Patient Withdrew Research Articles

Feasibility of the TARGET-EFT trial in frail and pre-frail cardiovascular inpatients

Abstract Funding Acknowledgements Type of funding sources: None. Background Older adults are at risk for hospital-acquired disability and deconditioning, often leading to the "post-hospitalization syndrome" of accelerated functional decline. We hypothesized that this syndrome could be prevented by a pragmatic multi-faceted intervention, and now report the initial experience and feasibility of our ongoing randomized clinical trial. Methods Patients admitted to the cardiovascular ward at a single academic center are screened with the Essential Frailty Toolset (EFT). Those ≥65 years with frailty (EFT: 3-5) or pre-frailty (EFT: 1-2) are eligible for the TARGET-EFT trial, in which they are randomly allocated to usual care or intervention. The intervention is targeted such that patients with physical weakness receive supervised exercise sessions (in addition to clinically-indicated physiotherapy), those with cognitive impairment receive stimulation activities, those with iron deficiency anemia receive intravenous iron sucrose, and those with malnutrition-related hypoalbuminemia receive protein supplements. The outcome is a composite score representing mobility, disability, activity, discomfort, and mood (EQ-5D-5L) ascertained by a blinded observer on the day of discharge and at 30 days post-hospitalization. Results To date, 77 out of a planned 144 patients have been randomized. The most common reasons for exclusion are age <65 years, expected discharge within <3 days and patient refusal. The median age is 80 years and length of stay is 8 days. In each group, 1 patient withdrew and 1 died. There were no intervention-related adverse events. Of the 39 intervention patients, 36 qualified for exercise and received an average of 6 sessions (46% of sessions were deferred because patients were away for tests, were bedrest post-procedures, or refused), 18 received cognitive stimulation, 15 received intravenous iron sucrose, and 16 received protein supplements. Conclusion The TARGET-EFT intervention is feasible and appears safe for frail and pre-frail patients hospitalized with acute cardiovascular disease. Given that nursing staff, physiotherapists, nutritionists and clinicians already address basic cognitive orientation, mobilization and nutritional/iron supplementation needs, it appears that adding targeted interventions for patients’ specific frailty deficits is feasible when shared amongst allied health professionals.

The Efficacy of the Dyson Air Purifier in Improving Asthma Control: Protocol for a Single-Center, Investigator-Led, Randomized, Double-Blind, Placebo-Controlled Trial.

BackgroundIndoor air quality has been shown to influence asthma control and outcomes. Air purifiers and high-efficiency particulate air filtration devices can improve indoor air quality by reducing the indoor levels of air pollution and allergens. However, the influence of this improved indoor air quality on asthma control remains unclear; hence, randomized controlled trials are needed to further elucidate this phenomenon.ObjectiveThis study aims to investigate the effect of reducing the levels of allergens and pollutants in the bedroom and living room through the use of Dyson air purifiers (Dyson Pure Cool) on asthma control.MethodsThis is an 18-month long, investigator-led, randomized, double-blinded, placebo-controlled, single-center trial. Subjects will be randomized in a 1:1 ratio to active or placebo Dyson filters. The primary outcome is the change in the scores of Asthma Control Questionnaire 6 and Asthma-specific Quality of Life Questionnaire from baseline. Secondary outcomes include changes in lung function (forced expiratory volume in one second, forced expiratory volume in one second/forced vital capacity ratio, and midexpiratory flows), peak expiratory flow measurements, airway hyperresponsiveness (assessed by methacholine bronchial challenge), fractional exhaled nitric oxide, and indoor air pollutant levels. The sample size will be 50 subjects, and all subjects will have a confirmed diagnosis of mild persistent to moderate persistent asthma along with an Asthma Control Questionnaire 6 score of >1.5.ResultsThis study was approved by the West Midlands Research Ethics Committee (18/WM/0277). The study results will be published in peer-reviewed scientific journals; presented at relevant scientific conferences; and shared in plain English with participants in our newsletters, in our clinics, and via the David Hide Asthma and Allergy Research Centre website. Our trial began in September 2019 and is expected to end in August 2021.ConclusionsThis is a double-blinded, placebo-controlled, randomized, investigator-led study to investigate the efficacy of a novel air purifier in improving asthma control in adults. The trial period of 18 months will facilitate the collection of robust data and will therefore generate clear signals. However, this extended trial duration may lead to patient withdrawal. Furthermore, this trial is conducted at a single center and in a location with a homogenous cohort of people, which may affect translatability. Nonetheless, it is hoped that the findings of this trial may help further inform clinicians regarding the utility of this novel device as an adjunct in asthma care.Trial RegistrationClinicalTrials.gov NCT04729530; https://clinicaltrials.gov/ct2/show/NCT04729530International Registered Report Identifier (IRRID)DERR1-10.2196/28624

Apixaban vs. warfarin in patients with left ventricular thrombus: a prospective multicentre randomized clinical trial‡.

Current guidelines recommend anticoagulation with a vitamin K antagonist to treat left ventricular (LV) thrombus after myocardial infarction (MI). Data on the use of direct oral anticoagulants (DOACs) in this setting are limited. The aim of the study was to assess the efficacy of apixaban vs. warfarin in treating LV thrombus after MI. We conducted a prospective, randomized, multicentre open-label clinical trial including patients with LV thrombus detected by 2D transthoracic echocardiography 1-14 days after acute MI. Thirty-five patients were enrolled in three medical centres; 17 patients were randomized to warfarin and 18 patients to apixaban. The primary outcome was the presence and size of LV thrombus 3 months after initiation of anticoagulation. Secondary outcomes were major bleeding, stroke or systemic embolism, re-hospitalization, and all-cause mortality. Mean LV thrombus size at enrolment was 18.5 mm×12.3mm in the warfarin group and 19.9 mm×12.4mm in the apixaban group (P=NS). Thirty-two patients completed 3 months follow-up. In the warfarin group, two patients withdrew, and in the apixaban group one patient died. Thrombus completely resolved in 14 of 15 patients in the warfarin group and in 16 of 17 patients in the apixaban group (P=NS and P=0.026 for non-inferiority). Two patients had major bleeding in the warfarin group, while no major bleeding events were recorded in the apixaban group. There was one stroke in the warfarin group and one death in the apixaban group. Our results suggest that apixaban is non-inferior to warfarin for treatment of patients with LV thrombus after acute MI with a 20% non-inferiority margin.

