Prespecified Primary End Point Research Articles

Phase II multi-center trial of optical coherence tomography as an adjunct to white light cystoscopy for intravesical real time imaging and staging of bladder cancer

BackgroundOptical coherence tomography (OCT) is a novel imaging modality that provides microstructural information of different tissue layers using near-infrared light. This prospective, multicenter phase II trial aimed to assess the accuracy of OCT-assisted cystoscopy for bladder tumor staging. MethodsPatients with primary or recurrent bladder tumors (Ta,T1) identified by outpatient cystoscopy were included. The primary objective was to assess the accuracy and positive predictive value of for determining tumor stage ≥T1 correlated by histopathology. 72 suspicious lesions from 63 patients were eligible to analyze in the study. All suspected lesions were evaluated with conventional cystoscopy, interpreted in real-time using OCT, and then resected. All results were compared to pathology. A total of 363 OCT images of tumor and normal mucosa in 25 patients were obtained to evaluate diagnostic efficacy of the computer-aided texture analysis algorithm. ResultsSensitivity and specificity for predicting invasive tumors (≥ T1, n = 17) were 58.8% and 92.7% for cystoscopy, 64.7% and 100% for OCT-assisted cystoscopy, respectively. Accuracy of cystoscopy and OCT-assisted cystoscopy for predicting invasive tumor was 84.7% and 91.7% (P = 0.063), respectively. Cystoscopy and OCT-assisted cystoscopy correctly predicted T stage in 52/72 and 59/72 cases, respectively (P = 0.016). Cystoscopy missed 2 more invasive tumors than OCT-assisted cystoscopy. Cystoscopy (14.3%, 1/7) and OCT-assisted cystoscopy (28.6%, 2/7) showed relatively low sensitivity in detecting muscle invasion. Computer aided texture analysis demonstrated 75.1% sensitivity, 64.0% specificity, and 74.4% accuracy for differentiating tumor and normal urothelium. ConclusionOCT-assisted cystoscopy is a real time noninvasive and simple procedure that enhanced the accuracy of staging bladder tumors and prediction of any tumor invasion. Though the study did not meet the prespecified primary endpoint, OCT imaging is a promising adjunct to cystoscopy that may supplement intraoperative decision-making during transurethral resection of bladder tumors and additional prospective studies are warranted.

Patient-centred outcomes and effect of disease progression on health status in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation receiving maintenance olaparib or placebo (SOLO1): a randomised, phase 3 trial

In the phase 3 SOLO1 trial, maintenance olaparib provided a significant progression-free survival benefit versus placebo in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation in response after platinum-based chemotherapy. We analysed health-related quality of life (HRQOL) and patient-centred outcomes in SOLO1, and the effect of radiological disease progression on health status. SOLO1 is a randomised, double-blind, international trial done in 118 centres and 15 countries. Eligible patients were aged 18 years or older; had an Eastern Cooperative Oncology Group performance status score of 0-1; had newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a BRCA mutation; and were in clinical complete or partial response to platinum-based chemotherapy. Patients were randomly assigned (2:1) to either 300 mg olaparib tablets or placebo twice per day using an interactive voice and web response system and were treated for up to 2 years. Treatment assignment was masked for patients and for clinicians giving the interventions, and those collecting and analysing the data. Randomisation was stratified by response to platinum-based chemotherapy (clinical complete or partial response). HRQOL was a secondary endpoint and the prespecified primary HRQOL endpoint was the change from baseline in the Functional Assessment of Cancer Therapy-Ovarian Cancer Trial Outcome Index (TOI) score for the first 24 months. TOI scores range from 0 to 100 (higher scores indicated better HRQOL), with a clinically meaningful difference defined as a difference of at least 10 points. Prespecified exploratory endpoints were quality-adjusted progression-free survival and time without significant symptoms of toxicity (TWiST). HRQOL endpoints were analysed in all randomly assigned patients. The trial is ongoing but closed to new participants. This trial is registered with ClinicalTrials.gov, NCT01844986. Between Sept 3, 2013, and March 6, 2015, 1084 patients were enrolled. 693 patients were ineligible, leaving 391 eligible patients who were randomly assigned to olaparib (n=260) or placebo (n=131; one placebo patient withdrew before receiving any study treatment), with a median duration of follow-up of 40·7 months (IQR 34·9-42·9) for olaparib and 41·2 months (32·2-41·6) for placebo. There was no clinically meaningful change in TOI score at 24 months within or between the olaparib and placebo groups (adjusted mean change in score from baseline over 24 months was 0·30 points [95% CI -0·72 to 1·32] in the olaparib group vs 3·30 points [1·84 to 4·76] in the placebo group; between-group difference of -3·00, 95% CI -4·78 to -1·22; p=0·0010). Mean quality-adjusted progression-free survival (olaparib 29·75 months [95% CI 28·20-31·63] vs placebo 17·58 [15·05-20·18]; difference 12·17 months [95% CI 9·07-15·11], p<0·0001) and the mean duration of TWiST (olaparib 33·15 months [95% CI 30·82-35·49] vs placebo 20·24 months [17·36-23·11]; difference 12·92 months [95% CI 9·30-16·54]; p<0·0001) were significantly longer with olaparib than with placebo. The substantial progression-free survival benefit provided by maintenance olaparib in the newly diagnosed setting was achieved with no detrimental effect on patients' HRQOL and was supported by clinically meaningful quality-adjusted progression-free survival and TWiST benefits with maintenance olaparib versus placebo. AstraZeneca and Merck Sharp & Dohme.

Randomized Evaluation of TriGuard 3 Cerebral Embolic Protection After Transcatheter Aortic Valve Replacement: REFLECT II.

