On the coordination chemistry of a bacterial siderophore cepabactin from a theoretical perspective.

Iron is one of the essential metals required by almost all living organisms. However, nature has certain constraints in distributing this element among tissues. Since polymeric oxide-bridged Fe (III) is the prominent source of Fe (III) ions, the insolubility of Fe (III) ions in aqueous systems reduces the direct uptake by cells. Secondly, the free-Fe entities which generate .OH radicals pave the way to the destruction of the cells. Hence, a protective coordination environment via sophisticated chemical systems is required for the acquisition of Fe, its successive transport, storage, and effective utilization in various tissues. Siderophores are polydentate ligands used by bacterial cells for Fe acquisition, with a relatively high affinity for Fe (III) ions. Secreted from the bacterial cells into the external aqueous medium, they sequester Fe to give a soluble complex which re-enters the organism at a specific receptor. Once it gets inside the cell, the Fe is released from the complex and utilized for essential biochemical reactions. The medicinal applications of these natural ligands, developing progressively in various research groups, necessitate the theoretical aspects of their coordination chemistry. This research paper deals with the coordination chemistry of one of the siderophores, cepabactin (Cep). The chemical computations confirm that the FeIII(Cep)3 complex is octahedral and high spin. The oxygen atoms of Cep, which are hard and negatively charged, thus act as electron donors in the FeIII(Cep)3 complex formation. This in turn makes the siderophores relatively less attractive towards Fe (II) ions.

High acceptability and viral suppression rate for first-Line patients on a dolutegravir-based regimen: An early adopter study in Nigeria.

Nigeria adopted dolutegravir (DTG) as part of first line (1L) antiretroviral therapy (ART) in 2017. However, there is limited documented experience using DTG in sub-Saharan Africa. Our study assessed DTG acceptability from the patient's perspective as well as treatment outcomes at 3 high-volume facilities in Nigeria. This is a mixed method prospective cohort study with 12 months of follow-up between July 2017 and January 2019. Patients who had intolerance or contraindications to non-nucleoside reverse-transcriptase inhibitors were included. Patient acceptability was assessed through one-on-one interviews at 2, 6, and 12 months following DTG initiation. ART-experienced participants were asked about side effects and regimen preference compared to their previous regimen. Viral load (VL) and CD4+ cell count tests were assessed according to the national schedule. Data were analysed in MS Excel and SAS 9.4. A total of 271 participants were enrolled on the study, the median age of participants was 45 years, 62% were female. 229 (206 ART-experienced, 23 ART-naive) of enrolled participants were interviewed at 12 months. 99.5% of ART-experienced study participants preferred DTG to their previous regimen. 32% of particpants reported at least one side effect. "Increase in appetite" was most frequently reported (15%), followed by insomnia (10%) and bad dreams (10%). Average adherence as measured by drug pick-up was 99% and 3% reported a missed dose in the 3 days preceding their interview. Among participants with VL results (n = 199), 99% were virally suppressed (<1000 copies/ml), and 94% had VL <50 copies/ml at 12 months. This study is among the first to document self-reported patient experiences with DTG in sub-Saharan Africa and demonstrated high acceptability of DTG-based regimens among patients. The viral suppression rate was higher than the national average of 82%. Our findings support the recommendation of DTG-based regimen as the preferred 1L ART.

Cabotegravir (Apretude) for Pre-exposure Prophylaxis for HIV Type 1 Infection.

Cabotegravir (Apretude) is an extended-release injectable HIV type 1 (HIV-1) antiretroviral integrase strand transfer inhibitor. Cabotegravir is labeled for use in adults and adolescents weighing at least 35 kg (77 lb) who are HIV-negative but at risk of HIV-1. It is used as pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection, the most common form of HIV.1.

