Treatment-related Events Research Articles

Absence of (sub-)acute cerebral events or lesions after electroporation ablation in the left-sided canine heart

Irreversible electroporation (IRE) is a nonthermal ablation modality. A 200-J application can create deep myocardial lesions, but gas bubbles are created at the ablation electrode. Cerebral effects of these bubbles are unknown. The purpose of this study was to investigate gas microemboli-induced brain lesions after IRE and radiofrequency (RF) ablation to the left side of the canine heart, using magnetic resonance imaging (MRI) and histopathology. In 11 canines, baseline cerebral MRI scans were performed. In 9 animals, after retrograde femoral artery access, 12 ± 4 200-J IRE applications were administered in the ascending aorta. In 2 animals, 30 minutes of irrigated 30-W RF ablation using 10-30g of contact force was applied in the left ventricle. At days 1 and 5 after ablation, MRI was repeated. The brain tissue then was histopathologically examined. All ablations and follow-up were uneventful. Intracardiac echography confirmed gas bubble formation after each IRE application. Neurologic examination was normal. MRI scans were normal in all animals at day 1 and were normal in 10 of 11 animals at day 5. In 1 animal, a single <2-mm-diameter lesion in the right temporal region could not be excluded as a small infarct or early hemorrhagic site. Histopathologic analysis of the same region showed no pathologic changes. In all other animals, gross and microscopic pathology were normal. MRI images alone or in combination with histologic follow-up did not reveal treatment-related embolic events. Gross and microscopic pathology did not reveal evidence of treatment-related embolic events. IRE seems to be a safe ablation modality for the brain.

“If you don’t have a word for something, you may doubt whether it’s even real” – how individuals with borderline personality disorder experience change

Objective: This study explored how psychological change was experienced and what treatment-related factors or events were perceived as supporting or hindering their process by individuals with borderline personality disorder. Methods: Eight BPD sufferers attended a 40-session psychoeducational group intervention at a community mental health care center. At intervention end, personal experience of meaningful change was explored in an in-depth interview and data were content-analyzed. Change in BPD symptoms was assessed by the Borderline Personality Disorder Severity Index IV interview. Results: The qualitative content analysis on subjectively perceived meaningful change yielded three core categories: (1) improved ability to observe and understand mental events, (2) decreased disconnection from emotions, emergence of new or adaptive emotional reactions and decrease in maladaptive ones, and (3) a new, more adaptive experience of self and agency. Accordingly, (1) learning and (2) normalizing emerged as the main categories of helpful treatment factors. In turn, treatment-related factors perceived as obstacles were: (1) aggression in the group, and (2) inflexibility. With respect to symptom change, four participants were considered clinically as remitted, and two showed a reliable change. Conclusions: Long-term psychoeducational group therapy seems to enhance mentalization / metacognitive functioning and promote self (or personality) integration in BPD patients.

The risks and trends of cardiac-specific mortality associated with chemotherapy or radiotherapy in a large cohort of non-elderly patients with non-small cell lung cancer.

BackgroundAnticancer treatment-related heart events is a major concern. However, the frequent occurrence time of cardiac death and the association between cardiac-specific mortality (CSM) and various lung lobes among non-elderly non-small cell lung cancer (NSCLC) patients after chemotherapy or radiotherapy (RT) are uncertain.MethodsData of patients aged 20–59 years and diagnosed with NSCLC during 1975–2014 were extracted from the Surveillance, Epidemiology and End Results (SEER) database. We divided them into four groups: no chemotherapy or RT, chemotherapy-only, RT-only and chemoradiation therapy (CRT). The Fine and Gray model was applied to evaluate the risks; the cumulative curves of CSM were established by Gray’s test. Furthermore, the forest graphs delineated the hazards of different tumor subsites to CSM as the survival time prolonged. Eventually, we analyzed and elucidated the tendency of CSM decade by decade.ResultsWe identified 121,302 patients and 3,423 died of heart diseases. In chemotherapy-only group, age, sex, race, marital status and surgery were significantly correlated to CSM while the subsite location of tumor was the key risk among RT-only patients. The hazard ratio (HR) of CSM was greatest in 2–5 years after RT (P=0.008, HR =2.30). CSMs of chemotherapy (P=0.130, HR =2.480) and CRT (P=0.028, HR =2.600) peaked in 1985–1994 and decreased sharply hereafter, whereas the CSMs of RT-only declined over time.ConclusionsThe risks of CSM after chemotherapy were similar to the common hazards of heart diseases; tumor in the left-lower lobe was a remarkable risk for patients receiving RT-only and the frequent occurrence of cardiac death was from the second year after RT. The CSMs of chemotherapy and CRT culminated in 1985–1994 and then descended; it declined all the time in RT-only group.

Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial

IntroductionWe report the final results of the phase 3 IMpower132 study evaluating atezolizumab plus carboplatin or cisplatin plus pemetrexed (APP) in patients with nonsquamous NSCLC. MethodsChemotherapy-naive patients with stage IV nonsquamous NSCLC without sensitizing EGFR or ALK genetic alterations were randomized in a one-to-one ratio to receive four or six cycles of carboplatin or cisplatin plus pemetrexed (PP) or APP every 3 weeks, followed by maintenance therapy with atezolizumab plus pemetrexed or pemetrexed alone. Co-primary end points were overall survival (OS) and investigator-assessed progression-free survival (PFS). ResultsThe intention-to-treat population included 578 patients (APP, n = 292; PP, n = 286). At the primary PFS analysis (May 22, 2018; median follow-up, 14.8 mo), APP exhibited significant PFS improvement versus PP (median = 7.6 versus 5.2 mo, stratified hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.49–0.72, p < 0.0001). OS for the APP group was numerically better but not statistically significant at the interim (May 22, 2018; median = 18.1 versus 13.6 mo, stratified HR = 0.81, 95% CI: 0.64–1.03, p = 0.0797) and final analyses (July 18, 2019; median = 17.5 versus 13.6 mo; stratified HR = 0.86, 95% CI: 0.71–1.06, p = 0.1546). The OS and PFS results favored APP versus PP across subgroups. Grade 3 or 4 treatment-related adverse events occurred in 54.6% (APP) and 40.1% (PP) of patients; grade 5 treatment-related events occurred in 3.8% and 2.9%, respectively. ConclusionsIMpower132 met its co-primary PFS end point but not its co-primary OS end point, with numerical improvement for OS in the APP arm. APP had a manageable safety profile, with no new or unexpected safety signals identified.

GCT-41. RESPONSE-BASED RADIATION THERAPY IN PATIENTS WITH NEWLY DIAGNOSED CENTRAL NERVOUS SYSTEM LOCALIZED GERMINOMA: A CHILDREN’S ONCOLOGY GROUP (COG) PROSPECTIVE PHASE 2 CLINICAL TRIAL

BACKGROUNDThe objective of stratum 2 of COG ACNS1123 was to evaluate children and young adults (3–21 years) with localized central nervous system (CNS) germinoma and investigate whether simplified pre-irradiation chemotherapy followed by response based dose-reduced whole ventricular irradiation (WVI) would maintain a high progression-free survival (PFS) while reducing long term treatment burden.METHODSPre-irradiation chemotherapy consisted of 4 cycles of carboplatin and etoposide every 21 days followed by response-based irradiation (XRT). Patients with a complete response (CR) to pre-XRT chemotherapy received 18Gy WVI + 12Gy boost to the tumor bed. Patients with partial response (PR) but less than 1.5 cm residual proceeded to 24Gy WVI + 12Gy boost. All patients were also enrolled on COG ALTE07C1 to prospectively evaluate and longitudinally model the cognitive, social and behavioral functioning.RESULTSDuring a total accrual time of 45.5 months from 05/2012 to 06/2018, 137 eligible patients were enrolled. Median age was 14.09 years (4.95–21.46), 73% were male, and 45.26% had elevated βhCG in serum and/or cerebrospinal fluid. Twenty-nine patients (21.17%) did not have tissue biopsy. Eleven patients underwent second-look surgery; 7 had mature teratoma and 4 had non-viable tumor. Eighty-one patients (59.13%) had a CR. There were 4 relapses in patients receiving 18Gy WVI + boost, but no deaths. No unexpected treatment-related events were observed. The estimated 3-year PFS was 94.4 ±2.7% among 74 evaluable subjects.CONCLUSIONThis study shows promise in XRT reduction for patients with localized CNS germinoma and CR. Long-term survival outcomes and ALTE07C1 data are being evaluated.

REGN5458, a BCMA x CD3 Bispecific Monoclonal Antibody, Induces Deep and Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

REGN5458, a BCMA x CD3 Bispecific Monoclonal Antibody, Induces Deep and Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

DREAMM-2: Single-Agent Belantamab Mafodotin (Belamaf) Effects on Patient-Reported Outcome (PRO) Measures in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

DREAMM-2: Single-Agent Belantamab Mafodotin (Belamaf) Effects on Patient-Reported Outcome (PRO) Measures in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Safety, Pharmacokinetics, and Efficacy of Olorinab, a Peripherally Acting, Highly Selective, Full Agonist of the Cannabinoid Receptor 2, in a Phase 2a Study of Patients With Chronic Abdominal Pain Associated With Crohn's Disease.