The REFLECT II (Randomized Evaluation of TriGuard 3 Cerebral Embolic Protection After Transcatheter Aortic Valve Implantation) trial was designed to investigate the safety and efficacy of the TriGUARD 3 (TG3) cerebral embolic protection in patients undergoing transcatheter aortic valve replacement. Cerebral embolization occurs frequently following transcatheter aortic valve replacement and procedure-related ischemic stroke occurs in 2% to 6% of patients at 30 days. Whether cerebral protection with TriGuard 3 is safe and effective in reducing procedure-related cerebral injury is not known. This prospective, multicenter, single-blind, 2:1 randomized (TG3 vs. no TG3) study was designed to enroll up to 345 patients. The primary 30-day safety endpoint (Valve Academic Research Consortium-2 defined) was compared with a performance goal (PG). The primary hierarchical composite efficacy endpoint (including death or stroke at 30days, National Institutes of Health Stroke Scale score worsening in hospital, and cerebral ischemic lesions on diffusion-weighted magnetic resonance imaging at 2 to 5days) was compared using the Finkelstein-Schoenfeld method. REFLECT II enrolled 220 of the planned 345 patients (63.8%), including 41 roll-in and 179 randomized patients (121 TG3 and 58 control subjects) at 18 US sites. The sponsor closed the study early after the U.S. Food and Drug Administration recommended enrollment suspension for unblinded safety data review. The trial met its primary safety endpoint compared with the PG (15.9% vs. 34.4% (p<0.0001). The primary hierarchal efficacy endpoint at 30days was not met (mean scores [higher is better]:-8.58 TG3 vs. 8.08 control; p=0.857). A post hoc diffusion-weighted magnetic resonance imaging analysis of per-patient total lesion volume above incremental thresholds showed numeric reductions in total lesion volume >500mm3 (-9.7%) and >1,000mm3 (-44.5%) in the TG3 group, which were more pronounced among patients with full TG3 coverage:-51.1% (>500mm3) and-82.9% (>1,000mm3). The REFLECT II trial demonstrated that the TG3 was safe compared with a historical PG but didnotmeet its pre-specified primary superiority efficacy endpoint.

Daratumumab plus RVd for newly diagnosed multiple myeloma: final analysis of the safety run-in cohort of GRIFFIN

The phase 2 GRIFFIN study of daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) for transplant-eligible, newly diagnosed multiple myeloma included a safety run-in phase followed by a randomized phase. The ongoing randomized phase has met its prespecified primary end point of an improved stringent complete response (sCR) rate after consolidation for D-RVd (reported elsewhere). Final analysis of the safety run-in cohort is reported herein and provides longer follow-up (median, 40.8 months) encompassing daratumumab plus lenalidomide (D-R) maintenance therapy. Patients in the safety run-in cohort (N = 16) received 4 induction cycles (D-RVd), high-dose melphalan supported by autologous stem cell transplant, 2 consolidation cycles (D-RVd), and 24 months of maintenance (D-R). By the end of consolidation, all patients had responded, with a best response of sCR in 9 (56.3%) patients; 8 (50.0%) patients were minimal residual disease (MRD) negative (10−5 threshold). After maintenance, 15 (93.8%) patients had achieved a best response of sCR, and 13 (81.3%) patients were MRD (10−5) negative. Estimated 36-month progression-free and overall survival rates were 78.1% and 93.8%, respectively. One death from progressive disease occurred in the patient who did not achieve sCR. Observed safety profiles were consistent with daratumumab and RVd. With >3 years of median follow-up, D-RVd achieved durable responses that deepened with D-R maintenance. This study was registered at www.clinicaltrials.gov as #NCT02874742.

Abstract PS10-27: A phase II proof-of-concept study of palbociclib (P) rechallenge in patients (pts) with hormone receptor (HR)[+]/HER2[-] metastatic breast cancer (MBC) and clinical benefit to prior P-based treatment (BIOPER)

Abstract Background: The addition of a cyclin-dependent kinase 4-6 inhibitor (CDK4/6i) to letrozole or fulvestrant significantly improves progression-free survival (PFS) and overall survival (OS) in HR[+]/HER2[-] MBC pts. At present, the optimal endocrine treatment (ET) after progression on a CDK4/6i remains unknown. However, preliminary findings revealed drivers of adaptive resistance more frequently related to ET than to CDK4/6i. BIOPER explored the efficacy and safety of continuing the same CDK4/6i in combination with a different ET agent beyond progression on prior P-based regimen in HR[+]/HER2[-] MBC and assessed predictive biomarkers to identify those pts who are more likely to benefit from this strategy. Methods: BIOPER (NCT03184090) is a multicenter, non-controlled, phase II trial. Eligible pts included pre- and post-menopausal women aged ≥18 years with HR[+]/HER2[-] MBC that showed a confirmed progressive disease (PD) after having achieved clinical benefit (response or stable disease ≥24 weeks) on immediately prior P plus ET-based regimen. Up to two prior ET lines and not more than one line of prior chemotherapy for MBC were allowed. Pts received P (oral, 75/100/125 mg/day 3 weeks on/1 week off) combined with ET of physician’s choice (including tamoxifen, exemestane, fulvestrant, anastrozole, or letrozole) until PD or unacceptable toxicity. Co-primary endpoints were clinical benefit rate (CBR) -in terms of complete or partial response [PR] and stable disease lasting ≥24 weeks as per RECIST 1.1 (H0: CBR≤5% versus H1: CBR≥20%)- and tumor molecular alterations in the cyclin D-CDK 4/6-retinoblastoma pathway detected at baseline as markers of resistance and sensitivity to P rechallenge. Secondary endpoints included investigator-assessed PFS, objective response rate (ORR), OS, and safety using the Common Terminology Criteria for Adverse Events (AEs) 4.03. Results: Between June 15, 2017 and April 25, 2019, a total of 33 pts from 21 centers in 2 countries were enrolled. Among the 33 pts who were included in the safety set, 1 patient who did not achieve clinical benefit on prior P-based regimen was excluded from the efficacy analysis (n=32). The median age was 59.5 years (range 42-80 years) and all pts were post-menopausal. A total of 25 (78.1%) pts had visceral disease (56.3% of whom with liver metastases), 16 (50%) had ECOG 0, and 19 (59.4%) presented ≥3 metastatic sites. Of 32 pts, 15 (46.9%) received letrozole, 14 (43.8%) received fulvestrant, and 3 (9.4%) exemestane. The median PFS for the prior P-based regimen was 13.8 months (mo) (95% confidence interval [CI] 5.6-47.1 mo). The median number of prior ET and chemotherapy lines for MBC was 2 (range 1-4). By the data cutoff date, 26 PFS events occurred, 5 pts were still on treatment, and 1 patient discontinued treatment because of investigator’s decision. The CBR was 34.4% (95% CI 18.6-53.2%) reaching the prespecified primary endpoint. The ORR was 3.1% (95% CI 0.1-16.2%) with 1 patient with PR. The median PFS was 2.6 mo (95% CI 1.8-5.5 mo). With a median follow-up of 11.8 mo, the OS data were immature with a total of 8 deaths (25%). The incidence of all grade (G) and G 3 or 4 (G3-4) AEs were 90.9% and 48.5%, respectively. The most common G3-4 AEs were neutropenia (42.4%) and leukopenia (6.1%). No discontinuations due to AEs and treatment-related deaths occurred. A comprehensive molecular tumor profiling will be presented during the symposium. Conclusions: Prolonging CDK4/6 blockade beyond progression on prior P-based treatment achieved the prespecified clinical benefit among pts with HR[+]/HER2[-] MBC. This strategy is currently being evaluated in the randomized phase II PALMIRA trial. Further research is ongoing to identify patient subgroups who could benefit from this treatment strategy. Citation Format: Antonio Llombart-Cussac, Javier Cortés, Beatriz Bellosillo Paricio, Miguel Gil Gil, Giuseppe Curigliano, José Manuel Pérez-García, Laura Comerma Blesa, Manuel Ruíz Borrego, Enrique Espinosa, Lourdes Calvo, Begoña Bermejo, Meritxell Bellet, Federico Rojo Todo, Juan de la Haba, Vanesa Quiroga, Alessandro Minisini, Ana Santaballa, Miguel Sampayo, Andrea Malfettone, Joan Albanell. A phase II proof-of-concept study of palbociclib (P) rechallenge in patients (pts) with hormone receptor (HR)[+]/HER2[-] metastatic breast cancer (MBC) and clinical benefit to prior P-based treatment (BIOPER) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-27.