Diagnostic finding on high-resolution computed tomography (HRCT) predicts a good response to pirfenidone in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a debilitating condition, with a life expectancy of 2 to 5 years after diagnosis. Pirfenidone is a drug that has been shown to reduce the decline in forced vital capacity (FVC). We sought to identify whether different patterns on high-resolution computed tomography (HRCT) have different clinical effects through a retrospective comparison of baseline values and changes in pulmonary function tests (PFTs) after treatment with pirfenidone. We retrospectively analyzed data from IPF patients treated with pirfenidone at Nanjing Drum Tower Hospital in Jiangsu Province, China. According to the HRCT pattern, the patients were divided into usual interstitial pneumonitis (UIP) and possible UIP groups. Baseline clinical characteristics and changes every 6 months in the PFTs during the follow-up period were compared between the 2 groups. A total of 65 consecutive patients were enrolled. According to the HRCT pattern, patients were clustered into the UIP group (n = 46) and possible UIP group (n = 19). No difference was observed in the baseline PFTs ratio between the 2 groups. The FVC values of the 2 groups were not significantly different at the initial treatment and at 6 and 12 months after pirfenidone treatment (P = .081, 0.099, and 0.236, respectively). The improvement in % diffusion capacity of the lung for carbon monoxide (%DLCO) was higher in the possible UIP group after 6 and 12 months of pirfenidone treatment (P = .149, 0.026, and 0.025, respectively). The annual decrease in FVC was not significantly different between the 2 groups, and the annual decrease in %DLCO in the UIP group was significantly higher than that in patients with the possible UIP type (-7.767 ±â€…12.797 vs 0.342 ±â€…20.358, P < .05). These results indicate that patients with IPF with a possible UIP pattern on HRCT showed indications of a good response to pirfenidone.

Effects of low-dose titration on the tolerability and safety of perampanel.

PURPOSE: To evaluate the effects of low-dose titration on the tolerability and safety of perampanel. METHODS: We retrospectively reviewed the records of 1065 patients who started perampanel therapy and compared the incidence of adverse events after standard titration (Group A: starting dose, 2 mg/day; titration speed, 2 mg/2 weeks or longer) and low-dose titration (Group B: starting dose, < 1 mg/day; titration speed, < 1 mg/2 weeks or longer). RESULTS: Adverse events were reported in 158 patients (14.8%) within the initial first 90 days of starting perampanel (mean concentration, 331 ng/mL). At 90 days, the cumulative incidence of adverse events was significantly higher in Group A than in Group B (24.5% vs. 16.3%, respectively; log-rank test p < 0.001). A Cox proportional hazards model also showed that low-dose titration decreased the incidence risk of adverse events (adjusted hazard ratio, 0.49; 95% confidence interval, 0.35-0.69). When the groups were stratified by use of enzyme-inducing antiseizure medications (inducers), Group A patients without inducers had a significantly higher cumulative incidence of adverse events than the other three subgroups (26.7%, p < 0.001). In patients taking 2 mg of perampanel, median concentrations in patients with or without inducers were 43 ng/mL and 204 ng/mL, respectively. CONCLUSION: Perampanel is generally initiated at 2 mg, but serum perampanel concentrations show substantial interindividual variation. Our study suggests that care must be taken when setting the starting dose of perampanel. In particular, low-dose titration is recommended in patients not taking inducers.

Formulation of antiretroviral nanocrystals and development into a microneedle delivery system for potential treatment of HIV-associated neurocognitive disorder (HAND).

HIV/AIDS remains a major global public health issue. While antiretroviral therapy is effective at reducing the viral load in the blood, up to 50% of those with HIV suffer from some degree of HIV-associated neurocognitive disorder, due to the presence of the blood-brain barrier restricting drugs from crossing into the central nervous system and treating the viral reservoir there. One way to circumvent this is the nose-to-brain pathway. This pathway can also be accessed via a facial intradermal injection. Certain parameters can increase delivery via this route, including using nanoparticles with a positive zeta potential and an effective diameter of 200 nm or less. Microneedle arrays offer a minimally invasive, pain-free alternative to traditional hypodermic injections. This study shows the formulation of nanocrystals of both rilpivirine (RPV) and cabotegravir, followed by incorporation into separate microneedle delivery systems for application to either side of the face. Following an in vivo study in rats, delivery to the brain was seen for both drugs. For RPV, a Cmax was seen at 21 days of 619.17 ± 73.32 ng/g, above that of recognised plasma IC90 levels, and potentially therapeutically relevant levels were maintained for 28 days. For CAB, a Cmax was seen at 28 days of 478.31 ± 320.86 ng/g, and while below recognised 4IC90 levels, does indicate that therapeutically relevant levels could be achieved by manipulating final microaaray patch size in humans.

Investigation of Fenebrutinib Metabolism and Bioactivation Using MS3 Methodology in Ion Trap LC/MS.