This randomized, open-label phase 2a study investigated the safety/tolerability, pharmacokinetics, and efficacy of olorinab-a highly selective, peripherally acting, full agonist of the cannabinoid receptor 2-in patients with Crohn's disease (CD) experiencing abdominal pain. Eligible subjects 18-80 years of age with quiescent to mildly active CD were randomized to receive olorinab 25 or 100 mg three times daily for 8 weeks. The primary objective was to assess safety/tolerability. Fourteen subjects received olorinab 25 mg (N = 6) or 100 mg (N = 8). Ten subjects [4 (67%) in the 25-mg group and 6 (75%) in the 100-mg group] reported a total of 34 treatment-emergent adverse events (TEAEs; 32 grade 1/2, not serious events; 2 grade 3, serious, not treatment-related events). No dose reductions or discontinuations due to TEAEs or deaths were reported. Dose-proportional increases in olorinab exposure from 25 to 100 mg were observed, with minimal accumulation at both doses. At week 8, the mean (SD) change from baseline in average abdominal pain score at peak olorinab plasma concentrations was -4.61 (1.77) in the 25-mg group (P = 0.0043) and -4.57 (2.17) in the 100-mg group (P = 0.0036). The change from baseline at week 8 in the mean (SD) number of pain-free days per week was +1.60 (2.61) in the 25-mg group and +2.33 (3.62) in the 100-mg group. No subject required pain medication on study. Patients with quiescent to mildly active CD receiving olorinab experienced mild-to-moderate adverse events and an improvement in abdominal pain scores in this study.

Final results of a dose escalation protocol of stereotactic body radiotherapy for poor surgical candidates with localized renal cell carcinoma

Background and purposeWe previously demonstrated the safety of doses up to 48 Gy in 4 fractions with stereotactic body radiotherapy (SBRT) in poor surgical candidates with localized renal cell carcinoma (RCC). In an additional expansion cohort, we aimed to assess the safety of further dose escalation to 48–60 Gy in 3 fractions. Material and methodsPatients were required to have localized RCC and be poor surgical candidates due to medical comorbidities. Dose-limiting toxicity (DLT) was defined as acute (<180 days) grade ≥3 gastrointestinal/genitourinary toxicity by CTCAEv4. Tumor response was assessed using RECIST 1.1 criteria measurements every 6 months for 3 years and optional percutaneous biopsy. ResultsGroups of 4, 4, and 3 patients received 48, 54, and 60 Gy in 3 fractions, respectively from 2012 to 2016. Median follow-up was 34.3 months. Zero DLTs were observed. Acute toxicities were limited to grade 1 fatigue and nausea in 45.5% and 18.1%. Late grade 2+ and grade 3+ possibly treatment-related events occurred in 18.1% and 9.1%, respectively. Three-year local control was 90% by RECIST 1.1 criteria. Five of 5 post-treatment biopsies in the expansion cohort were positive by Hematoxylin and Eosin staining. Three of the 5 patients with positive biopsies have been observed for 1.2–3.9 years without evidence of progression. ConclusionDose escalation to 60 Gy in 3 fractions was achieved without DLTs. Favorable local control rates were observed, and the interpretation of post-SBRT biopsies remains uncertain. Further studies comparing SBRT to percutaneous ablation for poor surgical candidates with RCC are warranted.

Continuous Remote Activity Monitoring In Head And Neck Cancer Patients Receiving Radiotherapy: An Initial Report On Patient Compliance And Utility From A Phase I Trial

The treatment of locally advanced head and neck cancer (HNC) requires multi-modality treatment and is associated with significant treatment-related toxicity. This results in burden to both patients and the healthcare system in the form of unplanned interventions. Remote activity monitoring (RAM) has been suggested to be a complementary means of identifying patients at risk, potentially providing a window for timely intervention. While previous reports have evaluated brief periods of RAM in HNC, the role of continuous RAM in HNC patients is not well defined. We evaluated the feasibility and utility of RAM in HNC patients undergoing radiotherapy (RT) or chemoradiotherapy (CRT). IRB approval was obtained (ClinicalTrials.gov Identifier: NCT03489252). Patients 18 years and older with HNC requiring RT per multi-disciplinary discussion were screened. Enrollees were provided a Fitbit Charge 3 at CT simulation (sim), instructed on use, and provided online accounts. Patients were advised to wear devices 22+ hours per day from sim to the final day of RT. Sim and treatment plans were designed by the treating radiation oncologist, with weekly on-treatment visits and standard monitoring. Clinical, treatment, and step count data were collected prospectively and recorded. The primary endpoint was RAM compliance defined as wearing the device 19+ hours daily for 80% of protocol days. Secondary endpoints included changes in daily steps and correlations between daily steps with significant treatment-related events (STRE) including feeding tube placement, emergency room (ER) visits, and hospitalizations. 21 patients were screened and 16 were enrolled in 2019. 82% had a diagnosis of oral cavity or oropharynx cancer. Patients were 39 – 78 years of age, Caucasian (100%), male (88%) smokers (69%), with a KPS of 90 (70 – 100). 69% received postoperative RT and 63% received CRT. As defined per protocol, 44% of patients were found to be compliant with RAM devices, with the remainder of patients wearing their devices a median of 53% (0% - 76%) of protocol days. 50% of patients had a STRE including feeding tube placement (38%), hospitalization (13%), and ER visits (6%). One patient expired due to sepsis after their first week of treatment. Median daily step count at baseline was 4966 (1494 - 11652), with an average drop in daily step count of -13% after 4 weeks of RT for all patients. When evaluating patients with STREs, daily step counts the week before their event (median week 4) decreased by -15% while patients without STREs had an average decrease of -5% at week 4 of treatment. Continuous RAM in HNC receiving RT is feasible in select patients, and may provide meaningful information for patients at risk of STREs. Additional studies evaluating patient reported outcomes with RAM are in development.