Co-administration of viscous fiber, Salba-chia and ginseng on glycemic management in type 2 diabetes: a double-blind randomized controlled trial

Viscous dietary fiber, functional seeds and ginseng roots have individually been proposed for the management of diabetes. We explored whether their co-administration would improve glycemic control in type 2 diabetes beyond conventional therapy. In a randomized, double-blind, controlled trial conducted at two academic centers (Toronto, Canada and Zagreb, Croatia), individuals with type 2 diabetes were assigned to either an active intervention (10g viscous fiber, 60g white chia seeds, 1.5g American and 0.75g Korean red ginseng extracts), or energy and fiber-matched control (53g oat bran, 25g inulin, 25g maltodextrose and 2.25g wheat bran) intervention for 24weeks, while on conventional standard of care. The prespecified primary endpoint was end difference at week 24 in HbA1c, following an intent-to-treat analysis adjusted for center and baseline. Between January 2016 and April 2018, 104 participants (60M:44F; mean ± SEM age 59 ± 0.8 years; BMI 29.0 ± 0.4kg/m2; HbA1c 7.0 ± 0.6%) managed with antihyperglycemic agent(s) (n = 98) or lifestyle (n = 6), were randomized (n = 52 test; n = 52 control). At week 24, HbA1c levels were 0.27 ± 0.1% lower on test compared to control (p = 0.03). There was a tendency towards an interaction by baseline HbA1c (p = 0.07), in which a greater reduction was seen in participants with baseline HbA1c > 7% vs ≤ 7% (- 0.56 ± 0.2% vs 0.03 ± 0.2%). Diet and body weight remained unchanged. The interventions were well tolerated with no related adverse events and with high retention rate of 84%. Co-administration of selected dietary and herbal therapies was well-tolerated and may provide greater glycemic control as add-on therapy in type 2 diabetes. Registration: Clinicaltrials.gov NCT02553382 (registered on September 17, 2015).

Phase II study of ipilimumab, nivolumab, and panitumumab in patients with KRAS/NRAS/BRAF wild-type (WT) microsatellite stable (MSS) metastatic colorectal cancer (mCRC).

7 Background: Panitumumab is a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR) and is a standard therapy in KRAS/NRAS/BRAF WT mCRC. Preclinical data shows that anti-EGFR therapy causes a tumor-specific adaptive immune response and immunogenic apoptosis, with functional adaptive immunity required to mediate efficacy. However, resistance to anti-EGFR antibody therapy inevitably develops and is associated with increased expression of CTLA-4 and PD-L1. We hypothesized that addition of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) to panitumumab will increase response rate in patients with KRAS/NRAS/BRAF WT MSS mCRC. Methods: LCCC1632 was a multicenter, single-arm, Simon’s two stage phase II clinical trial with a pre-specified safety run-in of panitumumab, ipilimumab, and nivolumab in KRAS/NRAS/BRAF WT, MSS mCRC (NCT03442569). Eligible patients must have received 1-2 prior lines of therapy and no prior anti-EGFR or immune checkpoint inhibitor therapy. Subjects received ipilimumab 1 mg/kg IV q6wk, nivolumab 240 mg IV q2wk, and panitumumab 6 mg/kg IV q2wk until progression, toxicity, or patient withdrawal. The primary endpoint was response rate at 12 weeks per RECIST 1.1, and key secondary endpoints included progression-free survival and duration of response. Results: A total of 56 subjects were enrolled 3/2018-6/2020. This included the 6-subject safety run-in, with 0/6 dose-limiting toxicities in first 12 weeks. The first stage of the Simon’s two-stage clinical trial (n=32) had sufficient response rate to merit full enrollment. There were 7 unevaluable subjects for the primary endpoint of 12-week response rate. Among 49 evaluable subjects, 12-week response rate was 35% (95% CI 21-48; n=17 responses). Twenty subjects had at least an unconfirmed response at any time. Median PFS was 5.7 months (95% CI 5.5-7.9). There was one treatment-related grade 5 adverse event of myocarditis. The most common treatment-related grade 3-4 AEs included lipase increased (9%), amylase increased (7%), ALT increased (5%), AST increased (5%), diarrhea (5%), hypophosphatemia (5%), and maculopapular rash (5%). Conclusions: The combination of panitumumab, ipilimumab, and nivolumab demonstrated evidence of activity and met its prespecified primary endpoint of 12-wk response rate criteria to merit further study. The PFS in this single-arm study compares favorably to expected PFS for anti-EGFR monotherapy in RAS wild-type patients, and results suggest activity of immune checkpoint inhibitors combined with anti-EGFR therapy in MSS mCRC. Clinical trial information: NCT03442569.

