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Supplementary data | The following is the Supplementary data to this article: | PMC10447494 | ||
Multimedia component1 | Supplementary data to this article can be found online at | PMC10447494 | ||
Introduction | deaths, Annual Trivalent | VIRUS, ADVERSE EVENTS, INFLUENZA B, INFLUENZA, INFLUENZA A, INFLUENZA, VIRAL ILLNESS | Influenza is an acute viral illness of the respiratory tract and poses a substantial public health burden in terms of morbidity, mortality, and costs. The World Health Organization (WHO) reported that 3–5 million cases of severe influenza occur each year worldwide, resulting in about 290,000 to 650,000 related deaths p... | PMC10449119 |
Materials and methods | PMC10449119 | |||
Study design | BLIND, INFLUENZA | This was an experimental, randomized, double blind, four arm parallel group bridging study to assess immune response and safety after one dose of quadrivalent and trivalent influenza HA vaccine in subjects 9–40 years old in clinically health children and adults aged 9–40 years. The study was a collaboration between the... | PMC10449119 | |
Study subjects | illness, fever, blood disorders, coagulopathy, chronic disease | BLOOD DISORDERS, INFLUENZA, ALLERGY TO EGGS, COAGULOPATHY, CHRONIC DISEASE, INFLUENZA | A total of 540 subjects were enrolled in this study. Subjects were enrolled from 3 primary care centers in Bandung City, Ibrahim Adjie Primary Health Center, Puter Primary Health Center, and Garuda Primary Health Center, from October 2017 to June 2018. The primary inclusion criteria included healthy children and adults... | PMC10449119 |
Randomization and blinding | For each subject recruited, the inclusion number was allocated in the chronological order of the subject, which was included in the trial from I-001 to I-180 (for the 9–12-year age group), II-001 to II-180 (for the 13–17-year age group), and III-001 to III-180 (for the 18–40-year age group). The subjects were randomize... | PMC10449119 | ||
Vaccines and vaccination schedule | The QIV vaccine was formulated by PT Bio Farma (Persero), Indonesia, using bulks imported from Japan. The investigational QIV contained 15 μg HA from each of 4 strains, A/California/7/2009 (X-179A) (H1N1) pdm09n, A/Hong Kong/4801/2014 (X-263) (H3N2), B/Texas/2/2013, and B/Phuket/3073/2013, in a 0.5 ml dose, with batch ... | PMC10449119 | ||
Sample size | The sample size was determined based on a 95% confidence interval (CI) and a test power of 80%. The required sample size was 112 in each batches, with the assumption that not all the subjects could complete the study, the total number of subjects was added at least 20% from the minimum requirement (N x 1.2) = 134. Appr... | PMC10449119 | ||
Study analysis | injection-site, redness, myalgia, fatigue, fever, swelling, pain, Redness, Fever, Fatigue | ADVERSE EVENTS, INFLUENZA, INDURATION, SECONDARY, REDNESS, HAND SWELLING, EVENTS, INFLUENZA | Demographic data were expressed as mean, standard deviation, and range values. Analysis of Geometric Mean Titer (GMT), seroprotection, and seroconversion rates between the vaccine groups was performed using Kruskal-Wallis and Chi-square or Kolmogorov-Smirnov tests. Values of The safety analyses were based on the intent... | PMC10449119 |
Results | The demographic characteristics of study participants showed a fair distribution in gender and age ( | PMC10449119 | ||
Demographic characteristics of study participants. | In this study, 405 and 135 subjects were enrolled in the QIV (Batch A, B and C) and TIV groups, respectively. Of the 405 subjects in the QIV group, three were excluded from immunogenicity analysis because of protocol non-compliance ( | PMC10449119 | ||
Flow Chart for the participants enrollment. | Comparison of the percentage of subjects with anti-HI titer ≥1:40 28 days after QIV and TIV was shown on | PMC10449119 | ||
Influenza seroprotection rate before and 28 days after immunization. | *Chi-square test.Comparison of GMT between subjects who received QIV and TIV was shown on | PMC10449119 | ||
Hemagglutination inhibition (HI) Geometric Mean Titers (GMT) before and 28 days after QIV and TIV immunization. | PMC10449119 | |||