Pharmacokinetic/pharmacodynamic and safety study of a single dose of evolocumab 140 mg in healthy Chinese subjects.

Evolocumab, a human monoclonal antibody that binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), markedly reduces low-density lipoprotein cholesterol (LDL-C). Here we characterize the pharmacokinetics, pharmacodynamics, safety, and tolerability of evolocumab manufactured at a new site administered in healthy Chinese subjects. This phase 1 study of a single subcutaneous 140-mg dose of evolocumab was conducted in healthy subjects of Chinese descent residing in Hong Kong. Subjects were followed through day 85. 20 subjects (all men) were enrolled. Mean (SD) age was 26.6 (8.5) years; baseline LDL-C was 2.4 (0.7) mmol/L. Mean (SD) evolocumab maximum serum concentration (Cmax) was 14.1 (5.0) μg/mL; area under the serum drug concentration-time curve from time 0 to time of last quantifiable concentration (AUClast) was 178 (80) day×μg/mL; AUC from time 0 to infinity (AUCinf) was 187 (80) day×μg/mL; terminal half-life was 5.95 (1.76) days; median time to reach Cmax (tmax) was 4.0 days. Maximum LDL-C decrease (-57.5%) was observed on day 15 and recovered to baseline by day 57. The most common adverse events (AEs) were nasal congestion (20%), oropharyngeal pain (15%), sneezing (15%), cough (10%), upper respiratory tract infection (10%), and diarrhea (10%). Most AEs were isolated incidences of mild severity, with no serious or treatment-related events. No anti-evolocumab antibodies were detected. A single 140-mg dose of evolocumab manufactured at the new site and administered in healthy Chinese subjects was associated with typical antibody pharmacokinetics, rapid and reversible decreases in LDL-C, and no new safety events.

Clinical outcomes of laparoscopic-based renal denervation plus adrenalectomy vs adrenalectomy alone for treating resistant hypertension caused by unilateral aldosterone-producing adenoma.

Previous studies describing renal denervation (RDN) from the intima of the renal artery for the treatment of resistant hypertension have reported variable efficacies, and RDN triggers renal intimal injury and atherosclerosis. This study aimed to evaluate the efficacy and safety of RDN from the adventitia of renal artery plus unilateral laparoscopic adrenalectomy to treat patients with resistant hypertension caused by unilateral aldosterone-producing adenoma (APA). A total of 60 consecutive patients with resistant hypertension caused by unilateral APA were enrolled in this study. Patients were randomly assigned to undergo RDN from the adventitia of the renal artery plus adrenalectomy (RDN group, n=30) or adrenalectomy alone (control group, n=30) and were followed up for 12months. The primary efficacy end point was the change in 24-hours mean ambulatory systolic blood pressure (SBP) from baseline to 12months. At the 12-month follow-up, the mean reduction of 24-hours average SBP and office SBP in the RDN group was 20.7±15.2 and 37.1±26.0mmHg, respectively, which was significantly higher than the mean reduction of 24-hours average SBP (11.9±11.1mmHg, P=.017) and the office SBP (25.9±16.8mmHg, P=.035) in the control group. Serum potassium levels returned to normal 12months post-procedure. Patients in the RDN group had higher proportion of cured clinical and biochemical outcomes than those in the control group (35.7% vs 17.9% in clinical outcome; 96.4% vs 89.3% in biochemical outcome, respectively). There were no procedural-, device-, or treatment-related safety events during the 12-month follow-up period between the groups. In conclusion, RDN from the adventitia of the renal artery plus unilateral laparoscopic adrenalectomy is more effective than adrenalectomy alone for treating resistant hypertension caused by unilateral APA.