Predictors and prognostic role of low myocardial mechano-energetic efficiency in chronic inflammatory arthritis.

To assess the variables associated with the status of low myocardial mechano-energetic efficiency (MEE) [the ratio between myocardial left ventricular (LV) work and magnitude of myocardial oxygen consumption] and whether low-MEE is a prognosticator of adverse cardiovascular outcome in patients with chronic inflammatory arthritis. A total of 432 outpatients with established chronic inflammatory arthritis without overt cardiac disease were recruited from March 2014-March 2016; 216 participants were used as comparison group. Low-MEE status was a priori identified by standard echocardiography at rest as less than 0.32 ml/s per g (5th percentile of MEE calculated in 145 healthy individuals). The pre-specified primary end-point of the study was a composite of cardiovascular death/hospitalization. Follow-up ended September 2019. MEE was significantly lower in chronic inflammatory arthritis patients than controls (0.35 ± 0.11 vs. 0.45 ± 0.10 ml/s per g; P < 0.001). Low-MEE was detected in 164 patients (38%). Independent predictors of low-MEE were older age, higher SBP, diabetes mellitus, LV concentric geometry and lower LV systolic function. During a follow-up of 36 (21-48) months, a primary end-point occurred in 37 patients (8.6%): 22/164 patients with low-MEE (13.4%) and 15/268 (5.6%) without low-MEE (P = 0.004). Low-MEE predicted primary end-points in multivariate Cox regression analysis [heart rate 2.23 (confidence interval 1.13-4.38), P = 0.02] together with older age, lower renal function and higher LV mass. Low-MEE is detectable in more than one-third of patients with chronic inflammatory arthritis and is associated with traditional cardiovascular risk factors and abnormalities in LV geometry and systolic function. In these patients low-MEE is a powerful prognosticator of adverse cardiovascular events.

Daratumumab (DARA) Plus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Patients with Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM): Updated Efficacy and Safety Analysis of the Safety Run-in Population of Griffin

Daratumumab (DARA) Plus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Patients with Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM): Updated Efficacy and Safety Analysis of the Safety Run-in Population of Griffin

Clinical Response of CD19 CAR-T Cells (relmacabtagene autoleucel, relma-cel) in Adults with Heavily-Pre-Treated Relapsed/Refractory (r/r) Large B-Cell Lymphoma in China

Currently, no CAR-T product has been approved for use in China despite having hundreds of active CAR-T trials. Relma-cel (JWCAR029) is a CAR-T product with a CAR construct comprised of a binding domain, derived from a murine CD19-specific mAb (FMC63), a CD3ζ activation domain, and a 4-1BB costimulatory domain, and manufactured in China with a commercial-ready, highly automated, single train process to select, activate, transduce and expand both CD4 and CD8 cells to a wide range of doses with consistent product attributes. Relma-cel was evaluated in the first prospective, single-arm, multi-center, pivotal study (RELIANCE Trial) of CAR-T therapy conducted under Chinese IND to support an NMPA-accepted BLA submission in r/r large B-cell lymphoma (LBCL) (NCT 04089215) and the preliminary results are presented herein. Eligible adult patients had measurable, histologically confirmed r/r LBCL, failed at least 2 prior therapies, including anthracycline and anti-CD20 agents, and not had allogeneic transplant within 90 days or primary CNS lymphoma. Patients were randomized to receive either 100×106 (low dose) or 150×106 (high dose) CAR+ T cells as a single infusion following fludarabine 25 mg/m2 &amp; cyclophosphamide 250 mg/m2 daily×3 as lymphodepletion. Patients were evaluated for efficacy (Lugano criteria, 2014), safety (CRS by Lee 2014, and all other events by CTCAE v4.03), and PK (by qPCR and flow cytometry). The protocol pre-specified and regulatory authority-agreed primary endpoint was 3 month ORR by landmark analysis to exclude a 3-month 20% ORR (Michael, 2017). Secondary endpoints included best overall response rate (BOR), duration of response (DOR), progression free survival (PFS), overall survival (OS), frequency/severity of AEs and CAR-T cell expansion. Investigators adjudicated disease response and progression based on imaging studies, pathology and clinical data; a sensitivity analysis was also conducted using an independent review committee adjudication. Between May 2018 and Dec 2019, 69 patients were screened, and 59 enrolled and treated with relma-cel, with median age of 56.0 years (18-75), 59.3% ECOG 1-2, and included several LBCL subtypes (DLBCL NOS 69.5%, TFL 15.3%, DHL/THL 5.1%, and PMBCL 6.8%) and nearly all with poor risk disease (81.4% treatment refractory, 45.8% ≥3 lines of prior therapies, 42.4% requiring bridging therapy, 39% IPI≥3). The median doses administered in low and high dose groups were 99.7×106 (range, 80.1-101.3) and 150.0×106 (range, 120.0-156.4) CAR+ T cells, respectively. Among the 58 efficacy evaluable patients, the primary analysis demonstrated a 3 month ORR of 58.6% (95% CI, 44.9-71.4) (the excluded patient had product that did not meet viability threshold criterion, but achieved CR at D29 that is ongoing for &amp;gt;1 year). As of Jun 17, 2020 data cut-off, BOR was 75.9% (95% CI, 62.8-86.1) with CR rate of 51.7% (95% CI, 38.2-65.1). With a median follow-up of 8.9 months, median OS were not reached, and 6 month DOR, PFS and OS were 60.0%, 54.2% and 90.8%, respectively. No improvement in efficacy outcomes was observed in the high dose group. Of 59 treated patients, grade ≥3 AEs occurring in &amp;gt;5% of patients were cytokine release syndrome (CRS), febrile neutropenia and lung infection (all, 5.1%). Grade ≥3 lab abnormalities in &amp;gt;10% of patients were neutrophil count decreased (30.5%), white blood cell count decreased (13.6%), leukopenia (10.2%) and neutropenia (10.2%). The rates of CRS, neurotoxicity (NT), death, and the use of tocilizumab/steroids are shown in Table 1. All events of CRS and NT resolved except for 1 patient with grade 4 CRS ongoing at the time of death as the result of sepsis at day 8. As of data cut off, no cases of severe cytopenia or severe infections occurred beyond 30 days of infusion. The two dose groups did not differ significantly in PK parameters (see Table 1). The RELIANCE Trial provided the first demonstration of licensure-quality CAR-T manufacturing and clinical trial data generation in r/r patients originating in China. These results with relma-cel demonstrate similar preliminary response rates and PK profiles while providing the potential for an improved toxicity profile in heavily-pre-treated patients with r/r DLBCL having poor risk features relative to other CD19-specific CAR-Ts approved in the US and EU. Figure Disclosures Zhang: JW Therapeutics (Shanghai) Co. Ltd: Current Employment, Current equity holder in private company. Yang:JW Therapeutics (Shanghai) Co. Ltd: Current Employment, Current equity holder in private company. Zhou:JW Therapeutics (Shanghai) Co. Ltd: Current Employment, Current equity holder in private company. Zheng:JW Therapeutics (Shanghai) Co. Ltd: Current Employment, Current equity holder in private company.

