Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD.

Background: The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.

A Proof-of-Concept Study of Sequential Treatment with the HDAC Inhibitor Vorinostat following BRAF and MEK Inhibitors in BRAFV600-Mutated Melanoma.

Purpose: The development of resistance limits the clinical benefit of BRAF and MEK inhibitors (BRAFi/MEKi) in BRAFV600-mutated melanoma. It has been shown that short-term treatment (14 days) with vorinostat was able to initiate apoptosis of resistant tumor cells. We aimed to assess the antitumor activity of sequential treatment with vorinostat following BRAFi/MEKi in patients with BRAFV600-mutated melanoma who progressed after initial response to BRAFi/MEKi.

The laboratory parameters-derived CoLab score as an indicator of the host response in ICU COVID-19 patients decreases over time: a prospective cohort study.

The CoLab score was developed and externally validated to rule out COVID-19 among suspected patients presenting at the emergency department. We hypothesized a within-patient decrease in the CoLab score over time in an intensive care unit (ICU) cohort. Such a decrease would create the opportunity to potentially rule out the need for isolation when the infection is overcome.

Serial electrical impedance tomography course in different treatment groups; The MaastrICCht cohort.

Purpose: To describe the effect of dexamethasone and tocilizumab on regional lung mechanics over admission in all mechanically ventilated COVID-19 patients.

Materials And Methods: Dynamic compliance, alveolar overdistension and collapse were serially determined using electric impedance tomography (EIT). Patients were categorized into three groups; no anti-inflammatory therapy, dexamethasone therapy, dexamethasone + tocilizumab therapy.

Higher levels of circulating desphospho-uncarboxylated matrix Gla protein over time are associated with worse survival: the prospective Maastricht Intensive Care COVID cohort.

Background: Extra-hepatic vitamin K-status, measured by dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP), maintains vascular health, with high levels reflecting poor vitamin K status. The occurrence of extra-hepatic vitamin K deficiency throughout the disease of COVID-19 and possible associations with pulmonary embolism (PE), and mortality in intensive care unit (ICU) patients has not been studied. The aim of this study was to investigated the association between dp-ucMGP, at endotracheal intubation (ETI) and both ICU and six months mortality.

A Nomogram to Predict Severe Toxicity in DPYD Wild-Type Patients Treated With Capecitabine-Based Anticancer Regimens.

DPYD-guided dosing has improved the safety of fluoropyrimidine-based chemotherapy in recent years. However, severe toxicity remains in ~ 23% of patients not carrying DPYD variant alleles treated with capecitabine. Therefore, we developed a predictive model based on patient-related and treatment-related factors aimed at estimating the risk of developing severe capecitabine-related toxicity.

Survival of Patients With Cancer With Variant Alleles and Dose-Individualized Fluoropyrimidine Therapy-A Matched-Pair Analysis.

Purpose: -guided fluoropyrimidine dosing improves patient safety in carriers of variant alleles. However, the impact on treatment outcome in these patients is largely unknown. Therefore, progression-free survival (PFS) and overall survival (OS) were compared between variant carriers treated with a reduced dose and wild-type controls receiving a full fluoropyrimidine dose in a retrospective matched-pair survival analysis.

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.

First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1).

Background: The phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors.

Methods: GSK3174998 (0.003-10 mg/kg) ± pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation.

A Single-arm Phase II Study Combining NLG207, a Nanoparticle Camptothecin, with Enzalutamide in Advanced Metastatic Castration-resistant Prostate Cancer Post-Enzalutamide.

Background: Despite the clinical efficacy of enzalutamide monotherapy in patients with advanced prostate cancer, therapeutic resistance and disease progression are inevitable. We proposed a study to evaluate NLG207, a nanoparticle-drug conjugate (NDC) of the potent topoisomerase I inhibitor camptothecin, in combination with enzalutamide, in patients with metastatic castration-resistant prostate cancer (mCRPC) following progression on enzalutamide.

Methods: This was a single-arm, optimal two-stage, phase II study to evaluate the efficacy of NLG207 in combination with enzalutamide in patients with mCRPC who received prior enzalutamide.

Dihydropyrimidine Dehydrogenase Phenotyping Using Pretreatment Uracil: A Note of Caution Based on a Large Prospective Clinical Study.

In clinical practice, 25-30% of the patients treated with fluoropyrimidines experience severe fluoropyrimidine-related toxicity. Extensively clinically validated DPYD genotyping tests are available to identify patients at risk of severe toxicity due to decreased activity of dihydropyrimidine dehydrogenase (DPD), the rate limiting enzyme in fluoropyrimidine metabolism. In April 2020, the European Medicines Agency recommended that, as an alternative for DPYD genotype-based testing for DPD deficiency, also phenotype testing based on pretreatment plasma uracil levels is a suitable method to identify patients with DPD deficiency.

Metabolic Disposition of Lurbinectedin, a Potent Selective Inhibitor of Active Transcription of Protein-Coding Genes, in Nonclinical Species and Patients.