Safety of PSMA-Targeted Molecular Radioligand Therapy with 177Lu-PSMA-617: Results from the Prospective Multicenter Phase 2 Trial RESIST-PC (NCT03042312).

The purpose of this analysis was to report the safety evaluation of 177Lu-PSMA-617 derived from the cohort of 64 patients exposed to 177Lu-PSMA-617 in the RESIST-PC trial NCT03042312 Methods: RESIST-PC was a prospective multicenter phase 2 trial. Patients with progressive metastatic castration-resistant prostate cancer after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, sufficient PSMA expression by PSMA PET, and no PSMA-negative soft-tissue lesions were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq per cycle) and received up to 4 cycles every 8 wk. The primary safety endpoint was assessed by collecting and grading adverse events using the Common Terminology Criteria for Adverse Events. Patients were followed until disease progression, death, serious or intolerable adverse events, study termination by sponsor, patient withdrawal, lost to follow-up, or 24 mo after the first cycle. Results: The study was closed at enrollment of 71 of 200 planned patients because of sponsorship transfer. A total of 64 (90.1%) patients received at least 1 cycle of 177Lu-PSMA-617: 28 (36%) in arm 1 (6.0 GBq) and 41 (64%) in arm 2 (7.4 GBq). There were 10 (43.5%), 19 (46.5%), and 29 (45.3%) patients who completed 4 cycles of 177Lu-PSMA-617 in the 6.0-GBq arm, 7.4-GBq arm, and overall, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade in the 6.0-GBq arm, the 7.4-GBq arm and overall, were dry mouth (47.8%; 63.4%; 57.8%, respectively), fatigue (56.5%; 51.2%; 53.1%, respectively), nausea (52.2%; 43.9%; 46.9%, respectively), and diarrhea (13.0%; 31.7%; 25.0%, respectively). Frequencies of all other TEAEs were comparable among the 2 groups (within 10% difference). Serious possibly drug-related TEAEs were reported for 5 (7.8%) patients overall (none were considered as probably or definitely related to treatment): 1 subdural hematoma grade 4, 1 anemia grade 3, 1 thrombocytopenia grade 4, 1 gastrointestinal hemorrhage grade 3, and 1 acute kidney injury grade 3. There were no clinically significant changes in vital signs in electrocardiograms in the 2 treatment groups. No trend to creatinine increase or increasing frequency of shifts from normal to abnormal over time for any hematologic parameter was noted. Conclusion:177Lu-PSMA-617 was safe and well-tolerated at 6.0 and 7.4 GBq per cycle given at 8-wk intervals with side effects easily managed with standard medical support. With established safety, further clinical trials applying individualized dosimetry and testing different 177Lu-PSMA-617 administration schemes (activity levels, time intervals) are needed to optimize tumor dose delivery and treatment efficacy.

Long-term safety of adjunctive cenobamate in patients with uncontrolled focal seizures: Open-label extension of a randomized clinical study.

SummaryObjectiveThis study was undertaken to examine long‐term (up to 7.8 years) retention rate, safety, and tolerability of the antiseizure medication (ASM) cenobamate as adjunctive treatment in the open‐label extension (OLE) of study YKP3089C013 (C013; ClinicalTrials.gov: NCT01397968).MethodsPatients who completed the 12‐week, multicenter, multinational, double‐blind, randomized, placebo‐controlled C013 study, which examined adjunctive cenobamate treatment of adults with uncontrolled focal seizures, were eligible to enroll in the OLE. During the OLE, dose adjustments of cenobamate and concomitant ASMs were allowed. Safety assessments included frequency of treatment‐emergent adverse events (TEAEs) and serious TEAEs, TEAE severity, and TEAEs leading to discontinuation. Probability of patient continuation in the OLE was examined using a Kaplan–Meier analysis.ResultsOne hundred forty‐nine patients entered the OLE (median duration of cenobamate treatment = 6.25 years). As of the data cutoff, 57% of patients (85/149) remained in the OLE (median treatment duration = 6.8 years, range = 6.4–7.8 years). The median modal daily cenobamate dose was 200 mg (range = 50–400 mg). The probability of treatment continuation at 1–6 years of cenobamate treatment was 73%, 67%, 63%, 61%, 60%, and 59%, respectively. Among patients who continued at 1 year (n = 107), the probability of continuing at Years 2–5 was 92%, 87%, 83%, and 82%. The most common discontinuation reasons were patient withdrawal (19.5%, 29/149), adverse event (10.1%, 15/149), and lack of efficacy (5.4%, 8/149). TEAEs leading to discontinuation in 1% or more of patients were fatigue (1.3%, 2/149), ataxia (1.3%, 2/149), and memory impairment or amnesia (1.3%, 2/149). Dizziness (32.9%, 49/149), headache (26.8%, 40/149), and somnolence (21.5%, 32/149) were the most frequently reported TEAEs and were primarily mild or moderate in severity.SignificanceLong‐term retention in the C013 OLE study demonstrated sustained safety and tolerability of adjunctive cenobamate treatment up to 7.8 years in adults with treatment‐resistant focal seizures taking one to three ASMs.