QIV batch-to-batch comparison. | Age 9–12 years: Age 13–17 years: Age 18–40 years: Solicited and unsolicited post-vaccination AEs were categorized as immediate (within 30 min), intermediate (30 min to 72 h), and delayed (72 h to 28 days) reactions (Figs | PMC10449119 | ||
Intensity of reported local and systemic adverse events (AEs). | PMC10449119 | |||
Intensity of reported local and systemic AEs on each QIV batch. | myalgia, pain | ADVERSE REACTION | Most local and systemic AEs reported in the QIV and TIV groups had mild intensity. Mild pain was the most local adverse reaction, which occurred in 15.3% and 17.8% of the subjects in the QIV and TIV groups, respectively. Mild myalgia was the most systemic adverse reaction, which occurred in 13.6% and 9.6% of the subjec... | PMC10449119 |
Discussion | injection-site, myalgia, Injection-site pain, fatigue, A/H1N1 | ADVERSE EVENTS, EVENT, INFLUENZA B, EMA, ADVERSE EFFECTS, EVENTS | This study was conducted on subjects aged 9–40 years, while a previous study by Dhamayanti et al. was conducted on infants to children aged 8 years [The inclusion of a fourth strain in QIV did not interfere with the EMA criteria for immune responses in adult vaccine recipients. In adults, post-vaccination seroprotectio... | PMC10449119 |
Conclusion | INFLUENZA, COMPLICATIONS, EMA | In conclusion, this study demonstrated that QIV can be reproducibly manufactured to yield a well-tolerated, safe, and immunogenic vaccine in people aged 9–40 years and that it met all EMA immunogenicity criteria in adults. In adults, inactivated QIV induced comparable immune responses to TIV for A strains and the B lin... | PMC10449119 | |
Supporting information | PMC10449119 | |||
CONSORT 2010 checklist of information to include when reporting a randomised trial*. | SITI | (DOC)Click here for additional data file.(PDF)Click here for additional data file.We would like to thank Dr. Iskandar, the Director of Bio Farma, for supporting this study. Thanks to Dr. Novilia S. Bachtiar, dr., M.Kes who has passed away for her contribution during various stages of the paper preparation. We would als... | PMC10449119 | |
Background | presenteeism | Loss of productivity is a result of absence from work (absenteeism) or of working with limitations due to illness (presenteeism). Recently, occupational mental health interventions have increasingly been delivered in digital format, as this is thought to be more convenient, flexible, easily accessible, and anonymous. H... | PMC10365609 | |
Objective | presenteeism | The aim of this study was to determine the effectiveness of an e-mental health intervention to reduce absenteeism and presenteeism in employees, as well as to investigate the mediating role of stress in this effect. | PMC10365609 | |
Methods | REGRESSION | Employees of six companies in two countries participated in a randomized controlled trial (n=210 in the intervention group and n=322 in the waitlist control group). Participants in the intervention group could use the Kelaa Mental Resilience app for 4 weeks. All participants were asked to complete assessments at baseli... | PMC10365609 | |
Results | The intervention did not have a direct effect on presenteeism or absenteeism, neither at postintervention nor at follow-up. Nevertheless, general stress significantly mediated the intervention effect on presenteeism ( | PMC10365609 | ||
Conclusions | stress reduction | While no direct effect of the e-mental health intervention on productivity was found in this study, our findings suggest that stress reduction could mediate the effect of the intervention on presenteeism and absenteeism. As such, e-mental health interventions that address stress in employees might also indirectly reduc... | PMC10365609 | |
Trial Registration | ClinicalTrials.gov NCT05924542; https://clinicaltrials.gov/study/NCT05924542 | PMC10365609 | ||
Introduction | PMC10365609 | |||
Background | depression, Lazarus and Folkman [, presenteeism | DISORDERS | Mental disorders and mental health–related conditions such as stress contribute to productivity loss, with an estimated cost of €400 billion (~US $440 billion) every year in Europe [In recent years, occupational mental health interventions [Studies about the effectiveness of e-mental health interventions to reduce abse... | PMC10365609 |