Sofosbuvir plus ribavirin and sofosbuvir plus ledipasvir in patients with genotype 1 or 3 hepatitis C virus and severe renal impairment: a multicentre, phase 2b, non-randomised, open-label study

There is a medical need for highly effective, safe, and well tolerated treatments for patients infected with hepatitis C virus (HCV) with severe renal impairment. We investigated the safety and efficacy of sofosbuvir with ribavirin or ledipasvir combined with sofosbuvir in a prospective study of patients with genotype 1 or 3 HCV infection and stage 4-5 chronic kidney disease (creatinine clearance by Cockcroft-Gault ≤30 mL/min) who were not on dialysis. This phase 2b, open-label, non-randomised, multicentre study in the USA and New Zealand investigated three sequentially enrolled cohorts of patients. Patients were recruited from ten hospitals and clinical research centres and were included if they had genotype 1 or 3 HCV infection, a creatinine clearance less than or equal to 30 mL/min, and were not on dialysis. In cohorts 1 and 2, patients received sofosbuvir (200 mg in cohort 1 and 400 mg in cohort 2) plus ribavirin 200 mg once per day for 24 weeks. In cohort 3, 18 patients received ledipasvir combined with sofosbuvir (90 mg ledipasvir and 400 mg sofosbuvir) once per day for 12 weeks. The primary efficacy endpoint was the proportion of patients achieving sustained virological response 12 weeks after the end of treatment (SVR12). Safety and pharmacokinetic data were also collected. The trial is registered with ClinicalTrials.gov, number NCT01958281, and is completed. This study was done between Oct 7, 2013, and Oct 29, 2017. In the sofosbuvir plus ribavirin cohorts, 32 patients were screened, of whom 20 were enrolled and assessed for efficacy and safety (ten patients in each cohort). In the ledipasvir plus sofosbuvir cohort, 33 patients were screened, of whom 18 were enrolled and assessed for treatment efficacy and safety. Four (40%, 95% CI 12-74) of ten patients in cohort 1 and six (60%, 26-88) of ten patients in cohort 2 achieved SVR12. All 18 (100%, 82-100) patients in cohort 3 achieved SVR12. Adverse events were mostly mild or moderate in severity. The most commonly reported adverse events overall were headache (eight [21%] of 38 patients), anaemia (seven [18%] of 38 patients), and fatigue (six [16%] of 38 patients). Eight patients had serious adverse events, none of which were treatment related. There were no treatment-related cardiac events or clinically significant changes in echocardiographic parameters or creatinine clearance by Cockcroft-Gault. In this phase 2b study, ledipasvir combined with sofosbuvir for 12 weeks was safe and effective in patients with genotype 1 HCV infection and stage 4-5 chronic kidney disease who were not on dialysis. Gilead Sciences.

Rivaroxaban as an Alternative Agent for Heparin-Induced Thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a high-risk adverse drug reaction because of its associated risk of life- and limb-threatening thrombosis. Rivaroxaban may be considered as an ideal nonheparin anticoagulant alternative for the management of HIT. In this preliminary retrospective study, the efficacy and safety of rivaroxaban to control the clinically suspected HIT (4Ts score 4 points or greater) were evaluated. Patients with chronic kidney disease, hepatic impairment, mechanical heart valves, and active bleeding were excluded. Forty-two eligible patients who received rivaroxaban for clinically suspected HIT were evaluated by medical records review, with 12-month follow-up after the first dose of rivaroxaban. End points included confirmed thrombosis (primary end point), mortality, and adverse treatment-related events. HIT-associated thrombosis was found in 17/42 (40.5%) patients before receiving rivaroxaban. After rivaroxaban therapy, platelet counts normalized in all patients, with only 1/42 (2.3%) patients developing new thrombosis. No hemorrhagic event was recorded in the patients. Twelve patients (28.6%) died, but the cause of death was not related to the thrombosis, hemorrhage, or adverse effects of rivaroxaban. Our findings are consistent with the available emerging data, suggesting that rivaroxaban is a safe and effective drug for the management of clinically suspected HIT. Rivaroxaban is a particularly valuable treatment option in developing countries, where there are issues of cost and availability of approved alternative agents.

Hyperferritinemia and acute kidney injury in pediatric patients receiving allogeneic hematopoietic cell transplantation.