Lurbinectedin is a novel and potent selective inhibitor of active transcription of protein-coding genes, triggering apoptosis of cancerous cells. It has been approved for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. Studies exploring the disposition and metabolism of lurbinectedin were performed in vitro and in vivo (by intravenous administration of lurbinectedin).

Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study.

Background: Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up.

Patients And Methods: ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers.

A Phase I, First-in-Human Study of GSK2849330, an Anti-HER3 Monoclonal Antibody, in HER3-Expressing Solid Tumors.

Background: GSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/Neuregulin 1 (NRG1) signaling in cancer cells, is engineered for enhanced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase I, first-in-human, open-label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors.

Patients And Methods: Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression.

Transtympanic Sodium Thiosulfate for Prevention of Cisplatin-Induced Ototoxicity: A Randomized Clinical Trial.

Objectives: To determine safety, feasibility, and preliminary activity of transtympanic injection of sodium thiosulfate (STS) against cisplatin-induced hearing loss (CIHL).DESIGN Randomized controlled trial.SETTING Tertiary cancer hospital.

A Phase I dose-escalation study of two cycles carboplatin-olaparib followed by olaparib monotherapy in patients with advanced cancer.

Preclinical studies have shown synergistic effects when combining PARP1/2 inhibitors and platinum drugs in BRCA1/2 mutated cancer cell models. After a formulation change of olaparib from capsules to tablets, we initiated a dose finding study of olaparib tablets bidaily (BID) continuously with carboplatin to prepare comparative studies in this patient group. Patients were included in a 3 + 3 dose-escalation schedule: olaparib 25 mg BID and carboplatin area under the curve (AUC) 3 mg*min/mL d1/d22, olaparib 25 mg BID and carboplatin AUC 4 mg*min/mL d1/d22, followed by increasing dose-levels of olaparib from 50 mg BID, 75 mg BID, to 100 mg BID with carboplatin at AUC 4 mg*min/mL d1/d22.

Monitoring of EGFR mutations in circulating tumor DNA of non-small cell lung cancer patients treated with EGFR inhibitors.

Purpose: We studied EGFR mutations in circulating tumor DNA (ctDNA) and explored their role in predicting the progression-free survival (PFS) of non-small cell lung cancer (NSCLC) patients treated with erlotinib or gefitinib.

Methods: The L858R, T790M mutations and exon 19 deletions were quantified in plasma using digital droplet polymerase chain reaction (ddPCR). The dynamics of ctDNA mutations over time and relationships with PFS were explored.

Phase I Study of Afatinib and Selumetinib in Patients with KRAS-Mutated Colorectal, Non-Small Cell Lung, and Pancreatic Cancer.

Lessons Learned: Afatinib and selumetinib can be combined in continuous and intermittent dosing schedules, albeit at lower doses than approved for monotherapy. Maximum tolerated dose for continuous and intermittent schedules is afatinib 20 mg once daily and selumetinib 25 mg b.i.

Phase I and Pharmacologic Study of Olaparib in Combination with High-dose Radiotherapy with and without Concurrent Cisplatin for Non-Small Cell Lung Cancer.

Purpose: To identify an MTD of olaparib, a PARP inhibitor, in combination with loco-regional radiotherapy with/without cisplatin for the treatment of non-small cell lung cancer (NSCLC).

Patients And Methods: Olaparib dose was escalated in two groups: radiotherapy (66 Gy/24 fractions in 2.75 Gy/fraction) with and without daily cisplatin (6 mg/m), using time-to-event continual reassessment method with a 1-year dose-limiting toxicity (DLT) period.

A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours.

Background: This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity.

Methods: Adult patients with advanced solid tumours received peposertib 100-200 mg once daily or 150-400 mg twice daily (BID) in 21-day cycles.

Selective Oral MEK1/2 Inhibitor Pimasertib in Metastatic Melanoma: Antitumor Activity in a Phase I, Dose-Escalation Trial.

Background: Pimasertib is a selective, potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor.

Objectives: The aim of this study was to describe the efficacy, safety, and pharmacodynamics of pimasertib at pharmacologically active doses in a cohort of patients with locally advanced/metastatic melanoma from a first-in-human study of pimasertib.

Methods: This was a phase I, open-label, two-part, dose-escalation study.

Selective Oral MEK1/2 Inhibitor Pimasertib: A Phase I Trial in Patients with Advanced Solid Tumors.

Background: The Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Ras/Raf/MEK/ERK) signaling cascade is frequently constitutively activated in human cancers. Pimasertib is a selective and potent adenosine triphosphate non-competitive MEK1/2 inhibitor.

Objective: Our objectives were to describe the results of a phase I, first-in-human, dose-escalation trial of pimasertib that investigated the maximum tolerated dose, recommended phase II dose, and safety, as well as other endpoints.

Dabrafenib plus trametinib in patients with BRAF-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial.

Background: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAF-mutated cancers.