Study Objectives and Hypotheses | The Kelaa Mental Resilience app, a science-based health and well-being mobile phone app provided by Soma Analytics (London, United Kingdom), was found to significantly decrease stress (β=–.15, SE=.04; First, we hypothesized that after using the app for 4 weeks, participants in the intervention group would report lower ... | PMC10365609 | ||
Methods | PMC10365609 | |||
Study Design and Procedures | BLIND | This study followed a longitudinal RCT experimental design with a 2-week follow-up. The trial started in January 2018 and ended in September 2018. Human resources managers were blind to the participants’ group allocation and participants were blind to the goals and hypotheses of the study; however, they were not blind ... | PMC10365609 | |
Participants | RECRUITMENT | The recruitment of employees from the private and public sector took place in six different European businesses in Germany, England, and Northern Ireland. Potential participants were informed about trial participation through intraorganization communication channels such as emails, newsletters, intranet posts, or word ... | PMC10365609 | |
Kelaa Mental Resilience App | Details of the app-based intervention tool have been previously reported [In the tracking module, through the use of scientifically validated questionnaires, the users of the app could track their stress levels, well-being, and resilience. Additionally, using inbuilt sensors (eg, accelerometer), they were also able to ... | PMC10365609 | ||
Measures | PMC10365609 | |||
Productivity Measures | The impact of health problems on the ability to undertake regular activities and to work over the previous week was assessed by means of the Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPAI:GH) [ | PMC10365609 | ||
Absenteeism | For absenteeism, the scores were calculated according to the following formula:[Number of hours missed from work because of health problems/(Number of hours missed from work because of health problems+Number of hours worked)]×100This resulted in a percentage of work time missed due to health ranging from 0 to 100, wher... | PMC10365609 | ||
Presenteeism | Based on the answer to the question “During the past 7 days, how much did health problems affect your productivity while you were working?,” the proportion of impairment while working due to health was calculated. This measure multiplied by 100 was used as a measure of presenteeism. This yielded a score of 0 to 100, wh... | PMC10365609 | ||
Stress | The Copenhagen Psychosocial Questionnaire-Revised Version (COPSOQ II) [ | PMC10365609 | ||
Ethical Considerations | Ethics approval was granted by an Independent Ethics Advisory Board (EAB) according to the European Commission Horizon 2020 Ethics Appraisal Procedure [ | PMC10365609 | ||
Statistical Analysis | cognitive stress, presenteeism | Descriptive statistics of the variables of interest were calculated for all the participants and for the two groups (intervention group vs control group) separately. Wilcoxon rank-sum tests and To test the intervention effect on presenteeism and absenteeism, we used multilevel modeling for repeated measures with measur... | PMC10365609 | |
Results | PMC10365609 | |||
Discussion | PMC10365609 | |||
Principal Findings | The Kelaa Mental Resilience app, a mobile-based intervention, has previously been shown to be effective in reducing stress in workers [In contrast to our findings, some previous studies reported significant effects of digital workplace interventions on presenteeism and absenteeism [ | PMC10365609 | ||
Strengths, Limitations, and Practical Implications | This research has several strengths. The fact that the study was conducted in different work environments, disciplines, and countries allowed the results to represent different working conditions. Furthermore, the Kelaa Mental Resilience app is grounded both in theory (ie, the JDR model [Some limitations also need to b... | PMC10365609 | ||