Acute kidney injury (AKI) often occurs in pediatric patients who received allogeneic hematopoietic cell transplantation (HCT). We evaluated the risk and effect of HCT-related AKI in pediatric patients. We retrospectively studied the survival and renal outcome of 69 children 100days and 1-year posttransplant in our institution in 2004-2016. Stage-3 AKI developed in 34 patients (49%) until 100days posttransplant. The 100-day overall survival (OS) rates of patients with stage-3 AKI were lower than those without it (76.5% vs. 94.3%, P= 0.035). The 1-year OS rates did not differ markedly between 21 post-100-day survivors with stage-3 AKI and 29 without it (80.8% vs. 87.9%, P= 0.444). The causes of 19 deaths included the relapse of underlying disease or graft failure (n= 11), treatment-related events (4), and second HCT-related events (4). Underlying disease of malignancy (crude hazard ratio (HR) 5.7; 95% confidence interval (CI), 2.20 to 14.96), > 1000ng/mL ferritinemia (crude HR 4.29; 95% CI, 2.11 to 8.71), stem cell source of peripheral (crude HR 2.96; 95% CI, 1.22 to 7.20) or cord blood (crude HR 2.29; 95% CI, 1.03 to 5.06), and myeloablative regimen (crude HR 2.56; 95% CI, 1.24 to 5.26), were identified as risk factors for stage-3 AKI until 100days posttransplant. Hyperferritinemia alone was significant (adjusted HR 5.52; 95% CI, 2.21 to 13.76) on multivariable analyses. Hyperferritinemia was associated with stage-3 AKI and early mortality posttransplant. Pretransplant iron control may protect the kidney of pediatric HCT survivors.

Radioembolization of hepatocarcinoma with 90Y glass microspheres: treatment optimization using the dose-toxicity relationship.

Transarterial radioembolization (TARE) is, by all standards, a radiation therapy. As such, according to Euratom Directive 2013/59, it should be optimized by a thorough treatment plan based on the distinct evaluation of absorbed dose to the lesions and to the non-tumoural liver (two-compartment dosimetry). Since the dosimetric prediction with 99mTc albumin macro-aggregates (MAA) of non-tumoural liver is much more accurate than the same prediction on lesions, treatment planning should focus on non-tumoural liver rather than on lesion dosimetry. The aim of this study was to determine a safety limit through the analysis of pre-treatment dosimetry with 99mTc-MAA single photon emission computed tomography (SPECT/CT), in order to deliver the maximum tolerable absorbed dose to non-tumoural liver. Data from intermediate/advanced hepato-cellular carcinoma (HCC) patients treated with 90Y glass microspheres were collected in this single-arm retrospective study. Injection was always lobar, even in case of bilobar disease, to avoid treating the whole liver in a single session. A three-level definition of liver decompensation (LD) was introduced, considering toxicity only in cases of liver decompensation requiring medical action (LD type C, LDC). We report LDC rates, receiver operating characteristic (ROC) analysis between LDC and NO LDC absorbed dose distributions, normal tissue complication probability (NTCP) curves and uni- and multivariate analysis of risk factors associated with toxicity. A 6-month timeline was defined as necessary to capture all treatment-related toxicity events. Previous transarterial chemoembolization (TACE), presence or extension of portal vein tumoural thrombosis (PVTT) and tumour pattern (nodular versus infiltrative) were not associated with tolerance to TARE. On the contrary, at the multivariate analysis, the absorbed dose averaged over the whole non-tumoural liver (including the non-injected lobe) was a prognostic indicator correlated with liver decompensation (odds ratio = 4.24). Basal bilirubin > 1.1mg/dL was a second even more significant risk factor (odds ratio = 6.35). NTCP analysis stratified with this bilirubin cut-off determined a 15% liver decompensation risk at 50Gy/90Gy for bilirubin >/< 1.1mg/dL. These results are valid for a 90Y glass microsphere administration 4days after the reference time. Given the low predictive accuracy of 99mTc-MAA on lesion absorbed dose reported by several authors, an optimized TARE with 90Y glass microspheres with lobar injection 4days after reference time should aim at an absorbed dose averaged over the whole non-tumoural liver of 50Gy/90Gy for basal bilirubin higher/lower than 1.1mg/dL, respectively.

Safety and efficacy of pembrolizumab monotherapy in patients with advanced colorectal MSI-h/dMMR cancers.

e16010 Background: Tumours that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) are likely to be immunogenic, triggering upregulation of immune checkpoint proteins. New therapeutic options are needed for patients with advanced colorectal cancer whose disease has progressed after 1 or more lines of therapy. We investigated the safety and efficacy of pembrolizumab, a monoclonal antibody to programmed cell death–1 protein (PD-1 in a cohort of colorectal MSI-H/dMMR cancers patients with previously treated with one line of therapy. Methods: Twenty two eligible patients with histologically/cytologically confirmed MSI-H/dMMR metastatic colorectal cancer who experienced failure with one line of prior therapy received pembrolizumab 200 mg every 3 weeks until disease progression or unacceptable toxicity The primary endpoint was objective response rate (ORR) per RECIST v1.1, as assessed by radiologic review and safety. Tumours were classified as MSI-H/dMMR when expression as detected by immunohistochemistry of at least one of four MMR proteins was absent, or when at least two allelic loci size shifts among the five analyzed microsatellite markers were detected by PCR. Results: Of 22 patients enrolled, median (range) age was 62 (39-78) years. Median follow-up was 15.6 months. The ORR was 36.8 % (95% CI, 29.3% to 42.8%). Median progression-free survival was5.3 months (95% CI, 2.9 to 5.9 months) and median overall survival was 21.5 months (95% CI, 12.8 months to not reached).Treatment-related adverse events occurred in 13 patients (59%). -Four patients (18%) had grade 3 to 5 treatment-related adverse events. There were no treatment-related fatal adverse events. Conclusions: Pembrolizumab monotherapy demonstrated durable clinical benefit and manageable safety in patients with metastatic MSI-H/dMMR colorectal cancer who had previously received 1 line of treatment. Further study of pembrolizumab for this group of patients is warranted.

