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"Jan, M. H."
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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
.
In the final analysis of all cohorts in the phase 2 ROAR basket trial, dabrafenib plus trametinib exhibited tumor-agnostic clinical activity in patients with rare
BRAFV800E
-mutated cancers, including anaplastic thyroid carcinoma, biliary tract cancer, low-grade glioma and hairy cell leukemia.
Journal Article
Low SARS-CoV-2 seroprevalence in blood donors in the early COVID-19 epidemic in the Netherlands
The world is combating an ongoing COVID-19 pandemic with health-care systems, society and economies impacted in an unprecedented way. It is unclear how many people have contracted the causative coronavirus (SARS-CoV-2) unknowingly and are asymptomatic. Therefore, reported COVID-19 cases do not reflect the true scale of outbreak. Here we present the prevalence and distribution of antibodies to SARS-CoV-2 in a healthy adult population of the Netherlands, which is a highly affected country, using a high-performance immunoassay. Our results indicate that one month into the outbreak (i) the seroprevalence in the Netherlands was 2.7% with substantial regional variation, (ii) the hardest-hit areas showed a seroprevalence of up to 9.5%, (iii) the seroprevalence was sex-independent throughout age groups (18–72 years), and (iv) antibodies were significantly more often present in younger people (18–30 years). Our study provides vital information on the extent of exposure to SARS-CoV-2 in a country where social distancing is in place.
The Netherlands is a country highly affected by the COVID-19 pandemic. In this study, Slot, Hogema and colleagues report a low SARS-CoV-2 seroprevalence one month into the outbreak and provide insights into virus exposure by region and age group when widespread non-pharmaceutical interventions are in place.
Journal Article
Practical Guidelines for Therapeutic Drug Monitoring of Anticancer Tyrosine Kinase Inhibitors: Focus on the Pharmacokinetic Targets
There is accumulating evidence for potential benefits of therapeutic drug monitoring (TDM) in the treatment of cancer with tyrosine kinase inhibitors (TKIs). Relationships between exposure and response (efficacy/toxicity) have been established for several TKIs. For example, the pharmacokinetic targets for efficacy of imatinib, sunitinib and pazopanib have been defined as trough plasma concentrations (
C
trough
) of >1,000, >50 and >20,000 ng/mL for selected indications, respectively. Dose adjustment based on pharmacokinetic targets could therefore increase response rates and duration. Furthermore, with appropriate target concentrations defined, excessive side effects in patients using the current fixed dosing strategy may be prevented. This review provides a practical guideline for TDM for the currently approved TKIs at 28 February 2013. The focus of this article is on the elaboration of exposure and response relationships of TKIs with proposed pharmacokinetic targets, mainly
C
trough
, and further on the interpretation of the pharmacokinetic targets with recommendations for dose titrations.
Journal Article
Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial
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 BRAFV600E-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAFV600E-mutated biliary tract cancer.
This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAFV600E-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAFV600E-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0–2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting.
Between March 12, 2014, and July 18, 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6–15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36–67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31–62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported.
Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAFV600E-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAFV600E mutations should be considered in patients with biliary tract cancer.
GlaxoSmithKline and Novartis.
Journal Article
Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers
Inhibition of poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP), a key enzyme for the repair of breaks in DNA, can lead to the accumulation of breaks in double-stranded DNA. The BRCA1 and BRCA2 proteins help to repair such breaks. In this phase 1 trial, the PARP inhibitor olaparib was shown to lack the severe toxic effects of conventional chemotherapy and to result in objective responses in tumors with a
BRCA
mutation.
In this phase 1 trial, the poly(ADP–ribose) polymerase inhibitor olaparib was shown to lack the severe toxic effects of conventional chemotherapy and to result in objective responses in tumors with a
BRCA
mutation.
Cellular DNA is continually subject to damage, which coordinated pathways act to repair, thereby maintaining genomic integrity and cell survival.
1
–
3
The poly(adenosine diphosphate [ADP]–ribose) polymerases (PARPs) are a large family of multifunctional enzymes, the most abundant of which is PARP1. It plays a key role in the repair of DNA single-strand breaks through the repair of base excisions.
4
,
5
The inhibition of PARPs leads to the accumulation of DNA single-strand breaks, which can lead to DNA double-strand breaks at replication forks. Normally, these breaks are repaired by means of the error-free homologous-recombination double-stranded DNA repair pathway,
6
key components of . . .