Conclusion | Soma Analytics/DNAFit | Overall, our findings suggest that the effects of a mobile mental health intervention on stress levels might have a positive effect on presenteeism and absenteeism in workers. However, such effects do not seem to be persistent 2 weeks after finishing using the intervention, except in the case of the impact of the inter... | PMC10365609 | |
Abbreviations | healthJob | cognitive behavioral therapyCopenhagen Psychosocial Questionnaire-Revised VersionEthics Advisory Boardelectronic mental healthJob Demands-Resources modelrandomized controlled trialWork Productivity and Activity Impairment Questionnaire: General Health V2.0 | PMC10365609 | |
Data Availability | The data sets generated during and/or analyzed during the current study are available from author SW on reasonable request. | PMC10365609 | ||
Purpose: | cancer | CANCER | Mistletoe extract (ME) is widely used for patients with cancer to support therapy and to improve quality of life (QoL). However, its use is controversial due to suboptimal trials and a lack of data supporting its intravenous administration. | PMC9973409 |
Materials and Methods: | tumor | TUMOR, SOLID TUMOR | This phase I trial of intravenous mistletoe (Helixor M) aimed to determine the recommended phase II dosing and to evaluate safety. Patients with solid tumor progressing on at least one line of chemotherapy received escalating doses of Helixor M three times a week. Assessments were also made of tumor marker kinetics and... | PMC9973409 |
Results: | nausea, fatigue, cancer, chills, Cancer | ADVERSE EVENTS, CANCER, DISEASE, CANCER | Twenty-one patients were recruited. The median follow-up duration was 15.3 weeks. The MTD was 600 mg. Treatment-related adverse events (AE) occurred in 13 patients (61.9%), with the most common being fatigue (28.6%), nausea (9.5%), and chills (9.5%). Grade 3+ treatment-related AEs were noted in 3 patients (14.8%). Stab... | PMC9973409 |
Conclusions: | toxicities | DISEASE, SOLID TUMOR | Intravenous mistletoe demonstrated manageable toxicities with disease control and improved QoL in a heavily pretreated solid tumor population. Future phase II trials are warranted. | PMC9973409 |
Significance: | cancers, nausea, fatigue, toxicities, chills | DISEASE, CANCERS | Although ME is widely used for cancers, its efficacy and safety are uncertain. This first phase I trial of intravenous mistletoe (Helixor M) aimed to determine phase II dosing and to evaluate safety. We recruited 21 patients with relapsed/refractory metastatic solid tumor. Intravenous mistletoe (600 mg, 3/week) demonst... | PMC9973409 |
Introduction | cancer, tumor, Tumor, pain | TUMOR, TUMOR, CANCER, DISEASE, SOLID TUMOR, HAND SWELLING, CYTOTOXICITY | Patients with cancer experience physical impairment and a decline in quality of life (QoL) related to disease and therapy. The use of complementary medicine to support treatment and improve QoL has been increasingly popular, rising from 25% of patients in the 1970s to 50% by 2000 (Preparations from ME are the most freq... | PMC9973409 |
Materials and Methods | cancer, autoimmune disease, Cancer | DISEASE PROGRESSION, CHRONIC INFECTION, BRAIN METASTASES, CANCER, SOLID TUMORS, METASTATIC DISEASE, ONCOLOGY, AUTOIMMUNE DISEASE, CANCER | Patients were recruited at the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center (SKCCC). Eligible adult patients (≥18 years) had advanced solid tumors and had received at least one standard systemic therapy with chemotherapy, immunotherapy, hormonal therapy, or other therapies for metastatic disease a... | PMC9973409 |
Study Treatment and Dose Escalation | DLTs | Helixor-M was administered intravenously on Monday, Wednesday, and Friday on a weekly basis. Four dose levels of mistletoe were evaluated: 150, 300, 600, and 900 mg. The dose frequency and starting and maximum dose levels were informed by the phase I trial of intravenous Helixor P (A traditional 3 + 3 method was employ... | PMC9973409 | |
Safety and Efficacy | Patients were followed for 28 days after the last dose. Thereafter, patients were contacted every 6 months to monitor overall survival (OS). Safety evaluations (clinical and laboratory examinations) were conducted every 28 days, beginning from the first dose. AEs were graded according to revised Common Terminology Crit... | PMC9973409 | ||
