SummaryBackgroundTrastuzumab duocarmazine is a novel HER2-targeting antibody–drug conjugate comprised of trastuzumab covalently bound to a linker drug containing duocarmycin. Preclinical studies ...showed promising antitumour activity in various models. In this first-in-human study, we assessed the safety and activity of trastuzumab duocarmazine in patients with advanced solid tumours. MethodsWe did a phase 1 dose-escalation and dose-expansion study. The dose-escalation cohort comprised patients aged 18 years or older enrolled from three academic hospitals in Belgium, the Netherlands, and the UK with locally advanced or metastatic solid tumours with variable HER2 status who were refractory to standard cancer treatment. A separate cohort of patients were enrolled to the dose-expansion phase from 15 hospitals in Belgium, the Netherlands, Spain, and the UK. Dose-expansion cohorts included patients aged 18 years or older with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Trastuzumab duocarmazine was administered intravenously on day 1 of each 3-week cycle. In the dose-escalation phase, trastuzumab duocarmazine was given at doses of 0·3 mg/kg to 2·4 mg/kg (3 + 3 design) until disease progression or unacceptable toxicity. The primary endpoint of the dose-escalation phase was to assess safety and ascertain the recommended phase 2 dose, which would be the dose used in the dose-expansion phase. The primary endpoint of the dose-expansion phase was the proportion of patients achieving an objective response (complete response or partial response), as assessed by the investigator using RECIST version 1.1. This ongoing study is registered with ClinicalTrials.gov, number NCT02277717, and is fully recruited. FindingsBetween Oct 30, 2014, and April 2, 2018, 39 patients were enrolled and treated in the dose-escalation phase and 146 patients were enrolled and treated in the dose-expansion phase. One dose-limiting toxic effect (death from pneumonitis) occurred at the highest administered dose (2·4 mg/kg) in the dose-escalation phase. One further death occurred in the dose-escalation phase (1·5 mg/kg cohort) due to disease progression, which was attributed to general physical health decline. Grade 3–4 treatment-related adverse events reported more than once in the dose-escalation phase were keratitis (n=3) and fatigue (n=2). Based on all available data, the recommended phase 2 dose was set at 1·2 mg/kg. In the dose-expansion phase, treatment-related serious adverse events were reported in 16 (11%) of 146 patients, most commonly infusion-related reactions (two 1%) and dyspnoea (two 1%). The most common treatment-related adverse events (grades 1–4) were fatigue (48 33% of 146 patients), conjunctivitis (45 31%), and dry eye (45 31%). Most patients (104 71% of 146) had at least one ocular adverse event, with grade 3 events reported in ten (7%) of 146 patients. No patients died from treatment-related adverse events and four patients died due to disease progression, which were attributed to hepatic failure (n=1), upper gastrointestinal haemorrhage (n=1), neurological decompensation (n=1), and renal failure (n=1). In the breast cancer dose-expansion cohorts, 16 (33%, 95% CI 20·4–48·4) of 48 assessable patients with HER2-positive breast cancer achieved an objective response (all partial responses) according to RECIST. Nine (28%, 95% CI 13·8–46·8) of 32 patients with HER2-low, hormone receptor-positive breast cancer and six (40%, 16·3–67·6) of 15 patients with HER2-low, hormone receptor-negative breast cancer achieved an objective response (all partial responses). Partial responses were also observed in one (6%, 95% CI 0·2–30·2) of 16 patients with gastric cancer, four (25%, 7·3–52·4) of 16 patients with urothelial cancer, and five (39%, 13·9–68·4) of 13 patients with endometrial cancer. InterpretationTrastuzumab duocarmazine shows notable clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profile. Further investigation of trastuzumab duocarmazine for HER2-positive breast cancer is ongoing and trials for HER2-low breast cancer and other HER2-expressing cancers are in preparation. FundingSynthon Biopharmaceuticals.