Safety and Efficacy of Induction and Maintenance Avelumab Plus R-CHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of the Phase II Avr-CHOP Study

Safety and Efficacy of Induction and Maintenance Avelumab Plus R-CHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of the Phase II Avr-CHOP Study

Mobile Interventional Stroke Team Model Improves Early Outcomes in Large Vessel Occlusion Stroke: The NYC MIST Trial.

Triage of patients with emergent large vessel occlusion stroke to primary stroke centers followed by transfer to comprehensive stroke centers leads to increased time to endovascular therapy. A Mobile Interventional Stroke Team (MIST) provides an alternative model by transferring a MIST to a Thrombectomy Capable Stroke Center (TSC) to perform endovascular therapy. Our aim is to determine whether the MIST model is more time-efficient and leads to improved clinical outcomes compared with standard drip-and-ship (DS) and mothership models. This is a prospective observational cohort study with 3-month follow-up between June 2016 and December 2018 at a multicenter health system, consisting of one comprehensive stroke center, 4 TSCs, and several primary stroke centers. A total of 228 of 373 patients received endovascular therapy via 1 of 4 models: mothership with patient presentation to a comprehensive stroke center, DS with patient transfer from primary stroke center or TSC to comprehensive stroke center, MIST with patient presentation to TSC and MIST transfer, or a combination of DS with patient transfer from primary stroke center to TSC and MIST. The prespecified primary end point was initial door-to-recanalization time and secondary end points measured additional time intervals and clinical outcomes at discharge and 3 months. MIST had a faster mean initial door-to-recanalization time than DS by 83 minutes (P<0.01). MIST and mothership had similar median door-to-recanalization times of 192 minutes and 179 minutes, respectively (P=0.83). A greater proportion had a complete recovery (National Institutes of Health Stroke Scale of 0 or 1) at discharge in MIST compared with DS (37.9% versus 16.7%; P<0.01). MIST had 52.8% of patients with modified Rankin Scale of ≤2 at 3 months compared with 38.9% in DS (P=0.10). MIST led to significantly faster initial door-to-recanalization times compared with DS, which was comparable to mothership. This decrease in time has translated into improved short-term outcomes and a trend towards improved long-term outcomes. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03048292.

Ten-year all-cause death after percutaneous or surgical revascularization for men and women with multivessel or left main coronary artery disease: insights from the SYNTAX extended survival study

Abstract Background In patients with complex coronary artery disease (CAD), women favored coronary artery bypass grafting surgery (CABG) compared to percutaneous coronary intervention (PCI) at 5 years in the SYNTAX trial, whereas mortality rates after PCI and CABG were not different in men. On the other hand, poor outcomes of women undergoing PCI were not observed in the PRECOMBAT and BEST trials. The long-term optimal revascularization strategy according to gender has not been fully evaluated. Purpose In the SYNTAX Extended Survival (SYNTAXES) study, no significant difference existed in all-cause death between PCI and CABG at 10 years. This study aimed to assess treatment effect of PCI and CABG for 10-year all-cause death according to gender. Methods The SYNTAXES study evaluated vital status up to 10 years in 1,800 patients with de novo three-vessel disease (3VD) and/or left main coronary artery disease (LMCAD) randomized to treatment with CABG or PCI in the SYNTAX trial, and the pre-specified primary endpoint was all-cause death at 10 years. In this prespecified analysis, all-cause death at 10 years according to gender in patients undergoing PCI or CABG was evaluated. Results Of 1800 patients, 402 (22.3%) were women and 1398 (77.7%) were men. In women, the rate of mortality was significantly higher in the PCI arm at 5 years than in the CABG arm (19.3% vs. 10.3%; Log-rank p=0.010, Figure A), but the rates of mortality were not different at 10 years between the PCI and CABG arms (33.0% vs. 32.5%; Log-rank p=0.600, Figure A). In men, the mortality rate tended to be higher in the PCI arm at 10 years than in the CABG arm (27.0% vs. 22.5%; Log-rank p=0.082, Figure B), although the mortality rates were not different at 5 years between the PCI and CABG arms (12.4% vs. 12.3%; Log-rank p=0.957, Figure B). Conclusion The efficacy of CABG observed at 5 years disappeared at 10 years in women, whereas the efficacy of CABG became apparent after 5 years in men. Figure 1 Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Erasmus University Medical Centre, Rotterdam, Netherlands, reference: MEC-2016-716

