2780. Reactogenicity Profile of Adjuvanted Recombinant Zoster Vaccine after Dose 2 According to the Intensity of the Same Event Experienced after Dose 1

Abstract Background In the pivotal clinical trials, ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229), the adjuvanted recombinant zoster vaccine (RZV) showed high efficacy against herpes zoster and postherpetic neuralgia. The incidence of reported solicited events was higher in RZV compared with placebo recipients. Methods In these phase III, observer-blind, placebo-controlled trials conducted in 18 countries, adults ≥50 years of age (YOA, ZOE-50) and ≥70 YOA (ZOE-70), randomized 1:1, received 2 doses of RZV or placebo 2 months apart. Injection-site and general events were solicited for 7 days after each dose via diary cards in a participant subset. For this post-hoc analysis, ZOE-50 and ZOE-70 data from participants having completed the diary cards for both RZV doses were pooled. The intensity of each solicited event after dose 2 was stratified by the intensity of the same event after dose 1. Results Solicited injection-site and general events were recorded for both RZV doses by 4,676 and 4,668 vaccinees, respectively (Figure 1). Of 1,235 vaccinees with no injection-site event at dose 1, 881 (71.3%) reported no injection-site event and 20 (1.6%) reported a grade 3 event after dose 2. A total of 433 (9.3%) vaccinees reported a grade 3 injection-site event, either after dose 1 or dose 2. Of 244 vaccinees with grade 3 injection-site events at dose 1, 79 (32.4%) also reported a grade 3 event after dose 2. Of 2,312 vaccinees with no general event at dose 1, 1,617 (69.9%) reported no general event and 67 (2.9%) reported a grade 3 event after dose 2. A total of 499 (10.7%) vaccinees reported a grade 3 general event, either after dose 1 or dose 2. Of 222 vaccinees with grade 3 general events at dose 1, 81 (36.5%) also reported a grade 3 general event after dose 2. In general, vaccinees who did not experience a certain event after dose 1, did not experience this event after dose 2 either. Most vaccinees reporting a specific event at high intensity after dose 1, reported the same event at a lower intensity (or not at all) after dose 2 (Figures 2 and 3). Conclusion While not powered to predict event intensity of the second RZV dose, our data provides an overview of event intensity after RZV dose 2 according to the intensity of the same event experienced after dose 1. Funding: GlaxoSmithKline Biologicals SA. Disclosures All authors: No reported disclosures.

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2779. Efficacy of the Adjuvanted Recombinant Zoster Vaccine According to Sex, Geographic Region, and Geographic Ancestry/Ethnicity: A Post-hoc Analysis

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.2456 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S981-S981

Author(s):

David O Willer ◽

Valentine Wascotte ◽

Joon Hyung Kim ◽

Toufik Zahaf ◽

Carla Talarico ◽

...

Keyword(s):