Concurrent nivolumab and ipilimumab with brain stereotactic radiosurgery for brain metastases from non-small cell lung cancer: A phase I trial.

2531 Background: Nivolumab (nivo) and ipilimumab (ipi) were found in the recent phase III CheckMate 227 trial to have an overall survival benefit over chemotherapy for advanced non-small cell lung cancer (NSCLC). However, patients (pts) with untreated brain metastasis (mets) were excluded from that trial. Because 30% of NSCLC pts develop brain mets, we tested nivo/ipi with concurrent stereotactic radiosurgery (SRS) for NSCLC pts with active brain mets. Methods: We report the safety data from the phase I portion of an ongoing phase I/II single-institution trial in which one treatment group was given SRS with nivo (3 mg/kg) every 2 weeks (wks) plus ipi (1 mg/kg) every 6 wks x 4 cycles, followed by maintenance nivo (480 mg) every 4 wks until disease progression, unacceptable toxicity, or withdrawal of consent. Brain SRS was delivered within 7 days of initiation of nivo/ipi. The primary endpoints were safety and 4-month (mo) intracranial progression-free survival (PFS). Dose-limiting toxicity (DLT) was defined as &gt; 15% intracranial toxicity (&gt;G3 hypophysitis / neurologic toxicity) or &gt; 30% extracranial toxicity (&gt;G3 non-dermatologic non-lab toxicity or &gt;G4 dermatologic / lab toxicity), refractory to medical management, assessed at 8 wks after treatment initiation. Target accrual for phase I was 10 evaluable pts, with enrollment suspended after every 5 pts for DLT assessment. Results: Since June 15, 2018, 13 pts were enrolled and 10 were evaluable for DLT. The median follow-up time was 6.8 mo (range 1.2‒18). As of January 6, 2020, only 1 pt had DLT-defined toxicity and thus the predefined stopping criteria were not met. This pt had G3 seizure right after SRS that resolved within a week, and then had increased but asymptomatic CNS edema 4 wks later. Aside from DLTs, 3 pts (25%) developed treatment-related G3 (elevated liver function tests, fatigue, nausea, adrenal insufficiency, and myocarditis) or G4 events (pneumonitis/acute respiratory distress syndrome in 1 pt with confirmed influenza at 7 mos after treatment initiation). This pt subsequently died of hemophagocytic lymphohistiocytosis (considered possibly related to the study drugs). Median intracranial PFS time was 9.7 mo, and the 4-mo intracranial PFS rate was 75%. Extracranial objective response rate was 33% in the 12 evaluable pts with a median response duration of 9.1 mo. Conclusions: Concurrent SRS withnivo/ipi was safe for pts with active NSCLC brain mets. Preliminary analyses of efficacy were encouraging for durable intracranial and extracranial response. Clinical trial information: NCT02696993 .

MON-521 An Open-Label, Single-Arm, Multicenter, Phase 2 Trial of Lenvatinib (LEN) for the Treatment of Anaplastic Thyroid Cancer (ATC)