Thalidomide and Dexamethasone Maintenance after Autologous Stem Cell Transplantation in Newly Diagnosed Korean Multiple Myeloma Patients: A Prospective Multi-Center Study in Asia

BackgroundMaintenance is a part of standard practice in multiple myeloma patients receiving induction followed by autologous stem cell transplantation (ASCT). Various regimens including thalidomide, lenalidomide and proteasome inhibitor are used as maintenance treatment. However, few prospective trials have been performed evaluating maintenance treatment in Asian myeloma patients. In this prospective multi-center trial, we evaluated the efficacy and toxicity of thalidomide-based maintenance therapy in Korean myeloma patients.MethodsWe conducted an open-label, prospective, multicenter phase II study. Patients with newly diagnosed multiple myeloma who underwent induction followed by ASCT were enrolled. Patients should not have refractoriness to previous thalidomide if the drug is included in induction regimen, and should have achieved at least partial response (PR) after ASCT. Patients received maintenance treatment of 100mg thalidomide daily for 28 days and 40mg dexamethasone for 4 days. The maintenance therapy was continued for one year unless there were disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was 1-year event-free-survival (EFS). Progression free survival (PFS), overall survival (OS), drug tolerability and safety were also evaluated.ResultsA total of 43 patients were enrolled. One-year EFS rate was 60.47% (95% confidence interval (CI), 44.34-73.26%). Progression-free survival (PFS) was 86.05% at 1-year and 72.09% at 2-year. Overall survival (OS) at 1-year and 2-year was 90.70% and 88.37%, respectively. Among 21 patients who did not acquire complete remission (CR) after ASCT, 4 patients reached CR after maintenance therapy. The maintenance treatment was discontinued in 15 patients (34.9%). The most common cause was adverse events (6 patients) followed by disease progression (4 patients). Rest of the patients terminated the treatment by patient's withdrawal (3 patients) and investigator's decision (2 patients). In each cycle, up to 23.3% of patients experienced dose reduction or delayed medication. Two leading causes of the schedule change were the adverse event and physician's decision. Grade 3 or 4 hematologic adverse events (AE) was upper respiratory infection (20 patients, 46.5%) followed by peripheral neuropathy (19 patients, 44.2%). Among the patients with neuropathy, 2 patients showed more than grade 3 symptom. Two patients showed serious adverse events (pneumonia and fulminant hepatitis). Thromboprophylaxis was performed in 37 patients using aspirin and one patient developed deep vein thrombosis during maintenance.ConclusionsThalidomide and dexamethasone maintenance for transplant eligible, newly diagnosed Korean multiple myeloma patients showed 1-year EFS and OS rate of 60.47% and 90.70% which is similar to the reports from western countries. Thalidomide and dexamethasone were tolerable as maintenance in Asian patients, although high hematologic toxicity draws concern. We concluded that thalidomide-based maintenance therapy is one of suitable option in Asian transplant eligible, newly diagnosed multiple myeloma patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Preliminary Results from an Ongoing Phase 1/2 Study of INCB053914, a Pan-Proviral Integration Sites for Moloney Virus (PIM) Kinase Inhibitor, in Patients with Advanced Hematologic Malignancies

Preliminary Results from an Ongoing Phase 1/2 Study of INCB053914, a Pan-Proviral Integration Sites for Moloney Virus (PIM) Kinase Inhibitor, in Patients with Advanced Hematologic Malignancies

Phase 1 Study of Lenalidomide and Ibrutinib in Combination with Rituximab in Relapsed and Refractory CLL and SLL

BackgroundAlthough effective, ibrutinib has a CR rate of 10% in relapsed/refractory CLL. Attempts to improve upon its activity include the addition of other agents. The combination of lenalidomide and rituximab has demonstrated an ORR 66%, CR 12% in this setting. Based on these data, we proposed a phase I study of rituximab, lenalidomide, and ibrutinib in relapsed/refractory CLL.MethodsPatients with previously treated CLL or SLL requiring treatment with adequate organ function, ECOG <2, and measurable disease were eligible. Patients received rituximab 375 mg/m2 Cycle 1-6 Day 1, lenalidomide as per cohort dose Cycle 1-12 Day 1-21, and ibrutinib 420 mg daily starting from Day 1 and continuing until progression or intolerance. Dose escalation used a standard 3+3 design from a starting level of lenalidomide 5 mg (DL1) and increasing to 15 mg (DL3) through 3 dose levels. Patients received allopurinol for tumor lysis prophylaxis. Aspirin was recommended for those at high risk for thrombosis. The primary endpoint was the recommended phase II doses (RP2D) of lenalidomide and ibrutinib for combination with rituximab in previously treated CLL/SLL. The secondary endpoints were safety and efficacy. Once the MTD was determined, there was to be a 10-patient expansion cohort.ResultsTwelve CLL patients were enrolled between May 2014 - January 2017: DL1 (n=3), DL2 (n=6), DL3 (n=3). Median age was 64 years (range 50-75); 83% were male, 67% had an ECOG score of 1, and 50% had Rai Stage III/IV disease. Prognostic features included: 42% del 13q, 42% trisomy 12, 25% del 11q, 8% del 17p, 67% umutated IGVH, 17% ZAP-70 expression 20%, and 50% CD38 expression > 30%. Patients had received a median of 1 prior therapy (1-7), primarily rituximab with fludarabine or bendamustine. Three pts had received lenalidomide > 2 years prior to enrollment; none had progressed on the agent. No patients had ibrutinib previously.There were 2 dose-limiting toxicities of grade 4 neutropenia at DL3, thus DL2 (L 10 mg, I 420 mg) was found to be the RP2D. Six patients withdrew from study: 1 due to progressive disease, 5 due to persistent grade 4 neutropenia despite G-CSF support. Prolonged grade 4 neutropenia occurred at all dose levels; 1 patient in DL2 was able to continue with dose reduction.Most common adverse events (all grades) were fatigue (67%), neutropenia (58%), infection (58%), thrombocytopenia (42%), edema (42%), pain (42%), rash (42%). Most common grade 3/4 adverse events were neutropenia (58%), thrombocytopenia (16%), and infection (16%). Serious adverse events included neutropenia, thrombocytopenia, hemolytic anemia, aspergillus pneumonia, rash, tumor lysis syndrome, urinary tract infection.The ORR for all patients was 66.7%; 1 patient achieved a CR. In DL1, 2 patients had stable disease and 1 patient had progressive disease. One patient in DL3 was not evaluable for response assessment as they withdrew for toxicity. The ORR at the RP2D was 100% (1 CR). Most patients achieved their best response at the first assessment of 10 weeks. At median follow-up time of 6.8 months, the median time on treatment was 6.4 mo (0.66-25+). The 12-month PFS was 91.9% (50.8-98.7%). There was no progression at the RP2D.ConclusionThe combination of rituximab, lenalidomide, and ibrutinib in relapsed/refractory CLL was associated with sustained grade 4 neutropenia, which prompted study withdrawal in several patients. It appeared to occur more frequently than previous reports with rituximab-lenalidomide (50%) or single-agent ibrutinib (30%). Preliminary ORR data of the regimen were comparable to prior reports of the rituximab-lenalidomide doublet and ibrutinib in this population. Furthermore, there was no significant improvement in CR rate. Given these findings, the study was terminated. DisclosuresUjjani:Gilead: Consultancy; Abbvie: Research Funding, Speakers Bureau; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding. Skarbnik:Genentech: Speakers Bureau; Gilead: Speakers Bureau; Abbvie: Other: Ad board, Speakers Bureau; Novartis: Speakers Bureau; Seattle Genetics: Speakers Bureau. Cheson:Celgene: Consultancy; Roche-genentech: Consultancy, Research Funding; Pharmacyclics: Research Funding.