Large Scale ◽

Geographic Region ◽

Phase Iii ◽

Post Herpetic Neuralgia ◽

Zoster Vaccine ◽

Post Hoc Analysis ◽

Point Estimates ◽

Recombinant Zoster Vaccine ◽

Post Hoc ◽

Placebo Recipients

Abstract Background The risk of herpes zoster (HZ) has been reported to vary by sex and ethnicity. In 2 large-scale clinical trials, ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229), the adjuvanted recombinant zoster vaccine (RZV) demonstrated high vaccine efficacy (VE) against HZ and post-herpetic neuralgia (PHN). We present a post-hoc analysis of RZV efficacy against HZ and PHN in the ZOE-50/70 population stratified by sex, geographic region and geographic ancestry/ethnicity. Methods The ZOE-50 and ZOE-70 studies were phase III, observer-blind, placebo-controlled trials conducted across 5 geographic regions. Adults ≥ 50 years of age (YOA; ZOE-50) and ≥ 70 YOA (ZOE-70), randomized 1:1, received 2 doses of RZV or placebo 2 months apart. Here, VE against HZ by sub-population was estimated from the ZOE-50 population (≥ 50 YOA) and the pooled ZOE-50/70 population (pooled ≥ 70 YOA), and VE against PHN by sub-population was evaluated in the pooled ≥ 70 YOA. Results VE was evaluated in 7,340 RZV and 7,413 placebo recipients ≥ 50 YOA (mean age: 62.3 [RZV], 62.2 [placebo] YOA) and 8,250 RZV and 8,346 placebo recipients in pooled ≥ 70 YOA (mean age: 75.5 [RZV, placebo] YOA). VE against HZ and PHN was similar for women and men in the ≥ 50 YOA and pooled ≥ 70 YOA (Tables 1 and 2). Point estimates for VE against HZ by geographic region ranged from 95.7% to 97.2% in ≥ 50 YOA and from 87.3% to 95.1% in pooled ≥ 70 YOA (Table 1). Point estimates for VE against PHN by geographic region ranged from 86.8% to 100% in pooled ≥ 70 YOA. VE was similar across geographic ancestry groups in pooled ≥ 70 YOA: VE point estimates against HZ ranged from 89.6% to 100% and VE against PHN ranged from 87.5% to 100% (Tables 1 and 2). VE against HZ was 88.1% and against PHN was 65.9% in Hispanic participants in pooled ≥ 70 YOA (Tables 1 and 2). Conclusion Acknowledging the limitations including the post-hoc character of these analyses and the small number of participants and cases available, our data suggest that RZV is efficacious against HZ and PHN irrespective of sex, geographic region, geographic ancestry, and ethnicity. Funding: GlaxoSmithKline Biologicals SA. Disclosures All authors: No reported disclosures.

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Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.6 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 6-6 ◽

Cited By ~ 29

Author(s):

Howard I. Scher ◽

Karim Fizazi ◽

Fred Saad ◽

Kim N. Chi ◽

Mary-Ellen Taplin ◽

...

Keyword(s):

Progression Free Survival ◽

Phase Iii ◽

Castration Resistant Prostate Cancer ◽

Post Hoc Analysis ◽

Castration Resistant ◽

Study Results ◽

Psa Progression ◽

Grade 3 ◽

Post Hoc ◽

The Impact

6 Background: ENZA increased median overall survival (OS) by 4.8 mo (P <0.001, HR 0.63) vs placebo (PBO) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) post-docetaxel in AFFIRM (HI Scher et al, NEJM 2012). Corticosteroids (CS) can activate AR signaling in nonclinical models (J Richards, Can Res 2012). In a multivariate model of AFFIRM data baseline CS use was associated with reduced OS (HI Scher et al. ESMO 2012 abstract 899PD). The impact of CS use during study treatment in AFFIRM was evaluated to test if concomitant CS use is also associated with inferior outcomes. Methods: Pts were randomized 2:1 to ENZA 160 mg/d or PBO. Pts were allowed but not required to take CS. OS was the primary endpoint. In a post-hoc analysis On-study CS use was defined as oral CS user for ≥ 1 day on study. Results: On study CS use was 48% in ENZA and 45% in PBO pts. Prognostic factors were slightly better in the no CS group compared to the CS group. Use of CS regardless of treatment was associated median OS of 11.5 mo (95% CI: 10.5, 13.0) for CS pts vs median OS NM (NM, NM) for no CS pts (HR=0.40; 95% CI: 0.33, 0.48). ENZA was consistently superior to PBO for OS, radiographic progression free survival (rPFS) and time to PSA progression (TTPP), regardless of CS use (Table). Pts on CS had higher rates of grade 3 - 4 adverse events (AE) compared to no CS pts: 63.3% vs 34.4% respectively. Conclusions: In this post-hoc analysis, on study CS use was associated with reduced OS and higher rates of grade 3 -4 AEs in mCRPC pts post-docetaxel. While CS pts had worse outcomes, ENZA was consistently superior to PBO regardless of on study CS use. The inferior outcomes in CS pts may be due to unmeasured confounders or the biologic properties of CS use itself. Clinical trial information: NCT00974311. [Table: see text]