Journal Article
Clinical Pharmacokinetics of Therapeutic Monoclonal Antibodies
Monoclonal antibodies (mAbs) have been used in the treatment of various diseases for over 20 years and combine high specificity with generally low toxicity. Their pharmacokinetic properties differ markedly from those of non-antibody-type drugs, and these properties can have important clinical implications. mAbs are administered intravenously, intramuscularly or subcutaneously. Oral administration is precluded by the molecular size, hydrophilicity and gastric degradation of mAbs. Distribution into tissue is slow because of the molecular size of mAbs, and volumes of distribution are generally low. mAbs are metabolized to peptides and amino acids in several tissues, by circulating phagocytic cells or by their target antigen-containing cells. Antibodies and endogenous immunoglobulins are protected from degradation by binding to protective receptors (the neonatal Fc-receptor [FcRn]), which explains their long elimination half-lives (up to 4 weeks). Population pharmacokinetic analyses have been applied in assessing covariates in the disposition of mAbs. Both linear and nonlinear elimination have been reported for mAbs, which is probably caused by target-mediated disposition. Possible factors influencing elimination of mAbs include the amount of the target antigen, immune reactions to the antibody and patient demographics. Bodyweight and/or body surface area are generally related to clearance of mAbs, but clinical relevance is often low. Metabolic drug-drug interactions are rare for mAbs. Exposure-response relationships have been described for some mAbs. In conclusion, the parenteral administration, slow tissue distribution and long elimination half-life are the most pronounced clinical pharmacokinetic characteristics of mAbs.
Journal Article
Placental Pathology, Perinatal Death, Neonatal Outcome, and Neurological Development: A Systematic Review
The placenta plays a crucial role during pregnancy for growth and development of the fetus. Less than optimal placental performance may result in morbidity or even mortality of both mother and fetus. Awareness among pediatricians, however, of the benefit of placental findings for neonatal care, is limited.
To provide a systematic overview of the relation between placental lesions and neonatal outcome.
Pubmed database, reference lists of selected publications and important research groups in the field.
We systematically searched the Pubmed database for literature on the relation between placental lesions and fetal and neonatal mortality, neonatal morbidity and neurological outcome. We conducted three separate searches starting with a search for placental pathology and fetal and neonatal mortality, followed by placental pathology and neonatal morbidity, and finally placental pathology and neurological development. We limited our search to full-text articles published in English from January 1995 to October 2013. We refined our search results by selecting the appropriate articles from the ones found during the initial searches. The first selection was based on the title, the second on the abstract, and the third on the full article. The quality of the selected articles was determined by using the Newcastle-Ottawa Quality Assessment Scale.
Placental lesions are one of the main causes of fetal death, where placental lesions consistent with maternal vascular underperfusion are most important. Several neonatal problems are also associated with placental lesions, whereby ascending intrauterine infection (with a fetal component) and fetal thrombotic vasculopathy constitute the greatest problem.
The placenta plays a key role in fetal and neonatal mortality, morbidity, and outcome. Pediatricians should make an effort to obtain the results of placental examinations.
Journal Article
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.
Results
Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median
T
max
1.1–2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3–6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients.
Conclusions
Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing.
Clinical trial registration
NCT02316197
Journal Article
Phase I/II study with ruthenium compound NAMI-A and gemcitabine in patients with non-small cell lung cancer after first line therapy
Summary
Background
This phase I/II study determined the maximal tolerable dose, dose limiting toxicities, antitumor activity, the pharmacokinetics and pharmacodynamics of ruthenium compound NAMI-A in combination with gemcitabine in Non-Small Cell Lung Cancer patients after first line treatment.
Methods
Initial dose escalation of NAMI-A was performed in a 28 day cycle: NAMI-A as a 3 h infusion through a port-a-cath at a starting dose of 300 mg/m
2
at day 1, 8 and 15, in combination with gemcitabine 1,000 mg/m
2
at days 2, 9 and 16. Subsequently, dose escalation of NAMI-A in a 21 day schedule was explored. At the maximal tolerable dose level of this schedule an expansion group was enrolled of which 15 patients were evaluable for response.
Results
Due to frequent neutropenic dose interruptions in the third week, the 28 day schedule was amended into a 21 day schedule. The maximal tolerable dose was 300 and 450 mg/m
2
of NAMI-A (21 day schedule). Main adverse events consisted of neutropenia, anemia, elevated liver enzymes, transient creatinine elevation, nausea, vomiting, constipation, diarrhea, fatigue, and renal toxicity.
Conclusion
NAMI-A administered in combination with gemcitabine is only moderately tolerated and less active in NSCLC patients after first line treatment than gemcitabine alone.
Journal Article