Daratumumab in Combination with Pomalidomide and Dexamethasone for Relapsed and/or Refractory Multiple Myeloma (RRMM) Patients with ≥2 Prior Lines of Therapy: Updated Analysis of MMY1001

Daratumumab in Combination with Pomalidomide and Dexamethasone for Relapsed and/or Refractory Multiple Myeloma (RRMM) Patients with ≥2 Prior Lines of Therapy: Updated Analysis of MMY1001

Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study

Savolitinib is a selective MET tyrosine-kinase inhibitor. We investigated the activity and safety of savolitinib in patients with pulmonary sarcomatoid carcinoma and other non-small-cell lung cancer (NSCLC) subtypes positive for MET exon 14 skipping alterations (METex14-positive). We did a multicentre, single-arm, open-label, phase 2 study across 32 hospitals in China. Eligible patients were 18 years or older with locally advanced or metastatic METex14-positive pulmonary sarcomatoid carcinoma or other NSCLC subtypes, had either presented with disease progression or toxicity intolerance towards one or more standard treatments or were deemed clinically unsuitable for standard treatment, were MET inhibitor-naive, and had measurable disease. Patients received either 600 mg (bodyweight ≥50 kg) or 400 mg (bodyweight <50 kg) of oral savolitinib once daily until disease progression, death, intolerable toxicity, initiation of other anti-tumour therapy, non-compliance, patient withdrawal, or patient discontinuation. Radiographic tumour evaluation was done at baseline, every 6 weeks within 1 year of the first dose, and every 12 weeks thereafter. The primary endpoint was objective response rate, defined as the proportion of patients with confirmed complete or partial responses by independent review committee (IRC) assessment. The primary endpoint was assessed in the tumour response evaluable set, which comprised all treated patients with a measurable lesion at baseline and at least one adequate scheduled post-baseline tumour assessment or the presence of radiological disease progression, with a sensitivity analysis done in the full analysis set, which comprised all patients who received at least one dose of savolitinib. Safety was also evaluated in the full analysis set. This study is registered with ClinicalTrials.gov, NCT02897479, and recruitment is complete, with treatment and follow-up ongoing. From Nov 8, 2016, to Aug 3, 2020, 84 patients with METex14 skipping alterations were screened for eligibility, of whom 70 were enrolled, received savolitinib, and comprised the full analysis set. The IRC-assessed tumour response evaluable set comprised 61 patients. At a median follow-up of 17·6 months (IQR 14·2-24·4), the IRC-assessed objective response rate was 49·2% (36·1-62·3; 30 of 61 patients) in the tumour response evaluable set and 42·9% (95% CI 31·1-55·3; 30 of 70 patients) in the full analysis set. All 70 patients reported at least one treatment-related adverse event. Treatment-related adverse events of grade 3 or more occurred in 32 (46%) patients, the most frequent of which were increased aspartate aminotransferase (n=9), increased alanine aminotransferase (n=7), and peripheral oedema (n=6). Treatment-related serious adverse events occurred in 17 (24%) patients, the most common being abnormal hepatic function (n=3) and hypersensitivity (n=2). One death due to tumour lysis syndrome in a patient with pulmonary sarcomatoid carcinoma was assessed to be probably related to savolitinib by the investigator. Savolitinib yielded promising activity and had an acceptable safety profile in patients with pulmonary sarcomatoid carcinoma and other NSCLC subtypes positive for METex14 skipping alterations. Savolitinib could therefore be a novel treatment option in this population. Hutchison MediPharma and AstraZeneca. For the Chinese translation of the abstract see Supplementary Materials section.

Stability of early anterior open bite treatment: a 2-year follow-up randomized clinical trial.

This 2-year-follow up study compared and evaluated the stability of early anterior open bite (AOB) treatment based on different appliances. Children from 7 to 10 years with Angle Class I, AOB larger than 1.0 mm and fully erupted maxillary and mandibular permanent central incisors were eligible. The initial sample was 99 patients distributed, by simple randomization, into four groups: BS (bonded spurs), CC (chincup), FPC (fixed palatal crib) and RPC (removable palatal crib). Cephalometric analysis was performed at baseline (T1), final (T2) and 2-year post-treatment (T3) by taking the overbite measurements as the main outcome. Blinding was possible to cephalometric analysis. At T3, with dropouts, there were 63 individuals, being BS (n=15; overbite 0.19 mm; 11.54 years; 10 female (F)/5 male (M)); CC (n=11; overbite -0.19 mm; 11.41 years; 8 F/3 M); FPC (n=21; overbite 1.23 mm; 11.44 years; 15 F/6 M) and; RPC (n=16; overbite 0.73 mm; 11.67 years; 6 F/10 M). Changes in dentoskeletal variables and breaking deleterious oral habits during the follow up were statically analyzed with p<.05. Mandibular skeletal linear measurements and vertical dental components have gradually increased with age, manly at pubertal growth spurt and at the establishment of permanent dentition after treatment. Incisor teeth extrusion had impact on AOB correction and stability in 4 groups, which recorded a 1.15 mm-improvement of overbite after treatment (T3-T2). The experimental appliances were effective with stable results, being FPC the device recorded the highest AOB correction and the lowest patient withdrawal rate.