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Toxicity and efficacy of bolus (BOL) versus continuous intravenous (CIV) dosing of doxorubicin (DOX) in soft tissue sarcoma (STS): Post hoc analysis of a prospective randomized trial.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.11023 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 11023-11023

Author(s):

Lee D. Cranmer ◽

Yao Lu ◽

Karla V. Ballman ◽

Elizabeth Trice Loggers ◽

Seth Pollack

Keyword(s):

Randomized Trial ◽

Proportional Hazards ◽

Performance Status ◽

Cox Proportional Hazards ◽

Phase Iii ◽

Hematologic Toxicity ◽

Post Hoc Analysis ◽

Kaplan Meier ◽

Grade 3 ◽

Post Hoc

11023 Background: DOX remains critical in STS treatment. Controversy exists regarding its optimal administration route (BOL vs CIV). BOL vs CIV could affect toxicity and/or efficacy. A randomized trial to assess this is unlikely. We conducted a post hoc analysis to explore differences in these routes of DOX administration. Methods: Data from a prospective randomized phase III study of doxorubicin with or without evofosfamide (TH-302) were used. At the discretion of treating physician, BOL or CIV DOX could be used. Grade 3-5 hematologic, non-hematologic and cardiac toxicities and treatment response were explored using multivariable logistic regression. OS and PFS were analyzed using Kaplan-Meier and Cox proportional hazards. Results: 640 subjects were enrolled (556 BOL, 84 CIV). Baseline differences in age, extent of disease and prior radiotherapy were controlled for in regression models. Hematologic toxicity was associated with age, performance status (PS) and cumulative (CUM) DOX dose. Non-hematologic toxicity was associated with age, PS, receipt of prior radiotherapy and CUM TH-302 dose. Cardiac toxicity was only associated with CUM DOX dose. Odds of response were strongly associated with CUM DOX dose (mg/m2, OR = 1.011, p < 0.0001), and, to a lesser extent, with CUM TH-302 dose (g/m2, OR = 1.081, p = 0.0008), STS subtype and prior radiotherapy. Comparing CIV to BOL DOX, neither OS (median 21.7m vs 18.3m, HR = 0.85, p = 0.29) nor PFS (median 6.1m vs. 6.1m, HR = 0.89, p = 0.43) was affected by manner of DOX administration (CIV vs BOL). Cox analyses indicated that factors reflecting tumoral biology and host status, rather than treatment received, were associated with OS (PS, histologic STS subtype, histologic grade, receipt of prior radiotherapy) and PFS (PS, treatment-related toxicity). Conclusions: Our analyses provide no evidence for superiority of either BOL or CIV administration of DOX as regards toxicity or efficacy in STS treatment. Thus, the logistically simpler BOL administration of DOX should be favored over CIV administration.

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2778. Impact of Reactogenicity on Quality of Life and Physical Functioning in Adults ≥50 Years Receiving Both Doses of the Adjuvanted Recombinant Zoster Vaccine

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.2455 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S980-S981

Author(s):

Kenneth E Schmader ◽

Myron J Levin ◽

Michael Chen ◽

Sean Matthews ◽

Megan Riley ◽

...

Keyword(s):

