Notes

Scientific significance of sFRP5, RBP-4 and also NT-proBNP in people with long-term cardiovascular failing.
This phase I dose de-escalation study aimed to assess the tolerability, safety, pharmacokinetics (PK), and efficacy of sequentially decreasing doses of sorafenib in combination (SAM) with atorvastatin (A, 10mg) and metformin (M, 500mg BD) in patients with advanced hepatocellular carcinoma (HCC).

Patients were enrolled in 1 of 4 sequential cohorts (10 patients each) of sorafenib doses (800mg, 600mg. 400mg, and 200mg) with A and M. Progression from one level to the next was based on prespecified minimum disease stabilization (at least 4/10) and upper limits of specific grade 3-5 treatment-related adverse events (TRAE).

The study was able to progress through all 4 dosing levels of sorafenib by the accrual of 40 patients. Thirty-eight (95%) patients had either main portal vein thrombosis or/and extra-hepatic disease. The most common grade 3-5 TRAEs were hand-foot-syndrome (grade 2 and grade 3) in 3 (8%) and transaminitis in 2 (5%) patients, respectively. The plasma concentrations of sorafenib peaked at 600mg dose, and the concentration threshold of 2400ng/mL was associated with higher odds of achieving time to exposure (TTE) concentrations >75% centile (odds ratio [OR] = 10.0 [1.67-44.93]; P = .01). The median overall survival for patients without early hepatic decompensation (n = 31) was 8.9 months (95% confidence interval [CI] 3.2-14.5 months).

The SAM combination in HCC patients with predominantly unfavorable baseline disease characteristics showed a marked reduction in sorafenib-related side effects. Studies using sorafenib 600mg per day in this combination along with sorafenib drug level monitoring can be evaluated in further trials.(Trial ID CTRI/2018/07/014865).
The SAM combination in HCC patients with predominantly unfavorable baseline disease characteristics showed a marked reduction in sorafenib-related side effects. Studies using sorafenib 600 mg per day in this combination along with sorafenib drug level monitoring can be evaluated in further trials.(Trial ID CTRI/2018/07/014865).Enfortumab vedotin is a first-in-class Nectin-4-directed antibody-drug conjugate approved by the US Food and Drug Administration for the treatment of patients with locally advanced or metastatic urothelial cancer (la/mUC) previously treated with a platinum-based chemotherapy and a programmed death receptor-1/programmed death-ligand 1 (PD-1/L1) inhibitor, or patients with la/mUC who are ineligible for cisplatin-based chemotherapy and have previously received one or more prior lines of therapy. Enfortumab vedotin is the only drug to have demonstrated survival benefit versus chemotherapy in a randomized controlled trial in patients with la/mUC previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor. The development of dermatologic events following the administration of enfortumab vedotin is anticipated given the expression of Nectin-4 in epidermal keratinocytes and skin appendages (eg, sweat glands and hair follicles). There is the potential for rare but severe and possibly fatal cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrosis, as described in the boxed warning of the US prescribing information for enfortumab vedotin. This manuscript describes the presumed pathophysiology and manifestations of dermatologic reactions related to enfortumab vedotin, and presents recommendations for prevention and treatment, to provide oncologists and other healthcare providers with an awareness of these potential adverse events to best anticipate and manage them.
D-0316 is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) developed for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR T790M mutation that progressed after prior treatment with the first- or second-generation EGFR-TKI.

This phase I, open-label, multicenter clinical trial evaluated daily oral D-0316 administration in dose-escalation (25 to 150mg; 17 patients) and dose-expansion (50, 100mg; 67 patients) cohorts for safety, tolerability, anti-tumor activity, and pharmacokinetics.

D-0316 was well tolerated at daily doses of 25 to 150mg and the maximum tolerated dose (MTD) was not reached. The most common treatment-related adverse events (AEs) were platelet count decreased, electrocardiogram QT corrected interval prolonged, anemia, rash, low white blood cell count, hypertriglyceridemia, high cholesterol, headache, pruritus, cough, and aspartate transaminase (AST) or alanine transaminase (ALT) increased. Most of AEs were grade 1 or 2. In the 50 and 100mg group, the overall response rate (ORR) was 33.3% and 45.5%, the disease control rate (DCR) was 86.7% and 93.9%, and the median PFS was 8.3 and 9.6 months, respectively. D-0316 exposure increased in proportion to dose from 25 to 150mg. The recommended phase II dose (RP2D) was 100mg.

D-0316 is safe, tolerable, and effective for patients with locally advanced/metastatic NSCLC with the EGFR T790M mutation who previously received EGFR-TKI.

NCT03452150.
NCT03452150.
Prolongation of overall survival (OS) is commonly evaluated as a primary endpoint in confirmative oncology clinical trials; however, it is potentially affected by subsequent treatments carried out in practice. To design and implement multi-regional clinical trials properly, we compared survival outcomes between Organisation for Economic Co-operation and Development (OECD) and non-OECD countries.