Background: ATC is aggressive, with a low 5-year patient (pt)-survival rate. Apart from recent advances in treating ATCs in pts with BRAF mutations, systemic treatments have limited efficacy and duration of response is short. In a small, phase 2 study conducted in Japan, 24% of pts with ATC achieved a partial response (PR) with LEN (Study 208 [Takahashi, Future Oncol. 2019]). This study (NCT02657369 [Study 213]) aimed to further evaluate the efficacy and safety of LEN in a broader population of pts with ATC. Methods: Study 213 was performed in collaboration with the International Thyroid Oncology Group and enrolled pts with ATC to receive LEN 24 mg/day. Key inclusion criteria were: histologic diagnosis of ATC, measurable disease per RECIST v1.1, ECOG score ≤1, and adequate organ function. Previous surgery, radiation, and neoadjuvant, adjuvant, or palliative chemotherapy for ATC were allowed. The primary end point (confirmed objective response rate [ORR]) was determined by investigator review per RECIST v1.1. Interim analysis was done after the first 20 evaluable pts completed ≥2 tumor assessments (baseline and 6-week scan) or discontinued treatment. Results: The study was halted for futility when the minimum threshold for ORR (15%) was not met at the interim analysis. The full analysis set (FAS) included 34 pts because the protocol allowed enrollment until the interim analysis was complete. The median pt age was 66.5 years old and most were female (n=21/34), white (n=27/34), and had been treated with 1 or 2 prior anticancer regimens (n=20/34). Unconfirmed PR was experienced in 1/20 pts (ORR 5%; 95% CI 0.1–24.9%) in the interim analysis set. In the FAS, 1/34 pts had a confirmed PR (cPR) (ORR 3%; 95% CI 0.1–15.8%). In the interim and FAS, median progression-free survival (2.6 and 2.6 months, respectively) and median OS (2.9 and 3.2 months, respectively) were similar. In addition to the 1 cPR, 7 pts had 22–63% shrinkage in tumor measurements but did not meet the response criteria (FAS). Grade 3/4 treatment-emergent (TE) adverse events (AEs) occurred in 82.4% of pts, and 61.8% of pts experienced grade 3/4 treatment-related AEs (FAS). Grade 5 TEAEs occurred in 14/34 pts and there were 27 deaths by the time of data cut-off. There were no treatment-related deaths, and no major treatment-related bleeding events occurred. Conclusion: In contrast to Study 208, Study 213 enrolled more pts with ATC (34 vs 17), more of whom had received prior chemotherapy (62% vs 41%). Additionally, in Study 208, all pts were Japanese and tumor assessments were conducted more frequently (4- vs 6-weekly). These differences may have contributed to the observed variation in results between the 2 studies. AEs observed were consistent with the safety profile of LEN or with ATC. Further investigation of LEN in combination with a checkpoint inhibitor may be warranted.

Safety, tolerability, pharmacokinetics, and immunogenicity of a human monoclonal antibody targeting the G glycoprotein of henipaviruses in healthy adults: a first-in-human, randomised, controlled, phase 1 study

The monoclonal antibody m102.4 is a potent, fully human antibody that neutralises Hendra and Nipah viruses in vitro and in vivo. We aimed to investigate the safety, tolerability, pharmacokinetics, and immunogenicity of m102.4 in healthy adults. In this double-blind, placebo-controlled, single-centre, dose-escalation, phase 1 trial of m102.4, we randomly assigned healthy adults aged 18-50 years with a body-mass index of 18·0-35·0 kg/m2 to one of five cohorts. A sentinel pair for each cohort was randomly assigned to either m102.4 or placebo. The remaining participants in each cohort were randomly assigned (5:1) to receive m102.4 or placebo. Cohorts 1-4 received a single intravenous infusion of m102.4 at doses of 1 mg/kg (cohort 1), 3 mg/kg (cohort 2), 10 mg/kg (cohort 3), and 20 mg/kg (cohort 4), and were monitored for 113 days. Cohort 5 received two infusions of 20 mg/kg 72 h apart and were monitored for 123 days. The primary outcomes were safety and tolerability. Secondary outcomes were pharmacokinetics and immunogenicity. Analyses were completed according to protocol. The study was registered on the Australian New Zealand Clinical Trials Registry, ACTRN12615000395538. Between March 27, 2015, and June 16, 2016, 40 (52%) of 77 healthy screened adults were enrolled in the study. Eight participants were assigned to each cohort (six received m102.4 and two received placebo). 86 treatment-emergent adverse events were reported, with similar rates between placebo and treatment groups. The most common treatment-related event was headache (12 [40%] of 30 participants in the combined m102.4 group, and three [30%] of ten participants in the pooled placebo group). No deaths or severe adverse events leading to study discontinuation occurred. Pharmacokinetics based on those receiving m102.4 (n=30) were linear, with a median half-life of 663·3 h (range 474·3-735·1) for cohort 1, 466·3 h (382·8-522·3) for cohort 2, 397·0 h (333·9-491·8) for cohort 3, and 466·7 h (351·0-889·6) for cohort 4. The elimination kinetics of those receiving repeated dosing (cohort 5) were similar to those of single-dose recipients (median elimination half-time 472·0 [385·6-592·0]). Anti-m102.4 antibodies were not detected at any time-point during the study. Single and repeated dosing of m102.4 were well tolerated and safe, displayed linear pharmacokinetics, and showed no evidence of an immunogenic response. This study will inform future dosing regimens for m102.4 to achieve prolonged exposure for systemic efficacy to prevent and treat henipavirus infections. Queensland Department of Health, the National Health and Medical Research Council, and the National Hendra Virus Research Program.