were likelier to experience HT3 on multivariable cox regression analysis, controlling for several clinical covariates, with a hazard ratio (HR) of 2.49, [(95% CI: 1.02-6.02), P=0.045] than colon cancer patients. While rectal cancer patients were more likely to experience HE than colon cancer patients on multivariable Cox regression analysis with a HR of 1.8 (95% CI: 0.95-3.75), this only trended in statistical significance, P=0.07. CONCLUSIONS: Rectal cancer patients are more likely than colon cancer patients to experience hematologic toxicities impacting the tolerance of standard of care chemotherapeutics during adjuvant therapy. Focused PBM sparing during radiation therapy for rectal cancer patients may improve tolerance of myelosuppressive chemotherapeutic agents delivered in the postoperative setting.