Recent works have demonstrated a significant reduction in cholesterol levels and increased oxidative stress in patients with coronavirus disease 2019 (COVID-19). The cause of this alteration is not ...well known. This study aimed to comprehensively evaluate their possible association during the evolution of COVID-19. This is an observational prospective study. The primary endpoint was to analyze the association between lipid peroxidation, lipid, and inflammatory profiles in COVID-19 patients. A multivariate regression analysis was employed. The secondary endpoint included the long-term follow-up of lipid profiles. COVID-19 patients presented significantly lower values in their lipid profile (total, low, and high-density lipoprotein cholesterol) with greater oxidative stress and inflammatory response compared to the healthy controls. Lipid peroxidation was the unique oxidative parameter with a significant association with the total cholesterol (OR: 0.982; 95% CI: 0.969-0.996;
= 0.012), IL1-RA (OR: 0.999; 95% CI: 0.998-0.999;
= 0.021) IL-6 (OR: 1.062; 95% CI: 1.017-1.110;
= 0.007), IL-7 (OR: 0.653; 95% CI: 0.433-0.986;
= 0.042) and IL-17 (OR: 1.098; 95% CI: 1.010-1.193;
= 0.028). Lipid abnormalities recovered after the initial insult during long-term follow-up (IQR 514 days); however, those with high LPO levels at hospital admission had, during long-term follow-up, an atherogenic lipid profile. Our study suggests that oxidative stress in COVID-19 is associated with derangements of the lipid profile and inflammation. Survivors experienced a recovery in their lipid profiles during long-term follow-up, but those with stronger oxidative responses had an atherogenic lipid profile.
Oncolytic viruses represent a unique type of agents that combine self-amplification, lytic, and immunostimulatory properties against tumors. A local and locoregional clinical benefit has been ...demonstrated upon intratumoral injections of an oncolytic herpes virus in melanoma patients, leading to its approval in the United States and Europe for patients without visceral disease (up to stage IVM1a). However, in order to debulk and change the local immunosuppressive environment of tumors that cannot be injected directly, oncolyitc viruses need to be administered systemically. Among different viruses, adenovirus has been extensively used in clinical trials but with few evidences of activity upon systemic administration. Preclinical efficacy of a single intravenous administration of our oncolytic adenovirus ICOVIR5, an adenovirus type 5 responsive to the retinoblastoma pathway commonly deregulated in tumors, led us to use this virus in a dose-escalation phase 1 trial in metastatic melanoma patients. The results in 12 patients treated with a single infusion of a dose up to 1 × 10
viral particles show that ICOVIR5 can reach melanoma metastases upon a single intravenous administration but fails to induce tumor regressions. These results support the systemic administration of armed oncolytic viruses to treat disseminated cancer.
Background: Despite impressive progression-free survival (PFS) results from PARP inhibitors (PARPi) in ovarian cancer, concerns about their effect on post-progression treatment outcomes have recently ...arisen, particularly when administered in the relapsed setting. Overlapping mechanisms of resistance between PARPi and platinum have been described, and optimal therapies upon progression to PARPi are unknown. We communicate real-world data (RWD) on outcomes of subsequent chemotherapy upon progression to PARPi used as maintenance in ovarian cancer relapses, particularly focusing on platinum rechallenge, according to BRCA status. Methods: Data from high-grade serous or endometrioid ovarian cancer patients who received subsequent chemotherapy after progression to maintenance PARPi in the relapsed setting, in 16 Catalan hospitals between August 2016 and April 2021, and who were followed-up until July 2021, were included. Endpoints were overall response rate (ORR), and PFS and overall survival (OS) measured from the subsequent chemotherapy starting date. Results: 111 patients were included 46 (41.4%) presented pathological BRCA1/2 mutations, 8 (7.5%) in other homologous recombination-related genes. Sixty-four patients (57.7%) had received two prior chemotherapy lines, including the one immediately prior to PARPi. PARPi were niraparib (n = 60, 54.1%), olaparib (n = 49, 44.1%), and rucaparib (n = 2, 1.8%). A total of 81 patients remained platinum-sensitive (PS population) after progression to PARPi (when progression-free interval PFI was >6 months after the last cycle of prior platinum) median PFI 12.0 months (interquartile range, IQR, 8.8−17.1). Of those, 74 were treated with subsequent platinum regimens, with the following results: ORR of 41.9%, median PFS (mPFS) of 6.6 months (95% CI 6−9.2), and median OS (mOS) of 20.6 months (95% CI 13.6−28.9). Analysis of these 74 patients according to BRCA status showed that PFIs for BRCA mutant and non BRCA-mutant patients were 13.6 IQR11.2−22.2 and 10.3 IQR 7.4−14.9 months, respectively (p = 0.010); ORR were 40.0% versus 43.6%, respectively; Rates of progression (as best response) to subsequent platinum were 45.7% versus 17.9%, respectively (p = 0.004); mPFS and mOS were 3.5 (95% CI 2.5−8.6) versus 7.5 months (95% CI 6.5−10.1, p = 0.03), and 16.4 (95% CI 9.3−27.5) versus 24.2 months (95% CI 17.2−NR, p = 0.036), respectively. Conclusion: This is the largest series of real-world data on ovarian cancer patients retreated with platinum in the post-PARPi scenario, separately analyzing BRCA mutant and non-mutant patients, to our knowledge. In our platinum-sensitive population, rechallenge with platinum after progression upon PARPi in the 3rd or later lines for ovarian cancer relapses shows relevant ORR and similar PFS outcomes to historical series of the prePARPi era. However, BRCA mutant patients presented significantly higher rates of progression under subsequent platinum and worse survival outcomes associated with subsequent platinum than non-BRCA-mutant patients.