The potential treatment of antroquinonol in adult patients with relapsed acute myeloid leukemia (AML).

e19001 Background: The prognosis of relapsed acute myeloid leukemia (R/R AML) remains poor and the management is challenging. Despite the increasing availability of targeted agents, the lower responses still represent a major obstacle to overcome. Antroquinonol is an isoprenyltransferase inhibitor with antitumor activity in vitro and xenograft models of AML. Our aim is to evaluate hematopoietic recovery with Antroquinonol in this phase IIa study. Here, the results from our phase IIa trial demonstrate the safety, tolerability, and activity of Antroquinonol in patients with relapsed AML. Methods: GHAML-2-001 is a phase IIa, open-label study in adult patients with relapsed acute myeloid leukemia or at initial diagnosis when no intensive treatment is possible. Antroquinonol 200 mg BID was administered in a 28-day cycle (up to six cycles). The primary endpoint is hematologic response rate. Secondary endpoints consist of 4-week survival, 24-week survival, duration of hematologic response and transfusion independence, and the response rates. Therapy was continued for as long as tolerated and there was continuing evidence of therapeutic benefit in the opinion of the investigator. Treatment response was assessed by the International Working Group (IWG) response criteria after each cycle. Results: Twelve eligible patients had a median age of 62.5 years (range, 42-69; 6 males, 6 females) and the whole process was conducted between March 2019 and February 2020. Of the two patients who did not complete the therapy period were due to the patient's decision to withdraw: One patient withdrew on day 7 and the other one withdrew on day 49. Among other ten patients who finished all six cycles (168 days), Antroquinonol showed excellent safety and favorable tolerability. At the end of the treatment, the rate of complete remission (CR/CRi) after 6-completed cycles was 50% (5/10) and the 24-week survival rate was 100%. Transfusion independence was achieved in 8 (80%) of 10 transfusion independence evaluable patients at the end of the 6th cycle treatment. Conclusions: In high-risk relapsed AML patients, orally administered Antroquinonol induced CRs and was well tolerated. This significant result suggests the potential of Antroquinonol for the therapy of this underserved population. Clinical trial information: NCT03823352. Clinical trial information: NCT03823352.

KRYSTAL-12: A randomized phase 3 study of adagrasib (MRTX849) versus docetaxel in patients (pts) with previously treated non-small-cell lung cancer (NSCLC) with KRASG12C mutation.

TPS9129 Background: Despite significant advances in chemotherapy and immunotherapy for advanced NSCLC, the majority of pts ultimately develop progressive disease associated with poor outcomes. KRAS is a key mediator of the RAS/MAPK signaling cascade that promotes cell growth and proliferation. KRASG12C mutations occur in 14% of NSCLC (adenocarcinoma), and mutations in KRAS are associated with a poor prognosis. Although KRAS has historically been undruggable, recent research into the development of agents that specifically bind mutant KRAS has led to the development of direct inhibitors of KRASG12C. Adagrasib, an investigational agent, is a potent, covalent inhibitor of KRASG12C that irreversibly and selectively binds to and locks KRASG12C in its inactive state. Adagrasib was optimized for favorable pharmacokinetic (PK) properties, including oral bioavailability, long half-life (̃24 h), and extensive tissue distribution. Initial results have demonstrated encouraging antitumor activity and tolerability of adagrasib monotherapy in pts with NSCLC harboring a KRASG12C mutation. Methods: KRYSTAL-12 is a multicenter, randomized Phase 3 study evaluating the efficacy of adagrasib (600 mg BID) vs docetaxel in pts with advanced NSCLC harboring a KRASG12C mutation who have progressed during or after treatment with a platinum-based regimen and an immune checkpoint inhibitor. The study is designed to demonstrate improvement in the dual primary endpoints of progression-free survival (PFS) and overall survival (OS). Secondary endpoints include safety, objective response rate (ORR) per RECIST 1.1, duration of response (DOR), plasma PK parameters of adagrasib, and patient-reported outcomes (PROs). The study will also explore correlations between gene alterations (at baseline and upon development of treatment resistance) and efficacy. Approximately 450 patients will be randomized in a 2:1 ratio to receive adagrasib or docetaxel and will be stratified by region (United States/Canada vs other countries) and sequential vs concurrent administration of prior platinum-based chemotherapy and anti–PD-1/PD-L1 antibody. The planned sample size is sufficiently powered for the hypothesized treatment effect of the endpoints. Pts will receive study treatment until disease progression, unacceptable adverse events, investigator decision to terminate treatment, or patient withdrawal. This study is currently enrolling and will be open at sites in the United States, Europe, and Asia. Clinical trial information: NCT04685135.

DREAM3R: Durvalumab with chemotherapy as first-line treatment in advanced pleural mesothelioma—A phase 3 randomized trial.