Pharmacodynamic Analysis | Serum was collected from patients at baseline, every 4 weeks, and after treatment to identify potential therapeutic targets, biomarkers, and response predictors. Carcinoembryonic antigen (CEA) was evaluated when clinically expressed. Serum analysis for cytokine production by peripheral blood mononuclear cells was perfo... | PMC9973409 | ||
Quality | The Investigational New Drug (IND) application for this study was approved by the FDA. The study was approved by the Johns Hopkins University Institutional Review Board. All patients (or their legal representatives) gave written informed consent before enrollment. The study was conducted in accordance with the Declarat... | PMC9973409 | ||
Statistical Analysis | DLTs | Patient baseline characteristics and AEs were summarized, and the number of patients treated at each dose level and their DLTs were tabulated. AEs were tabulated by type and grade. The best objective response and time to progression were plotted for individual patients. Kaplan–Meier curves were plotted for progression-... | PMC9973409 | |
Data Availability | The trial data are available upon request through communication with the corresponding author. | PMC9973409 | ||
Results | PMC9973409 | |||
Baseline Patient Characteristics | uterine leiomyosarcoma cancer, melanoma | SOLID TUMORS, MELANOMA, SYNOVIAL SARCOMA | Between March 2017 and January 2021, 21 patients with advanced solid tumors, including 7 colorectal, 3 ovarian, 2 pancreatic, and 1 each with appendix, basal cell, breast, lung, melanoma, neuroendocrine, salivary, synovial sarcoma, and uterine leiomyosarcoma cancer, were treated with ME. The median follow-up duration w... | PMC9973409 |
Safety | toxicity | The MTD was determined to be 600 mg three times a week. Dose-level summary with DLTsNote: Four patients, 2 each at dose levels 150 and 600 mg, missed more than 25% of the first 4 weeks of treatments. Therefore, 2 additional patients were recruited for each dose level.Abbreviations: DLT: dose-limiting toxicity.AEs of an... | PMC9973409 | |
Reasons for Discontinuation | DISEASE PROGRESSION | Fifteen of the 21 patients (71.4%) discontinued because of disease progression ( | PMC9973409 | |
Clinical Activity | NSCLC, PD, tumor, death | TUMOR, DISEASE, BEST, SMALL CELL LUNG CANCER, NSCLC | Seventeen patients (80.9%) had follow-up scans after baseline to evaluate tumor response. Their best tumor response is shown in Best objective response. NSCLC: non–small cell lung cancer; PD: progressive disease; SD: stable disease. Note: Waterfall plot of patients treated with Helixor-M and had follow-up scans after b... | PMC9973409 |
Tumor Marker Kinetics | DISEASE | Serum CEA was positive in 7 patients (JHU-002, 009, 005, 007, 014, 015, 016) and increased over time in 3 patients at doses of 150 and 300 mg, and was stable over time in 2 patients with doses of 600 and 900 mg; the remaining 2 patients had baseline CEA level only (Serum cytokines, chemokines and growth factors were an... | PMC9973409 | |
Longitudinal Outcomes and QoL | DISEASE | The median progression-free survival was 46 days [95% confidence interval (CI), 44–48 days]. The median OS was 10.1 months (95% CI, 3.5 months to not reached). No significant difference was observed across dose levels. The median total score of FACT-G first increased from 79.7 [interquartile range (IQR), 65.5–93] at we... | PMC9973409 | |
Discussion | nausea, tumor, fatigue, toxicity, toxicities, ill, chills | RECRUITMENT, DISEASE, SOLID TUMORS, TUMOR | To our knowledge, this was the first phase I trial to assess the safety and antitumor activity of intravenous Helixor-M in patients with heavily pretreated advanced solid tumors. We found that the MTD was 600 mg three times a week. The product was found to have an overall manageable safety profile. One patient disconti... | PMC9973409 |
Supplementary Material | cancer, tumor | ADVERSE EVENTS, CANCER, TUMOR | Supplementary Materials and Methods show the trial protocolClick here for additional data file.Table S1 shows summary of all adverse eventsClick here for additional data file.Table S2 shows treatment-related adverse events by dose levelClick here for additional data file.Table S3 shows reasons for discontinuation with ... | PMC9973409 |