Fenebrutinib is an orally available Bruton tyrosine kinase inhibitor. It is currently in multiple phase III clinical trials for the management of B-cell tumors and autoimmune disorders. Elementary in-silico studies were first performed to predict susceptible sites of metabolism and structural alerts for toxicities by StarDrop WhichP450™ module and DEREK software; respectively. Fenebrutinib metabolites and adducts were characterized in-vitro in rat liver microsomes (RLM) using MS3 method in Ion Trap LC-MS/MS. Formation of reactive and unstable intermediates was explored using potassium cyanide (KCN), glutathione (GSH) and methoxylamine as trapping nucleophiles to capture the transient and unstable iminium, 6-iminopyridin-3(6H)-one and aldehyde intermediates, respectively, to generate a stable adducts that can be investigated and analyzed using mass spectrometry. Ten phase I metabolites, four cyanide adducts, five GSH adducts and six methoxylamine adducts of fenebrutinib were identified. The proposed metabolic reactions involved in formation of these metabolites are hydroxylation, oxidation of primary alcohol to aldehyde, n-oxidation, and n-dealkylation. The mechanism of reactive intermediate formation of fenebrutinib can provide a justification of the cause of its adverse effects. Formation of iminium, iminoquinone and aldehyde intermediates of fenebrutinib was characterized. N-dealkylation followed by hydroxylation of the piperazine ring is proposed to cause the bioactivation to iminium intermediates captured by cyanide. Oxidation of the hydroxymethyl group on the pyridine moiety is proposed to cause the generation of reactive aldehyde intermediates captures by methoxylamine. N-dealkylation and hydroxylation of the pyridine ring is proposed to cause formation of iminoquinone reactive intermediates captured by glutathione. FBB and several phase I metabolites are bioactivated to fifteen reactive intermediates which might be the cause of adverse effects. In the future, drug discovery experiments utilizing this information could be performed, permitting the synthesis of new drugs with better safety profile. Overall, in silico software and in vitro metabolic incubation experiments were able to characterize the FBB metabolites and reactive intermediates using the multistep fragmentation capability of ion trap mass spectrometry.

Efficacy of Pirfenidone and Nintedanib in Interstitial Lung Diseases Other than Idiopathic Pulmonary Fibrosis: A Systematic Review.

Pirfenidone and nintedanib are antifibrotic medications approved for idiopathic pulmonary fibrosis treatment by regulatory agencies and available for clinical use worldwide. These drugs have been shown to reduce the rate of decline in forced vital capacity and the risk of acute exacerbation among patients with idiopathic pulmonary fibrosis. Recent data suggest that different interstitial lung diseases with a progressive pulmonary fibrosis phenotype can share similar pathogenetic and biological pathways and could be amenable to antifibrotic therapies. Indeed, historical management strategies in interstitial lung disease have failed to identify potential treatments once progression has occurred despite available drugs. In this systematic review, we summarized data on the efficacy of pirfenidone and nintedanib in interstitial lung diseases other than idiopathic pulmonary fibrosis as well as ongoing and upcoming clinical trials. We identify two well-designed trials regarding nintedanib demonstrating the efficacy of this drug in slowing disease progression in patients with interstitial lung diseases other than idiopathic pulmonary fibrosis. On the other hand, results on the use of pirfenidone in interstitial lung diseases other than idiopathic pulmonary fibrosis should be interpreted with more caution on the basis of trial limitations. Several randomized control trials are underway to improve the quality of evidence in the interstitial lung disease field.

Trametinib-Resistant Melanoma Cells Displaying MITFhigh/NGFRlow/IL-8low Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug Rechallenge.

Despite significant advances in targeted therapies against the hyperactivated BRAFV600/MEK pathway for patients with unresectable metastatic melanoma, acquired resistance remains an unsolved clinical problem. In this study, we focused on melanoma cells resistant to trametinib, an agent broadly used in combination therapies. Molecular and cellular changes were assessed during alternating periods of trametinib withdrawal and rechallenge in trametinib-resistant cell lines displaying either a differentiation phenotype (MITFhigh/NGFRlow) or neural crest stem-like dedifferentiation phenotype (NGFRhigh/MITFlow). Neither drug withdrawal nor drug rechallenge induced cell death, and instead of loss of fitness, trametinib-resistant melanoma cells adapted to altered conditions by phenotype switching. In resistant cells displaying a differentiation phenotype, trametinib withdrawal markedly decreased MITF level and activity, which was associated with reduced cell proliferation capacity, and induced stemness assessed as NGFR-positive cells and senescence features, including IL-8 expression and secretion. All these changes could be reversed by trametinib re-exposure, which emphasizes melanoma cell plasticity. Trametinib-resistant cells displaying a dedifferentiation phenotype were less responsive presumably due to the already low level of MITF, a master regulator of the melanoma phenotype. Considering new directions of the development of anti-melanoma treatment, our study suggests that the phenotype of melanomas resistant to targeted therapy might be a crucial determinant of the selection of second-line therapy for melanoma patients.