TPS8586 Background: Standard first line treatment for unresectable malignant pleural mesothelioma (MPM) is platinum-based chemotherapy with pemetrexed. Two recent, single-arm, phase 2 trials (DREAM1 and PrE05052) combining the PD-L1 inhibitor durvalumab and standard first line cisplatin and pemetrexed (CP) exceeded pre-specified criteria for proceeding to phase 3. DREAM3R aims to determine the effectiveness of adding durvalumab to first line CP chemotherapy in advanced MPM. Methods: Treatment-naïve patients with advanced MPM will be randomised (2:1) to EITHER durvalumab 1500 mg every 3 weeks plus doublet chemotherapy (cisplatin 75 mg/m2 and pemetrexed 500 mg/m2) every 3 weeks for 4-6 cycles, followed by durvalumab 1500 mg every 4 weeks until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4-6 cycles, followed by observation. The target sample size is 480 patients (320 durvalumab, 160 control) recruited over 27 months, with follow up for an additional 24 months. This provides over 85% power if the true hazard ratio for overall survival is 0.70, with 2-sided alpha of 0.05, assuming a median survival of 15 months in the control group. Key inclusion criteria: MPM of any histological subtype; measurable disease as per RECIST 1.1 modified for mesothelioma (mRECIST 1.1) without prior radiotherapy to these sites; ECOG PS 0-1; and, adequate hematologic, renal, and liver function tests. Key exclusion criteria: prior systemic anticancer treatment for MPM; diagnosis based only on cytology or fine needle aspiration biopsy; contraindication to immunotherapy; and conditions requiring immunosuppressives or corticosteroids. Stratification: Age (18-70 years vs. &gt; 70), sex, histology (epithelioid vs. non-epithelioid), and region (USA vs. ANZ). The primary endpoint is overall survival. Secondary endpoints include progression-free survival; objective tumour response (by mRECIST 1.1 and iRECIST); adverse events; health-related quality of life; and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DREAM and PrE0505 studies, PD-L1 expression, tumour mutation burden, nuanced genomic characteristics, and HLA subtypes) in tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma. Clinical trial information: NCT04334759. and ACTRN 12620001199909.

Bevacizumab biosimilar (MB02) and reference bevacizumab in patients with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC) (STELLA study): Multiple Imputation analysis.

e15003 Background: Stella Trial is a phase III, multinational, double-blind and randomized study to confirm clinical similarity between MB02 and EU-bevacizumab in patients with stage IIIB/IV no squamous NSCLC. 627 subjects with newly diagnosed or recurrent stage IIIb/IV NSCLC were randomized 1:1 to receive either MB02 or EU-bevacizumab plus chemotherapy (paclitaxel and carboplatin) every 3-week cycle for six cycles (week 18) followed by MB02/bevacizumab in blinded monotherapy until disease progression, treatment intolerance, death, patient withdrawal or end of study (w52). An approach targeting the MI of the continuous sum of target diameters (mm), and subsequent categorization of Overall Response (OR) was performed as sensitivity analysis for the assessment of the primary endpoint. Multiple Imputation (MI) has emerged as a credible method to assess the effects of missing data (MD), an inescapable problem with a potential ability to undermine research results' strength and validity in a clinical study, providing the user with a valuable toolset to sufficiently account for the varying types of MD and appropriately adjust the assumptions. Methods: The primary endpoint of the study was Objective Response Rate (ORR) at week 18 per an Independent Radiological Committee (IRC) in the Intention to treat set (ITT). The ORR was analysed with a Cochran-Mantel-Haenszel model, including the stratification factors of sex, smoking status, disease diagnosis and disease stage, comparing the stratified estimates risk difference (RD). In addition, these results were analysed implementing a pattern-mixture MI process accounting for missing at random (MAR) and missing not at random (MNAR) data based on the sum of target diameters in subjects without tumour response data or falling into the categories NonCR/NonPD or non-evaluable (NE). Results: The clinical equivalence of MB02 with EU-bevacizumab is demonstrated by the efficacy data provided through the primary endpoint and the MI sensitive analysis applied. The MI (MAR and MNAR) represents an added value that supports the biosimilarity of MB02 and EU-bevacizumab. The results for the primary analysis of the RD in ORR at w18 in the ITT set were entirely contained within the boundaries of predefined margins (±12): -4.02 [95% CI: -11.76 to 3.71]). Under MI, the ORR RD showed similarity at 95% CIs (-1.92; 95% CI: -10.02 to 6.19) and using the multiple imputations for subjects without tumour response data (missing, NonCR/NonPD or NE), the ORR RD was -2.22 with 95% CI of (-10.54 to 6.10) at w18 in the ITT. Conclusions: The clinical equivalence of MB02 with EU-bevacizumab is demonstrated by the efficacy data provided through the primary endpoint and the MI sensitive analysis applied. The MI (MAR and MNAR) represent an added value that supports the biosimilarity of MB02 and EU-bevacizumab. Clinical trial information: NCT03296163.

Combination of famitinib with camrelizumab plus nab-paclitaxel as first-line treatment for patients with immunomodulatory advanced triple-negative breast cancer (FUTURE-C-PLUS): A prospective, single-arm, phase 2 study.

1007 Background: Camrelizumab (anti-PD-1 antibody) and nab-paclitaxel (nab-P) have demonstrated promising anti-tumour activity in patients with immunomodulatory (IM) subtype metastatic triple negative breast cancer (TNBC), with 52.6% of ORR observed in heavily pretreated patients in our previous umbrella trial (FUTURE). As antiangiogenic agents were known to enhance the response to immune checkpoint inhibitors, we assessed the efficacy and safety of novel triplet combination of famitinib (tyrosine kinase inhibitor targeting VEGFR-2, PDGFR and c-kit), camrelizumab and nab-paclitaxel in patients with IM subtype advanced TNBC. Methods: In this prospective, single-arm, phase 2 study, eligible patients were 18-70 years and had treatment-naive IM subtype unresectable locally advanced or metastatic TNBC. IM subtype was defined as CD8+ by immunohistochemistry. Eligible patients received camrelizumab (200 mg iv, d1, 15, q4w) with nab-P (100 mg/m2 iv, d1, 8, 15, q4w) and famitinib (20 mg po qd, d1-28, q4w). Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. In the absence of intolerable toxicity, nab-P was to be administered for a minimum of 6 cycles. Primary endpoint was objective response rate according to RECIST v1.1. We explored the predictive biomarkers using targeted sequencing with a 484-gene panel. Results: From Oct 2019 to Oct 2020, 48 patients were enrolled. Confirmed objective responses were achieved in 39 (81.3%; 95% CI 70.2%-92.3%) of 48 patients in the intention-to-treat population and in 39 (84.8%; 95% CI 74.4%-95.2%) of 46 patients in the per-protocol population. Median time to response was 1.8 months (95% CI 1.8-2.0 months). With a median follow-up of 9.0 months, progression-free survival (PFS) and duration of response data were not mature. Thirty patients (62.5%) are still on the study treatment. The 9-month PFS rate was 60.2% (95% CI, 43.2% to 77.3%). Grade 3 or 4 adverse events were neutropenia (33.3%), anaemia (10.4%), febrile neutropenia (10.4%), thrombocytopenia (8.3%), hypertension (4.2%), hypothyroidism (4.2%), proteinuria (2.1%), septicemia (2.1%) and immune related myocarditis (2.1%). Adverse events that led to the discontinuation of any agent occurred in 6.3% of the patients. Two patients had treatment-related serious adverse events. No treatment-related deaths were reported. Biomarker analysis showed that somatic mutations of GSK3A may have the potential to predict immunotherapy response. Conclusions: Addition of famitinib to camrelizumab and nab-paclitaxel showed promising antitumour activity as first-line therapy with manageable toxicity profile for IM subtype advanced TNBC patients. Results from ongoing randomized controlled trial FUTURE-SUPER (NCT 04395989) are eagerly awaited. Clinical trial information: NCT04129996 .