VCN-01 is an oncolytic adenovirus (Ad5 based) designed to replicate in cancer cells with dysfunctional RB1 pathway, express hyaluronidase to enhance virus intratumoral spread and facilitate ...chemotherapy and immune cells extravasation into the tumor. This phase I clinical trial was aimed to find the maximum tolerated dose/recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01 adenovirus in patients with advanced cancer.
Part I: patients with advanced refractory solid tumors received one single dose of VCN-01. Parts II and III: patients with pancreatic adenocarcinoma received VCN-01 (only in cycle 1) and nab-paclitaxel plus gemcitabine (VCN-concurrent on day 1 in Part II, and 7 days before chemotherapy in Part III). Patients were required to have anti-Ad5 neutralizing antibody (NAbs) titers lower than 1/350 dilution. Pharmacokinetic and pharmacodynamic analyses were performed.
26% of the patients initially screened were excluded based on high NAbs levels. Sixteen and 12 patients were enrolled in Part I and II, respectively: RP2D were 1×10
viral particles (vp)/patient (Part I), and 3.3×10
vp/patient (Part II). Fourteen patients were included in Part III: there were no DLTs and the RP2D was 1×10
vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1×10
vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1×10
vp). In patients with pancreatic adenocarcinoma overall response rate were 50% (Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies (day 8). A second viral plasmatic peak and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients. Increased levels of immune biomarkers (interferon-γ, soluble lymphocyte activation gene-3, interleukin (IL)-6, IL-10) were found after VCN-01 administration.
Treatment with VCN-01 is feasible and has an acceptable safety. Encouraging biological and clinical activity was observed when administered in combination with nab-paclitaxel plus gemcitabine to patients with pancreatic adenocarcinoma.
NCT02045602.
ABTL0812 is an autophagy inducer that promotes cancer cell death by activation of cytotoxic autophagy selectively in tumour cells. ABTL0812 induces endoplasmic reticulum stress and blocks the ...Akt-mTOR axis; both actions converge to activate a robust and sustained autophagy leading to cancer cell death. Preclinical data supported the initiation of clinical trials in patients with cancer.
This first-in-human trial consisted of an escalation phase (3 + 3 design), followed by an expansion phase, to assess safety and tolerability of ABTL0812. Secondary objectives were determining the recommended phase II dose (RP2D), clinical antitumour activity, pharmacokinetics (PK) and pharmacodynamics (PD).
A total of 29 patients were enrolled and treated; fifteen patients were treated in four escalation dosing cohorts (ranging from 500 mg once a day to 2000 mg twice a day) and fourteen in the expansion phase (dosed with 1300 mg three times a day). No maximum tolerated dose was attained, and RP2D was determined by PK/PD modelling. Most drug-related adverse events were gastrointestinal grade I–II. Correlation between drug levels and pAkt/Akt ratio was found. Two cases of long-term (>1 year) stable disease were observed.
ABTL0812 is safe and has an acceptable tolerability profile, allowing a long-term oral dosing. RP2D of 1300 mg three times a day was determined according to PK/PD modelling, and preliminary antitumour efficacy was observed.