Acknowledgments | Wilfried Tröger | We thank Dr. Peter Hinderberger, Dr. Nasha Winters, Dr. Roman Huber, Dr. Wilfried Tröger, and Dr. Gunver Kienle for your willingness to share your insights, knowledge, and expertise in mistletoe treatment.To the patients and their families who participated, we extend our heartfelt thanks for your trust. Your contributi... | PMC9973409 | |
Authors’ Disclosures | tumor | DIAZ, TUMOR | C.J. Paller reports grants from Believe Big and NCI, grants and other from Helixor during the conduct of the study. C.F. Meyer reports personal fees from Deciphera, AAdi, BioAlta, and Adaptimmune outside the submitted work. S. Gaillard reports personal fees from Arcus, Elevar Therapeutics, Immunogen, Lumanity, Novartis... | PMC9973409 |
Authors’ Contributions | PMC9973409 | |||
References | PMC9973409 | |||
Purpose | cancers | CANCERS | To determine the safety and efficacy of PARP plus PD-L1 inhibition (olaparib + durvalumab, O + D) in patients with advanced solid, predominantly rare cancers harbouring homologous recombination repair (HRR) defects. | PMC10403555 |
Patients and methods | In total, 48 patients were treated with O + D, 16 with | PMC10403555 | ||
Results | PEComa, cancers, tumour | CANCERS, ENDOMETRIAL CANCER, ADVERSE EVENTS, TUMOUR, PECOMA, CHOLANGIOCARCINOMA | The PFS6 rate was 35% and 38% with durable objective tumour responses (OTR) in 3(19%) and 3(9%) in groups 1 and 2, respectively. Rare cancers achieving an OTR included cholangiocarcinoma, perivascular epithelioid cell (PEComa), neuroendocrine, gallbladder and endometrial cancer. O + D was safe, with five serious advers... | PMC10403555 |
Conclusions | toxicity, cancers, HRR defects | CANCERS | O + D demonstrated no new toxicity concerns and yielded a clinically meaningful PFS6 rate and durable OTRs across several cancers with HRR defects, including rare cancers. | PMC10403555 |
Subject terms | PMC10403555 | |||
Background | DNA DAMAGE | Homologous recombination repair (HRR) is comprised of interwoven pathways that function in the repair of DNA double-stranded breaks and interstrand crosslinks [The use of poly-ADP ribose polymerase (PARP) inhibitors has synthetically lethal activity in the presence of non-functional HRR. Olaparib monotherapy has yielde... | PMC10403555 | |
Patients and methods | PMC10403555 | |||
Study design and participants | Cancer | ONCOLOGY, DISEASE, CANCER | This was a Phase II, open-label trial conducted at a single Australian centre (ACTRN12617001000392) within the framework of the Cancer Molecular Screening and Therapeutics (MoST) program [Patients were required to have an Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2; evaluable disease by Response... | PMC10403555 |
Ethics approval and consent | The study was performed in accordance with the Declaration of Helsinki, with central or institutional ethics and local research governance approval. The MoST program has been approved by the St Vincent’s Hospital Sydney Human Research Ethics Committee (reference, HREC/16/SVH/23), as has this clinical trial. All partici... | PMC10403555 | ||
Endpoints | tumour, TTP | TTP, TUMOUR | The primary endpoint was the clinical activity of O + D, as measured by progression-free survival at 6 months (PFS6). PFS6 is the Kaplan–Meier estimate of the proportion of patients who remain alive and progression-free at 6 months from the date of registration. Secondary endpoints included objective tumour response, o... | PMC10403555 |
Exploratory biological analyses | cancers, Tumour, T-cell inflammation, tumour | CANCERS, TUMOUR, MICROSATELLITE INSTABILITY, TUMOUR, INFILTRATING, APPENDIX | Where available, prior germline testing results were retrieved for all patients. When HRR alterations identified at screening met bioinformatic thresholds for potentially germline, germline testing was performed. Determination of a post hoc HRR defect score was planned but could not be undertaken due to tissue and sequ... | PMC10403555 |