Subcutaneous daratumumab (DARA SC) plus lenalidomide versus lenalidomide alone as maintenance therapy in patients (pts) with newly diagnosed multiple myeloma (NDMM) who are minimal residual disease (MRD) positive after frontline autologous stem cell transplant (ASCT): The phase 3 AURIGA study.

TPS8054 Background: DARA, a human anti-CD38 IgGκ monoclonal antibody, is approved in many countries as monotherapy in relapsed/refractory MM (RRMM) and in combination with standard of care (SoC) in RRMM and NDMM. However, no clinical studies have yet compared DARA maintenance versus SoC maintenance. The ongoing phase 3 AURIGA study will evaluate the addition of DARA to lenalidomide maintenance among pts with NDMM who are MRD positive after SoC induction and ASCT. The primary endpoint is the conversion rate to MRD negativity after 1 year of maintenance therapy. Methods: This open-label, multicenter, randomized phase 3 study will enroll approximately 214 pts in the United States aged 18-79 years with NDMM who receive ≥4 cycles of induction followed by ASCT. Pts must enroll within 6 months of ASCT, be naïve for anti-CD38 treatment, have a very good partial response or better per IMWG criteria, and be MRD positive at a threshold of 10–5 by next generation sequencing (NGS) within 30 days of screening. Pts will be stratified by cytogenetic risk (high vs standard/unknown) and randomized 1:1 to 28-day cycles of lenalidomide maintenance (10 mg PO; D1-28 [dose increasing to 15 mg if tolerated]) ± DARA SC (DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE® drug delivery technology, Halozyme, Inc., San Diego, CA, USA; QW Cycle 1-2, Q2W Cycles 3-6, Q4W C7+). Treatment will continue for up to 36 cycles or until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint is MRD conversion rate after 12 months of maintenance treatment, defined as the proportion of pts who achieve MRD negativity (10–5) by NGS. Additional MRD assessments occur after 18, 24, and 36 months of maintenance. While MRD negativity is associated with improved long-term outcomes for pts with MM and is an emerging, validated prognostic factor, this study is among the first to use MRD negativity as a primary study endpoint. Importantly, MRD negativity allows for earlier efficacy assessment than traditional endpoints such as progression-free survival (PFS) and overall survival (OS). Secondary endpoints include overall MRD conversion rate at any time, sustained MRD negativity lasting ≥12 months, PFS, OS, response rates, duration of complete response, changes in health-related quality of life, and safety. Due to the COVID-19 pandemic, this study has been amended to improve enrollment access by allowing up to 12 months from start of induction therapy to ASCT to mitigate against ASCT delays and to allow greater flexibility for screening and laboratory assessments. Clinical trial information: NCT03901963.

Efficacy of HX008 in high microsatellite instability/mismatch repair–defificient (MSI-H/dMMR) solid tumors: Results from a multicenter phase II open-label study.

2572 Background: The subsequent treatment choices are limited for the patients with advanced solid tumors who had failed the standard therapies. PD-1 blockade monotherapy demonstrated robust antitumor activity in patients with MSI-H/dMMR. The aim of this study is to identify the efficacy and safety of HX008, an anti-PD-1 monoclonal antibody, in patients with advanced MSI-H/dMMR solid tumors. Methods: Eligible patients were age ≥18 years with histologically/cytologically confirmed advanced MSI-H/dMMR solid tumors, who have failed at least one line of standard systemic therapy. MSI-H/dMMR status was assessed centrally. Patients received HX008 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed 9 weeks after the first treatment, then every 6 weeks for the first year of therapy, and every 12 weeks thereafter. The primary end point was objective response rate (ORR) per RECIST1.1. Results: One hundred patients were enrolled from October 2018 to December 2020, with a median age of 53 (range 20-74) years. All of the patients were ≥ second-line patients. The most common cancer types were colorectal cancer (N=74) and gastric cancer (N=10). Median follow-up is 8.97 (range 0.03-25.53) months at the time of data cutoff. Among 86 patients who had reached the initial response evaluation, there were 8 CR, 33 PR, 24 SD, 17 PD and 4 NE. ORR was 47.67% (95%CI 36.79%-58.73%), and DCR was 75.58% (95%CI 65.13%-84.20%). ORR and DCR for the 66 colorectal cancer patients were 50% (95%CI 37.43-62.57%) and 75.76% (95%CI 63.64-85.46%). Median PFS was not reached (95%CI 6.18-NR) for all enrolled patients, while the 6-month and 12-month PFS rates were 62.66% (95%CI 50.98%-72.31%) and 52.70% (95%CI 39.96%-63.94%), respectively. Median OS was not reached. Treatment-related adverse events occurred in 77 patients (77%). Twelve patients (12%) had grade 3 or 4 treatment-related adverse events and there were no grade 5 treatment-related adverse events. The grade 3 or 4 treatment-related adverse events with incidence &gt;1% included anemia (2%) and leukopenia (2%). Immune-related adverse events were observed in 15 patients (15%), including hypothyroidism in 9 patients (all were grade 1-2), and hepatitis, hyperglycemia, myocarditis, creatin kinase/creatin kinase MB increased, hypopigmentation of the vulva, rash, each in 1 patient. Conclusions: HX008 as a ≥second-line therapy showed promising efficacy and a manageable safety profile in patients with MSI-H/dMMR advanced solid tumors. Clinical trial information: NCT03704246.