Individual patient data from industry-sponsored multi-regional phase III oncology trials were obtained from the Project Data Sphere. Patients of each arm were divided into several subgroups based on race and country where patients were enrolled. We defined the member countries of the OECD. Cox regression analysis was conducted to estimate the hazard ratio (HR) for progression-free survival (PFS) and OS between the different subgroups in each trial, followed by a meta-analysis to estimate the summary HR and its confidence interval with a random-effect model.

Eleven arms from 10 clinical trials were eligible for the analysis. No statistically significant difference was observed in PFS and OS between Caucasian and Asian. A prolongation of OS was observed in patients enrolled in the OECD group compared with non-OECD group, while no statistically significant difference was observed in PFS.

The economic status and healthcare environment of countries where patients reside have an impact on the outcome of OS. Clinical trial sponsors are recommended to consider carefully how to properly design oncology clinical trials including the selection of countries and data management of subsequent treatments.
The economic status and healthcare environment of countries where patients reside have an impact on the outcome of OS. Clinical trial sponsors are recommended to consider carefully how to properly design oncology clinical trials including the selection of countries and data management of subsequent treatments.
The outcomes of metastatic hormone-sensitive prostate cancer (mHSPC) have significantly improved through treatment intensification, yet Black representation in those studies is suboptimal.

A multi-institutional, retrospective analysis of Black men with mHSPC was conducted, focusing on baseline demographics, treatment patterns, genomic profiles, clinical outcomes including prostate-specific antigen response, time to castrate-resistant prostate cancer (CRPC), and subsequent treatments.

A total of 107 patients, median age 64 years, 62% with de novo metastases at diagnosis and 64% with high-volume disease, were included. Twenty-nine patients (27%) were treated with androgen deprivation therapy (ADT) with and without first generation anti-androgens, while 20%, 38% and 5% received chemotherapy, abiraterone, and enzalutamide, respectively. At time of data cut-off, 57 (54%) patients had developed CRPC, with a median time to CRPC of 25.4 months (95% CI 20.3-30.4). The median time to CRPC was 46.3 months (18.9-73rent molecular profile relative to White patients with potential therapeutic implications.Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. For the vast majority of patients with advanced CRC (ie, for those in whom metastatic tumors are unresectable), treatment is palliative and typically involves chemotherapy, biologic therapy, and/or immune checkpoint inhibition. In recent years, the use of adoptive T-cell therapy (ACT), leveraging the body's own immune system to recognize and target cancer, has become increasingly popular. Unfortunately, while ACT has been successful in the treatment of hematological malignancies, it is less efficacious in advanced CRC due in part to a lack of productive immune infiltrate. Sodium Monensin cell line This systematic review was conducted to summarize the current data for the efficacy and safety of ACT in advanced CRC. We report that ACT is well tolerated in patients with advanced CRC. Favorable survival estimates among patients with advanced CRC receiving ACT demonstrate promise for this novel treatment paradigm. However, additional stage I/II clinical trials are needed to establish the efficacy and safety of ACT in patients with CRC.
Complementary medicines (CM) are frequently used by patients with cancer. Controversy exists over the effectiveness and risk that CM may add to conventional cancer therapy. The incidence of CM use among patients enrolled in phase III clinical trials is unknown.

Medication lists from 6 international phase III clinical trials were retrospectively reviewed to identify patients using CM. Patients had metastatic breast, colorectal, or lung cancers. Quality of life, adverse events, overall survival, and progression-free survival were compared between CM users and non-users. Baseline differences between groups were adjusted with propensity score matching groups.

Seven hundred and six of 3446 patients (20.5%) used at least one CM. CM use was highest among patients with breast cancer (35.6%). CM users had more favorable baseline prognostic factors (ECOG 0-1, non-smoking status, younger age, and fewer metastases). CM use was associated with lower rates of adverse events (50% vs. 62%, P = .002) and quality of lifepotential interactions with clinical trial drugs.
We conducted a phase II study of the combination of pembrolizumab with capecitabine and oxaliplatin (CAPOX) in patients with advanced biliary tract carcinoma (BTC) to assess response rate and clinical efficacy. Exploratory objectives included correlative studies of immune marker expression, tumor evolution, and immune infiltration in response to treatment.

Adult patients with histologically confirmed BTC were enrolled and received oxaliplatin and pembrolizumab on day 1 of cycles 1-6. Capecitabine was administered orally twice daily as intermittent treatment, with the first dose on day 1 and the last dose on day 14 of cycles 1-6. Starting on cycle 7, pembrolizumab monotherapy was continued until disease progression. The primary endpoint was progression-free survival (PFS). Secondary endpoints were safety, tolerability, feasibility, and response rate. Immunohistochemistry (IHC) for PD-L1 and immune infiltrates was analyzed in paired tumor biopsies, as well as bulk transcriptome and exome profiling for five patients and single-cell RNA sequencing for one partial responder.
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