The G118R plus R263K Combination of Integrase Mutations Associated with Dolutegravir-Based Treatment Failure Reduces HIV-1 Replicative Capacity and Integration.

Human immunodeficiency virus (HIV) treatment with antiretroviral regimens containing integrase strand transfer inhibitors such as dolutegravir (DTG) and bictegravir (BIC) offers high levels of protection against the development of drug resistance mutations. Despite this, resistance to DTG and BIC can occur through the development of the R263K integrase substitution. Failure with DTG has also been associated with the emergence of the G118R substitution. G118R and R263K are usually found separately but have been reported together in highly treatment-experienced persons who experienced treatment failure with DTG. We used cell-free strand transfer and DNA binding assays and cell-based infectivity, replicative capacity, and resistance assays to characterize the G118R plus R263K combination of integrase mutations. R263K reduced DTG and BIC susceptibility ~2-fold, in agreement with our previous work. Single-cycle infectivity assays showed that G118R and G118R plus R263K conferred ~10-fold resistance to DTG. G118R alone conferred low levels of resistance to BIC (3.9-fold). However, the G118R plus R263K combination conferred high levels of resistance to BIC (33.7-fold), likely precluding the use of BIC after DTG failure with the G118R plus R263K combination. DNA binding, viral infectivity, and replicative capacity of the double mutant were further impaired, compared to single mutants. We propose that impaired fitness helps to explain the scarcity of the G118R plus R263K combination of integrase substitutions in clinical settings and that immunodeficiency likely contributes to its development.

[Neurological perspective in the choice of direct oral anticoagulants for prevention of stroke in atrial fibrillation]. / Perspectiva neurológica en la elección del anticoagulante oral directo para la prevención del accidente cerebrovascular en fibrilación auricular.

Non-valvular atrial fibrillation (AF) is the most prevalent arrhythmia with high embolic potential, and one of the main and growing causes of stroke. The main objective of anticoagulation in patients with AF is prevention of stroke. Until recently, anticoagulation with vitamin K antagonists (VKAs) was the only available option. Direct oral anticoagulants (DOACs), such as the direct thrombin inhibitor dabigatran, or the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, have a more favorable effectiveness/safety profile compared to VKAs. There are no studies comparing the efficacy of DOACs with each other. The choice of a DOAC arose from patient carachterictis, physician preferences, cost, and accessibility. Between 1-2% of patients correctly treated with a DOAC experience a stroke each year. The possibility of having a reversal agent should be taken into account when choosing a DOAC, especially due to the residual risk of stroke occurrences even under DOACs. Currently, in our country only dabigatran has a reversing agent available, making it the only DOAC that does not contraindicate the use of intravenous thrombolysis. This should be taken into account when choosing the DOAC for the prevention of thromboembolic events in patients with AF.

La fibrilación auricular no valvular (FA) es la arritmia con potencial embolígeno más prevalente y una de las principales y crecientes causas de accidente cerebrovascular isquémico (ACVi). El principal objetivo del uso de la anticoagulación en pacientes con FA es la prevención del ACVi. Hasta hace poco tiempo, la anticoagulación con antagonistas de la vitamina K (AVKs) era la única opción disponible. Los anticoagulantes orales directos (DOACs) como el inhibidor directo de la trombina, dabigatrán, o los inhibidores directos del factor Xa, rivaroxabán, apixabán y edoxabán, tienen un perfil de efectividad/seguridad más favorable en comparación con los AVKs. No existen estudios que comparen la efectividad de los DOACs entre sí. La elección del DOAC depende de múltiples factores específicos del paciente, preferencias del médico, costos y accesibilidad. Entre 1-2% de los pacientes correctamente tratados con un DOAC intercurre con un ACVi cada año. La posibilidad de contar con un agente reversor debería ser tenida en cuenta al momento de la elección del DOAC, especialmente por el riesgo residual de ocurrencia de ACVi. En la actualidad, en nuestro país solo el dabigatrán cuenta con un agente reversor disponible y lo convierte en el único DOAC que no contraindica el uso de trombolisis intravenosa con rtPA. Esta situación debería ser considerada en el momento de la elección del DOAC para la prevención de eventos tromboembólicos en pacientes con FA.

Trametinib in Patients With NF1-, GNAQ-, or GNA11-Mutant Tumors: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocols S1 and S2.