Transcatheter Aortic Valve Replacement in Low-risk Patients With Bicuspid Aortic Valve Stenosis

The outcomes of transcatheter aortic valve replacement (TAVR) in low-risk patients with bicuspid aortic valve stenosis have not been studied in a large scale, multicentered, prospective fashion. To evaluate the procedural safety, efficacy, and 30-day outcomes of TAVR in patients with bicuspid aortic stenosis at low surgical risk. The Low Risk Bicuspid Study is a prospective, single-arm trial study with inclusion/exclusion criteria developed from the Evolut Low Risk Randomized Trial. Follow-up is planned for 10 years. Patients underwent TAVR at 25 centers in the United States who were also participating in the Evolut Low Risk Randomized Trial from December 2018 to October 2019. Eligible patients had severe bicuspid aortic valve stenosis and met American Heart Association/American College of Cardiology guideline indications for aortic valve replacement. Patients underwent attempted implant of an Evolut or Evolut PRO transcatheter aortic valve, with valve size based on annular measurements. The prespecified primary end point was the incidence of all-cause mortality or disabling stroke at 30 days. The prespecified primary efficacy end point was device success defined as the absence of procedural mortality, the correct position of 1 bioprosthetic heart valve in the proper anatomical location, and the absence of more than mild aortic regurgitation postprocedure. A total of 150 patients underwent an attempted implant. Baseline characteristics include mean age of 70.3 (5.5) years, 48.0% female (n = 72), and a mean Society of Thoracic Surgeons score of 1.4 (0.6%). Most patients (136; 90.7%) had Sievers type I valve morphology. The incidence of all-cause mortality or disabling stroke was 1.3% (95% CI, 0.3%-5.3%) at 30 days. The device success rate was 95.3% (95% CI, 90.5%-98.1%). At 30 days, the mean (SD) AV gradient was 7.6 (3.7) mm Hg and effective orifice area was 2.3 (0.7) cm2. A new permanent pacemaker was implanted in 22 patients (15.1%). No patients had greater than mild paravalvular leak. Transcatheter aortic valve replacement in low-surgical risk patients with bicuspid aortic valve stenosis achieved favorable 30-day results, with low rates of death and stroke and high device success rate. ClinicalTrials.gov Identifier: NCT03635424.

A 3year post-intervention follow-up on mortality in advanced heart failure (EVITA vitamin D supplementation trial).

AimsVitamin D supplementation is widely used in the clinical setting, but its effects on mortality and cardiovascular outcomes in patients with heart failure are unclear. This paper reports outcome data that were collected during follow‐up of 3 years after closure of the EVITA trial (a 3 year randomized, placebo‐controlled, intervention study with 4000 IU vitamin D daily in patients with advanced heart failure), to capture potential latency effects of vitamin D supplementation on clinical outcomes.Methods and resultsThe prespecified primary endpoint was overall mortality. Secondary endpoints included hospitalization, mechanical circulatory support implantation, high urgent listing for heart transplantation, and heart transplantation. For group comparisons, we used Cox regression models with a time‐dependent categorical covariate. The calculated net difference in circulating 25‐hydroxyvitamin D between the vitamin D and placebo groups dropped from 60.9 nmol/L at the end of the active study period to 3.2 nmol/L at the end of the post‐intervention period. During the entire 6 year period, 73 patients (36.5%) died in the placebo group and 76 (38.8%) in the vitamin D group. Out of these 149 patients, 36 and 39 died during the first 3 years, and 37 and 37 during the second 3 years, respectively. The hazard ratio (HR) for mortality in the vitamin D versus the placebo group was 1.06 [95% confidence interval (CI): 0.68–1.66] for the first 3 years and 1.07 (95% CI: 0.68–1.70) for the 3 year post‐intervention follow‐up. Compared with the placebo group, the HRs for hospitalization and for mechanical circulatory support implant were significantly higher in the vitamin D group during vitamin D supplementation (HR = 1.31, 95% CI: 1.01–1.68 and HR = 2.01, 95% CI: 1.08–3.76, respectively) but not after vitamin D discontinuation (HR = 1.10, 95% CI: 0.62–1.94 and HR = 0.99, 95% CI: 0.38–2.56, respectively). There was no significant time‐dependent effect on the risk of high urgent listing for heart transplantation and heart transplantation.ConclusionsNo beneficial latency effects of vitamin D supplementation on overall mortality could be demonstrated. Instead, the disappearance of unfavourable findings in the vitamin D group (higher HRs for hospitalization and for mechanical circulatory support implant) after vitamin D discontinuation supports the assumption of adverse vitamin D effects on the cardiovascular system at doses of 4000 IU daily.

MM-350: Daratumumab (DARA) + Lenalidomide/Bortezomib/Dexamethasone (RVd) in African American/Black Patients (Pts) with Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM): Subgroup Analysis of GRIFFIN