NCT02201823.
•The present First-in-human (FiH) study showed that ABTL0812 long-term oral treatment is safe.•Recommended phase II dose was determined by pharmacokinetics/ pharmacodynamics modelling, using pAkt as a surrogate biomarker.•Preliminary efficacy signs were detected, including long-term disease stabilisations.
Retinitis Pigmentosa (RP) is a clinically and genetically heterogeneous disorder that results in inherited blindness. Despite the large number of genes identified, only ~ 60% of cases receive a ...genetic diagnosis using targeted-sequencing. The aim of this study was to design a whole genome sequencing (WGS) based approach to increase the diagnostic yield of complex Retinitis Pigmentosa cases.
WGS was conducted in three family members, belonging to one large apparent autosomal dominant RP family that remained unsolved by previous studies, using Illumina TruSeq library preparation kit and Illumina HiSeq X platform. Variant annotation, filtering and prioritization were performed using a number of open-access tools and public databases. Sanger sequencing of candidate variants was conducted in the extended family members.
We have developed and optimized an algorithm, based on the combination of different open-access tools, for variant prioritization of WGS data which allowed us to reduce significantly the number of likely causative variants pending to be manually assessed and segregated. Following this algorithm, four heterozygous variants in one autosomal recessive gene (USH2A) were identified, segregating in pairs in the affected members. Additionally, two pathogenic alleles in ADGRV1 and PDZD7 could be contributing to the phenotype in one patient.
The optimization of a diagnostic algorithm for WGS data analysis, accompanied by a hypothesis-free approach, have allowed us to unmask the genetic cause of the disease in one large RP family, as well as to reassign its inheritance pattern which implies differences in the clinical management of these cases. These results contribute to increasing the number of cases with apparently dominant inheritance that carry causal mutations in recessive genes, as well as the possible involvement of various genes in the pathogenesis of RP in one patient. Moreover, our WGS-analysis approach, based on open-access tools, can easily be implemented by other researchers and clinicians to improve the diagnostic yield of additional patients with inherited retinal dystrophies.
The management of unsolved inherited retinal dystrophies (IRD) cases is challenging since no standard pipelines have been established. This study aimed to define a diagnostic algorithm useful for the ...diagnostic routine and to address unsolved cases. Here, we applied a Next-Generation Sequencing-based workflow, including a first step of panel sequencing (PS) followed by clinical-exome sequencing (CES) and whole-exome sequencing (WES), in 46 IRD patients belonging to 42 families. Twenty-six likely causal variants in retinal genes were found by PS and CES. CES and WES allowed proposing two novel candidate
(
and a X-linked region including
), both abundantly expressed in human retina according to RT-PCR and immunohistochemistry. After comparison studies, PS showed the best quality and cost values, CES and WES involved similar analytical efforts and WES presented the highest diagnostic yield. These results reinforce the relevance of panels as a first step in the diagnostic routine and suggest WES as the next strategy for unsolved cases, reserving CES for the simultaneous study of multiple conditions. Standardizing this algorithm would enhance the efficiency and equity of clinical genetics practice. Furthermore, the identified candidate genes could contribute to increase the diagnostic yield and expand the mutational spectrum in these disorders.
Abstract Endometrial carcinoma is the most common cancer of the female genital tract. This review article discusses the usefulness of molecular techniques to classify endometrial carcinoma. Any ...proposal for molecular classification of neoplasms should integrate morphological features of the tumors. For that reason, we start with the current histological classification of endometrial carcinoma, by discussing the correlation between genotype and phenotype, and the most significant recent improvements. Then, we comment on some of the possible flaws of this classification, by discussing also the value of molecular pathology in improving them, including interobserver variation in pathologic interpretation of high grade tumors. Third, we discuss the importance of applying TCGA molecular approach to clinical practice. We also comment on the impact of intratumor heterogeneity in classification, and finally, we will discuss briefly, the usefulness of TCGA classification in tailoring immunotherapy in endometrial cancer patients. We suggest combining pathologic classification and the surrogate TCGA molecular classification for high-grade endometrial carcinomas, as an option to improve assessment of prognosis.
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