Statistical considerations | This trial comprised of three modules of 16 patients each as defined by the MoST framework protocol [ | PMC10403555 | ||
Results | PMC10403555 | |||
Patient disposition and baseline characteristics | PANCREATIC ADENOCARCINOMA, APPENDIX | Of 162 molecularly eligible patients, 96 patients received a MoST MTB recommendation indicating trial eligibility. Forty-eight patients were subsequently enrolled on trial over a 15-month period (November 2017 and February 2019) and allocated to the two study cohorts (groups 1 and 2). Reasons for non-enrolment on trial... | PMC10403555 | |
Primary clinical endpoint | After a median follow-up period of 34 months, the PFS6 rate was 35% (95% confidence interval (CI), 13– 58%) in group 1 and 38% (95% CI 21–54%) in group 2. The median PFS was 3.7 (95% CI 1.8–7.8) and 3.6 months (95% CI 1.7–7.1) in group 1 and group 2, respectively. The Kaplan–Meier analyses are shown in Fig. | PMC10403555 | ||
Swimmer plot characterising secondary trial endpoints by the individual patients within each group. | Group 1: | PMC10403555 | ||
Safety and tolerability | anaemia, nausea, vomiting | ADVERSE EVENTS, DISEASE, ANAEMIA | In terms of treatment exposure, four patients came off the study whilst receiving olaparib alone and did not commence durvalumab: two due to progressive disease and two due to adverse events. The median relative dose intensity (the ratio of administered doses to planned doses) was 100% (range 70–100%). The dose of olap... | PMC10403555 |
Predictors of response to PARP inhibition | Eight (17%) patients had ClinVar pathogenic/ likely pathogenic germline variants in | PMC10403555 | ||
Predictors of response to immunotherapy | death, tumour | TUMOUR | Fifteen (94%) in group 1 and 31 (97%) in group 2 had an evaluable TMB; 7 and 3 patients in group 1 and 2, respectively, had a high TMB of ≥10 mutations/megabase. In group 1 median PFS was 4.3 months for high, compared with 2.9 months for low TMB (HR 0.35, 95% CI 0.10–1.23; log-rank PD-L1 expression was available for 13... | PMC10403555 |
Detailed overview of the qualifying and co-occurring mutational profile for individual patients. | cancer histotype, tumour, TTP | TTP, TUMOUR | Includes select clinical outcomes—best response, progression-free survival ≥ 6 months, time to progression 2 to time to progression 1 ratio, TTP2/TTP1 ≥ 1.3) by treatment group; clinical parameters—cancer histotype, no. of prior lines of treatment, prior platinum; and biomarkers of interest—genomic alteration type, tum... | PMC10403555 |
Discussion | histotype-based, cancers, toxicity, tumours, cancer, TTP, high-grade glioma, cancer deaths, tumour, gallbladder cancers, cancer histotypes, cholangiocarcinoma | CANCERS, PERIVASCULAR EPITHELIOID CELL TUMOUR, ADVERSE EVENTS, GALLBLADDER ADENOCARCINOMA, DISEASE, TUMOURS, METASTATIC CHOLANGIOCARCINOMA, CANCER, RELAPSED OVARIAN CANCER, TUMOUR, NEUROENDOCRINE CARCINOMA, GALLBLADDER CANCERS, TTP, CHOLANGIOCARCINOMA | In this signal-seeking trial, 14 of 48 patients (29%) achieved either an OTR or a favourable TTP ratio. This encouraging result fulfils the original co-primary endpoint of objective response and TTP2/1 >1.3.O + D demonstrates a signal of clinical activity with a PFS6 rate of 35% (group 1) and 38% (group 2) across a ran... | PMC10403555 |
Conclusion | cancer | CANCER | In sum, this study demonstrates a modest signal of activity for olaparib and durvalumab in understudied cancer populations. Clinical benefit was greatest amongst patients with | PMC10403555 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41416-023-02311-0. | PMC10403555 | ||
Acknowledgements | The authors thank all study participants and their families. We kindly acknowledge Astra Zeneca for funding and provision of olaparib and durvalumab for the trial. | PMC10403555 | ||
Author contributions | AJ, DT, MB and LS contributed to the conceptualisation and development of the trial. MK, TC, CB, US, ST, FL and DT contributed to the correlative science within this manuscript. ST, MK, FL, DE, CL, JS, AJ and DT contributed to the implementation, investigation and clinical trial analysis. JG, FL, ST, MK, MB, PM, AJ and... | PMC10403555 |
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