Context: To optimize treatment of Black pts with multiple myeloma, a greater understanding of differences in outcomes in Black pts vs. White pts is needed. In GRIFFIN, DARA plus RVd (D-RVd) improved rates and depth of response in autologous stem cell transplant (ASCT)-eligible NDMM pts. Here, we report a subgroup analysis of Black pts from GRIFFIN. Design: Between 2016 and 2018, pts in the United States were randomized 1:1 to RVd ± DARA and received 4 induction cycles, high-dose therapy, ASCT, 2 consolidation cycles, and maintenance with R ± DARA for 24 mo. The pre-specified primary endpoint was stringent complete response (sCR) rate by end of consolidation, which occurred at a median follow-up of 13.5 mo. Results below are based on longer follow-up (22.1 mo). Results: Two hundred seven pts (D-RVd, n=104; RVd, n=103) were randomized; 32 (15%) pts were Black (D-RVd, n=14; RVd, n=18), and 161 (78%) pts were White (D-RVd, n=85; RVd, n=76). Baseline demographics were generally similar between treatment arms in Black and White pts. D-RVd vs RVd improved the sCR rate by end of consolidation in Black (10 [71%]; 6 [33%]) and White pts (35 [43%]; 24 [34%]). Including post-consolidation data, sCR with D-RVd vs. RVd was achieved by 12 (86%) and 7 (39%) Black pts and 50 (61%) and 33 (46%) White pts. ORR by end of consolidation was improved for D-RVd vs. RVd in Black pts (14 [100%] vs. 17 [94%]), as were rates of ≥CR (12 [86%] vs. 7 [39%]) and minimal residual disease at 10−5 (5 [36%] vs. 3 [17%]). Grade 3/4 TEAEs (≥25%) with D-RVd/RVd included neutropenia (Black pts, 50%/22%; White pts, 41%/16%), lymphopenia (29%/39%; 23%/16%), and thrombocytopenia (29%/11%; 14%/8%). Grade 3/4 infections for D-RVd/RVd occurred in 36%/17% of Black and 20%/23% of White pts. IRRs occurred in 29% of Black and 45% of White pts. Conclusions: GRIFFIN demonstrated that D-RVd improved responses in the Black NDMM pt subgroup, but larger studies are needed to better define the magnitude of DARA benefit in Black pts. Improved recruitment of Black pts in clinical trials is needed to understand disease biology and response to therapy among racial groups. To optimize treatment of Black pts with multiple myeloma, a greater understanding of differences in outcomes in Black pts vs. White pts is needed. In GRIFFIN, DARA plus RVd (D-RVd) improved rates and depth of response in autologous stem cell transplant (ASCT)-eligible NDMM pts. Here, we report a subgroup analysis of Black pts from GRIFFIN. Between 2016 and 2018, pts in the United States were randomized 1:1 to RVd ± DARA and received 4 induction cycles, high-dose therapy, ASCT, 2 consolidation cycles, and maintenance with R ± DARA for 24 mo. The pre-specified primary endpoint was stringent complete response (sCR) rate by end of consolidation, which occurred at a median follow-up of 13.5 mo. Results below are based on longer follow-up (22.1 mo). Two hundred seven pts (D-RVd, n=104; RVd, n=103) were randomized; 32 (15%) pts were Black (D-RVd, n=14; RVd, n=18), and 161 (78%) pts were White (D-RVd, n=85; RVd, n=76). Baseline demographics were generally similar between treatment arms in Black and White pts. D-RVd vs RVd improved the sCR rate by end of consolidation in Black (10 [71%]; 6 [33%]) and White pts (35 [43%]; 24 [34%]). Including post-consolidation data, sCR with D-RVd vs. RVd was achieved by 12 (86%) and 7 (39%) Black pts and 50 (61%) and 33 (46%) White pts. ORR by end of consolidation was improved for D-RVd vs. RVd in Black pts (14 [100%] vs. 17 [94%]), as were rates of ≥CR (12 [86%] vs. 7 [39%]) and minimal residual disease at 10−5 (5 [36%] vs. 3 [17%]). Grade 3/4 TEAEs (≥25%) with D-RVd/RVd included neutropenia (Black pts, 50%/22%; White pts, 41%/16%), lymphopenia (29%/39%; 23%/16%), and thrombocytopenia (29%/11%; 14%/8%). Grade 3/4 infections for D-RVd/RVd occurred in 36%/17% of Black and 20%/23% of White pts. IRRs occurred in 29% of Black and 45% of White pts. GRIFFIN demonstrated that D-RVd improved responses in the Black NDMM pt subgroup, but larger studies are needed to better define the magnitude of DARA benefit in Black pts. Improved recruitment of Black pts in clinical trials is needed to understand disease biology and response to therapy among racial groups.

Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial

AimsDespite the effects of statins in reducing cardiovascular events and slowing progression of coronary atherosclerosis, significant cardiovascular (CV) risk remains. Icosapent ethyl (IPE), a highly purified eicosapentaenoic acid ethyl ester, added to a statin was shown to reduce initial CV events by 25% and total CV events by 32% in the REDUCE-IT trial, with the mechanisms of benefit not yet fully explained. The EVAPORATE trial sought to determine whether IPE 4 g/day, as an adjunct to diet and statin therapy, would result in a greater change from baseline in plaque volume, measured by serial multidetector computed tomography (MDCT), than placebo in statin-treated patients.Methods and resultsA total of 80 patients were enrolled in this randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis as documented by MDCT (one or more angiographic stenoses with ≥20% narrowing), be on statin therapy, and have persistently elevated triglyceride (TG) levels. Patients underwent an interim scan at 9 months and a final scan at 18 months with coronary computed tomographic angiography. The pre-specified primary endpoint was change in low-attenuation plaque (LAP) volume at 18 months between IPE and placebo groups. Baseline demographics, vitals, and laboratory results were not significantly different between the IPE and placebo groups; the median TG level was 259.1 ± 78.1 mg/dL. There was a significant reduction in the primary endpoint as IPE reduced LAP plaque volume by 17%, while in the placebo group LAP plaque volume more than doubled (+109%) (P = 0.0061). There were significant differences in rates of progression between IPE and placebo at study end involving other plaque volumes including fibrous, and fibrofatty (FF) plaque volumes which regressed in the IPE group and progressed in the placebo group (P < 0.01 for all). When further adjusted for age, sex, diabetes status, hypertension, and baseline TG, plaque volume changes between groups remained significantly different, P < 0.01. Only dense calcium did not show a significant difference between groups in multivariable modelling (P = 0.053).ConclusionsIcosapent ethyl demonstrated significant regression of LAP volume on MDCT compared with placebo over 18 months. EVAPORATE provides important mechanistic data on plaque characteristics that may have relevance to the REDUCE-IT results and clinical use of IPE.