PURPOSE: NCI-MATCH is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatment subprotocols. This report combines two subprotocols evaluating trametinib, a MEK1/2 inhibitor, in patients with Neurofibromatosis 1 (NF1[S1] or GNA11/Q [S2]) altered tumors. METHODS: Eligible patients had tumors with deleterious inactivating NF1 or GNA11/Q mutations by the customized Oncomine AmpliSeq panel. Prior MEK inhibitor treatment was excluded. Glioblastomas (GBMs) were permitted, including malignancies associated with germline NF1 mutations (S1 only). Trametinib was administered at 2 mg once daily over 28-day cycles until toxicity or disease progression. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS) at 6 months, PFS, and overall survival. Exploratory analyses included co-occurring genomic alterations and PTEN loss. RESULTS: Fifty patients were eligible and started therapy: 46 with NF1 mutations (S1) and four with GNA11 mutations (S2). In the NF1 cohort, nonsense single-nucleotide variants were identified in 29 and frameshift deletions in 17 tumors. All in S2 had nonuveal melanoma and GNA11 Q209L variant. Two partial responses (PR) were noted in S1, one patient each with advanced lung cancer and GBM for an ORR of 4.3% (90% CI, 0.8 to 13.1). One patient with melanoma in S2 had a PR (ORR, 25%; 90% CI, 1.3 to 75.1). Prolonged stable disease (SD) was also noted in five patients (four in S1 and one in S2) with additional rare histologies. Adverse events were as previously described with trametinib. Comutations in TP53 and PIK3CA were common. CONCLUSION: Although these subprotocols did not meet the primary end point for ORR, significant responses or prolonged SD noted in some disease subtypes warrants further investigation.

Dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors.

BACKGROUND: Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines. METHODS: Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones. RESULTS: Twenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3 + 3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N = 12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150 mg twice daily, oral trametinib 2 mg once daily, and intravenous AT13387 260 mg/m2 on days 1, 8, and 15. The best response was a partial response in two patients and stable disease in eight patients, with an overall response rate of 9.5% (90% exact confidence interval [CI], 2%-27%), a disease control rate of 47.6% (90% CI, 29%-67%), and a median overall survival of 5.1 months (90% CI, 3.4-7.6 months). There were no consistent proteomic changes associated with response or resistance, although responders did have reductions in BRAF expression, and epidermal growth factor receptor downregulation using HSP90 inhibition was observed in one patient who had colorectal cancer. CONCLUSIONS: HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.

Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial.

BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110 .

Apixaban thromboprophylaxis in ambulatory patients with cancer and obesity: Insights from the AVERT trial.

BACKGROUND: The use of direct oral anticoagulants (DOACs) in obese patients is uncertain. It is unclear if body mass index (BMI) affects the safety and efficacy of DOACs for the primary prevention of venous thromboembolism (VTE) in high-risk ambulatory patients with cancer. We sought to determine the outcomes associated with the use of apixaban for the primary prevention of cancer-associated VTE according to BMI. METHODS: The randomized, double-blinded, placebo-controlled AVERT trial evaluated apixaban thromboprophylaxis in intermediate-to-high risk ambulatory cancer patients receiving chemotherapy. For this post-hoc analysis, the primary efficacy and safety outcomes were objectively confirmed VTE and clinically relevant bleeding (major and clinically relevant non-major bleeding), respectively. Obesity was defined as BMI ≥30 kg/m2. RESULTS: Among 574 patients randomized, 217 (37.8 %) patients had BMI ≥30 kg/m2. Obese patients were overall younger, more likely to be female, had higher creatinine clearance and hemoglobin, lower platelet count, and better ECOG performance status. Compared to placebo, apixaban thromboprophylaxis was associated with reduced VTE in both obese (hazard ratio [HR] 0.26; 95 % confidence interval [CI], 0.14-0.46; p < 0.0001) and non-obese (HR 0.54; 95%CI, 0.29-1.00; p = 0.049) patients. The HR for clinically relevant bleeding (apixaban vs. placebo) was numerically higher in obese (2.09; 95%CI, 0.96-4.51; p = 0.062) than non-obese subjects (1.23; 95%CI, 0.71-2.13; p = 0.46), but overall in line with the risks observed in the general trial population. CONCLUSIONS: In the AVERT trial enrolling ambulatory cancer patients receiving chemotherapy, we found no substantial differences in the efficacy or safety of apixaban thromboprophylaxis across obese and non-obese subjects.