Patient-reported symptoms, functioning, and quality of life (QoL) in patients treated with cemiplimab monotherapy for first-line treatment of advanced NSCLC with PD-L1 ≥ 50%: Results from EMPOWER-Lung 1 study.

9078 Background: Cemiplimab, a PD-1 inhibitor, improved survival and progression-free survival vs platinum doublet chemotherapy (chemo) in patients (pts) with advanced NSCLC and PD-ligand(L)1 expression ≥50% in the EMPOWER-Lung 1 Phase 3 study (NCT03088540). Since pts with advanced NSCLC have a high symptom burden that adversely impacts QoL and functioning, these outcomes were evaluated as secondary endpoints in the clinical trial. Methods: Pts with advanced NSCLC with PD-L1 expression ≥50% and ECOG performance status ≤1 were randomized to IV cemiplimab 350 mg Q3W (n=356) or platinum doublet chemo (n=354). At baseline (BL) and day 1 of each treatment cycle (C) to C15, pts were administered the EORTC core questionnaire (QLQ-C30) and its lung cancer specific module (QLQ-LC13) to assess symptoms, functioning, and Global Health Status (GHS)/QoL. In the intent-to-treat population, mixed-effects repeated measures models were used to estimate least squares (LS) mean change from BL on all scales. Kaplan–Meier analysis estimated time to definitive deterioration, defined as worsening ≥10 points from BL observed at all subsequent time points or patient withdrawal after worsening; hazard ratios (HR) with 95% CIs estimated the likelihood of definitive deterioration. Results: BL scores showed moderate to high levels of functioning and low symptom burden. Cemiplimab-treated pts had lower likelihood of definitive deterioration vs chemo on key symptoms of dyspnea, cough, pain in chest, pain in other body parts, fatigue, nausea/vomiting, appetite loss, constipation, and diarrhea vs chemo (all P&lt;.05). Treatment-related symptoms of peripheral neuropathy and alopecia had a lower likelihood of definitive deterioration with cemiplimab vs chemo (both P&lt;.05). Cemiplimab resulted in significantly greater improvements vs chemo on all functioning scales and reduced the likelihood of definitive deterioration as indicated by HR &lt;1 (Table). GHS/QoL improvements with cemiplimab at C2 were maintained to C15; LS mean change (SE) from BL across all timepoints was 7.1 (1.0) for cemiplimab vs 1.7 (1.2) for chemo ( P&lt;.0001). Conclusions: In pts with advanced NSCLC and PD-L1 expression ≥50%, cemiplimab significantly improved GHS/QoL, functioning, and most symptoms vs chemo. Over 1 year of treatment, cemiplimab delayed worsening of key lung cancer symptoms and functioning. Clinical trial information: NCT03088540. [Table: see text]

Efficacy and safety of HLX10, a novel anti-PD-1 antibody, in patients with previously treated unresectable or metastatic microsatellite instability-high or mismatch repair-deficient solid tumors: A single-arm, multicenter, phase 2 study.

2566 Background: Microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) in cells render them susceptible to immune checkpoint blockages. This study aimed to evaluate the efficacy and safety of HLX10, a fully humanized monoclonal antibody against PD-1, in patients with unresectable or metastatic MSI-H/dMMR solid tumors who have progressed on or been intolerant to standard therapies. Methods: In this single-arm, open-label, multicenter, phase 2 study (NCT03941574), patients (18≤ age ≤75 years) with histologically/cytologically confirmed unresectable or metastatic MSI-H/dMMR solid tumors were recruited to receive 3 mg/kg HLX10 every two weeks intravenously for up to 2 years until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was objective response rate (ORR) assessed by IRRC (evaluated every 6 weeks for the first 48 weeks and every 12 weeks thereafter) per RECIST v1.1. Secondary endpoints included ORR assessed by investigators, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. All eligible patients who received at least one dose of HLX10 were included in the safety analyses. Results: As of Jan 9, 2021, 108 patients were enrolled and 68 with locally or centrally confirmed MSI-H were included in the main efficacy analysis population. Among the 68 patients, the median follow-up duration was 7.7 (range: 1.1–16.4) months and the median age was 53.0 (range: 23.0–72.0) years. MSI-H tumor types included colorectal cancer (n = 54), endometrial cancer (n = 5), gastric cancer (n = 4), breast cancer (n = 2), small intestine cancer (n = 2) and fallopian tube cancer (n = 1). IRRC and investigator assessed ORR were 38.2% (95% CI: 26.7–50.8%; 2 complete response) and 35.3% (95% CI: 24.1–47.8%) respectively in the main efficacy analysis population. Median DoR, PFS and OS have not been reached. 105 (97.2%) patients experienced treatment-emergent adverse events (TEAEs), most commonly anemia (34.3%), hypoproteinemia (27.8%) and increased aspartate aminotransferase (25.0%). 53 (49.1%) patients had grade 3 or worse TEAEs, most commonly anemia (8.3%), progressive disease (6.5%), increased γ- glutamyltransferase (5.6%) and intestinal obstruction (5.6%). 52 (48.1%) patients had immune-related adverse events (irAEs) while 10 (9.3%) had grade 3 or worse irAEs. 3 (2.8%) deaths (2 PD and 1 intestinal obstruction) that might be related to the study drug were reported. Conclusions: HLX10 provides encouraging antitumor activity with a manageable safety profile in patients with MSI-H/dMMR solid tumors who have progressed on or been intolerant to standard therapies. As an effective tissue-agnostic treatment, HLX10 possesses the potential to improve patients’ clinical outcomes. Clinical trial information: NCT03941574.