Phase II trial of bevacizumab and sorafenib in recurrent ovarian cancer patients with or without prior-bevacizumab treatment

ObjectiveTo examine whether blocking multiple points of the angiogenesis pathway by addition of sorafenib, a multi-kinase inhibitor against VEGFR2/3, Raf, c-Kit, and PDGFR, to bevacizumab would yield clinical activity in ovarian cancer (OvCa). MethodsThis phase II study tested bevacizumab plus sorafenib in two cohorts; bevacizumab-naïve and bevacizumab-exposed patients. Bevacizumab (5 mg/kg IV every 2 weeks) was given with sorafenib 200 mg bid 5 days-on/2 days-off. The primary objective was response rate using a Simon two-stage optimal design. Progression-free survival (PFS) and toxicity were the secondary endpoints. Exploratory correlative studies included plasma cytokine concentrations, tissue proteomics and dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI). ResultsBetween March 2007 and August 2012, 54 women were enrolled, 41 bevacizumab-naive and 13 bevacizumab-prior, with median 5 (2–9) and 6 (5–9) prior systemic therapies, respectively. Nine of 35 (26%) evaluable bevacizumab-naive patients attained partial responses (PR), and 18 had stable disease (SD) ≥ 4 months. No responses were seen in the bevacizumab-prior group and 7 (54%) patients had SD ≥ 4 months, including one exceptional responder with SD of 27 months. The overall median PFS was 5.5 months (95%CI: 4.0–6.8 months). Treatment-related grade 3/4 adverse events (≥5%) included hypertension (17/54 [31%]; grade 3 in 16 patients and grade 4 in one patient) and venous thrombosis or pulmonary embolism (5/54 [9%]; grade 3 in 4 patients and grade 4 in one patient). Pretreatment low IL8 concentration was associated with PFS ≥ 4 months (p = .031). ConclusionsThe bevacizumab and sorafenib combination did not meet the pre-specified primary endpoint although some clinical activity was seen in heavily-pretreated bevacizumab-naive OvCa patients with platinum-resistant disease. Anticipated class toxicities required close monitoring and dose modifications.

0739 Efficacy and Safety of AXS-12 in the Treatment of Narcolepsy: Results from a Phase 2, Double-Blind, Placebo-Controlled, Crossover Trial

Abstract Introduction Narcolepsy is a chronic, debilitating, neurological disease characterized by excessive daytime sleepiness (EDS), cataplexy, and sleep-wake dysregulation. Existing treatments are limited, provide variable efficacy, and have significant tolerability issues. AXS-12 (reboxetine) is a potent, and highly selective norepinephrine reuptake inhibitor with potential for therapeutic differentiation in narcolepsy. Methods The CONCERT study was a Phase 2, double-blind, randomized, placebo-controlled, crossover trial of AXS-12 in narcolepsy subjects exhibiting moderate and severe symptoms of cataplexy and EDS. Subjects were randomized (1:1) to treatment with AXS-12 followed by placebo, or placebo followed by AXS-12. AXS-12 dosing was 8mg/day for week 1, escalated to 10mg/day for week 2. Crossover occurred after a one-week down-titration/washout. The primary endpoint was the change in weekly cataplexy attacks from baseline, averaged over the 2-week treatment period for overall treatment effect. Secondary endpoints included improvements in EDS, cognitive function, sleep quality and sleep-related symptoms. Results Twenty-one subjects were randomized. The baseline mean weekly number of cataplexy attacks was 30.0 and mean ESS score was 18.1, reflecting moderate and severe illness on both core symptoms. AXS-12 met the prespecified primary endpoint, demonstrating a statistically significantly greater reduction in the mean number of weekly cataplexy attacks (-13.0 with AXS-12 vs -0.3 with placebo; p&amp;lt;0.001) over 2 weeks of treatment. Statistically significant reductions in EDS were observed for AXS-12 compared to placebo, assessed by changes in the Epworth Sleepiness Scale (-6.0 vs -3.1; p=0.003), number of weekly inadvertent naps (-5.88 vs -0.98; p&amp;lt;0.001). AXS-12 was associated with improved cognitive function (p&amp;lt;0.002) and sleep quality (p&amp;lt;0.007), and reduced night awakenings (p&amp;lt;0.05). Rapidity of effect was observed with significant symptomatic improvements occurring as early as week 1 starting at the lower 8mg dose. AXS-12 was safe and well-tolerated with no serious adverse events or discontinuations due to adverse events. Conclusion AXS-12 is a novel approach for the treatment of narcolepsy with the potential for comprehensive clinical symptom management compared to current treatments. In this Phase 2 study, AXS-12 resulted in statistically significant improvements in cataplexy, excessive sleepiness, cognitive function and night awakenings in patients with narcolepsy with a favorable safety profile. Support Axsome Therapeutics.

PMU85 MISSION IMPOSSIBLE? REIMBURSEMENT SUCCESS WITH FAILED PHASE III TRIAL

In order to obtain regulatory approval, drug manufacturers must robustly demonstrate a positive benefit:risk balance. Large, multicentre, randomised Phase III trials that demonstrate statistically significant comparative benefits according to a pre-specified primary endpoint are regarded as the gold standard basis for marketing authorization. Some products have secured marketing authorizations despite not showing statistical significance in the primary endpoint of their phase III trials. This research evaluates how commercially viable products with a ‘failed’ phase III trial have fared in reimbursement assessment by major payers. The EMA website was screened for therapies that had been authorized based on a Phase III trial readout which failed to meet its primary endpoint. HTA decisions from EU5 payers (NICE, HAS, G-BA, AEMPS, AIFA) were then screened for these therapies and key data extracted (to 08/01/2020). Atezolizumab, ataluren and pembrolizumab obtained EMA authorisation in second-line (2L) urothelial carcinoma (2017), DMD (2014) and 2L HNSCC (2018), respectively, despite not showing statistical significance in the primary endpoint of their phase III trials. Ataluren was approved based on a Phase II trial under a conditional marketing authorization, whilst atezolizumab and pembrolizumab were approved in a different population to the pre-specified primary endpoint. In the case of pembrolizumab, it was approved in a subset of the trial population where a significant effect was demonstrated. 10 HTA appraisals were identified for the three products (3, 5 and 2 for atezolizumab, ataluren, and pembrolizumab, respectively). 3/3 (100%), 3/5 (60%), and 0/2 (0%) of appraisals were positive and recommended reimbursement for atezolizumab, ataluren, and pembrolizumab, respectively. Despite failed primary endpoints in phase III trials, some therapies have secured regulatory approvals and translated these into successful payer reimbursement.