Quality Of Life ◽

Physical Functioning ◽

Short Form ◽

Phase Iii ◽

Medical Attention ◽

Zoster Vaccine ◽

Sf 36 ◽

Recombinant Zoster Vaccine ◽

Grade 3

Abstract Background The adjuvanted recombinant zoster vaccine (RZV) is efficacious in preventing herpes zoster in adults ≥ 50 years. The current study investigates whether the vaccinees’ quality of life (QoL) and physical functioning (PF) are impacted by local and systemic reactions due to RZV. In a previous report of this phase III, open-label, multicenter study (NCT02979639), overall PF and QoL were not significantly affected by a first RZV dose. [1] Here we report the results from the same study after a second RZV dose and safety results from dose 1 up to study end. Methods Adults aged ≥ 50 years were to receive 2 doses of RZV 2 months apart. Changes in mean Short Form health survey (SF-36) PF score between pre- and post-each RZV dose for 7 days, QoL, reactogenicity and safety were assessed. Results 401 adults received dose 1 and 391 received dose 2 of RZV. Post-second RZV dose, the reported solicited local symptoms were pain (75.1%), erythema (22.4%) and swelling (13.9%), and the most frequent solicited systemic symptoms were fatigue (46.3%), headache (37.5%) and myalgia (32.9%). Grade 3 solicited symptoms were reported by 7.2% (local) and 11.1% (general) of participants, and 5 (1.2%) participants reported reactogenicity triggering medical attention post-second RZV dose. From first dose up to study end, 14 (3.5%) participants reported 21 serious adverse events, none related to RZV. In days 1–2, post-second RZV dose, a transient, clinically-important decrease in SF-36 PF score (table) was seen in those reporting grade 3 solicited symptoms, which impacted activities such as walking and climbing stairs. Overall, during the 7 days post-second RZV dose, a mean change of −0.4 points was observed from the mean baseline score, indicating the PF was not clinically meaningfully impacted. No overall quality-adjusted-life-year loss was recorded. Conclusion Overall, the QoL and PF of adults ≥ 50 years were not affected post-second RZV dose; a transient impact was observed in adults with grade 3 reactogenicity. These results and the observed reactogenicity and safety profile are consistent with first RZV dose results, as well as that of previous studies with the RZV vaccine in adults of similar age. Funding: GlaxoSmithKline Biologicals SA. 1. Schmader et al., Abstract 2488, IDWeek 2018 Disclosures All authors: No reported disclosures.

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Efficacy and serious adverse events profile of the adjuvanted recombinant zoster vaccine in adults with pre-existing potential immune-mediated diseases: a pooled post hoc analysis on two parallel randomized trials

Rheumatology ◽

10.1093/rheumatology/keaa424 ◽

2020 ◽

Cited By ~ 1

Author(s):

Alemnew F Dagnew ◽

Debora Rausch ◽

Caroline Hervé ◽

Toufik Zahaf ◽

Myron J Levin ◽

...

Keyword(s):

Adverse Events ◽

Age Groups ◽

Zoster Vaccine ◽

Post Dose ◽

Serious Adverse Events ◽

Post Hoc Analysis ◽

Immune Mediated ◽

Recombinant Zoster Vaccine ◽

Post Hoc ◽

Placebo Recipients

Abstract Objective In the ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) phase 3 clinical trials, the adjuvanted recombinant zoster vaccine (RZV) demonstrated ≥90% efficacy in preventing herpes zoster (HZ) in all age groups ≥50 years. Given the increased HZ risk associated with certain underlying autoimmune diseases or their treatment regimes, we conducted a post hoc analysis of RZV’s efficacy against HZ and safety profile [specifically, the occurrence of serious adverse events (SAEs)] in ZOE-50/70 participants who reported pre-existing potential immune-mediated diseases (pIMDs) at enrolment and were not on immunosuppressive therapies. Methods Adults aged ≥50 (ZOE-50) and ≥70 (ZOE-70) years were randomized to receive two doses of RZV or placebo 2 months apart. In this subgroup analysis of participants with at least one pIMD at enrolment, the efficacy was calculated for two-dose recipients who did not develop confirmed HZ before 30 days post-dose 2. SAE occurrence was evaluated for all participants who received at least one dose. Results Of the 14 645 RZV and 14 660 placebo recipients from the ZOE-50/70 studies, 983 and 960, respectively, reported at least one pre-existing pIMD at enrolment and were included in these analyses. The most frequent pre-existing conditions were psoriasis, spondyloarthropathy and RA. Efficacy against HZ was 90.5% (95% CI: 73.5, 97.5%) overall with the lowest being 84.4% (95% CI: 30.8, 98.3%) in the 70–79-year-old age group. SAEs and fatal SAEs were similar between RZV and placebo recipients. Conclusion In ZOE-50/70 participants with pre-existing pIMDs, RZV was highly efficacious against HZ and SAE incidence was similar between RZV and placebo recipients. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT01165177 (ZOE-50), NCT01165229 (ZOE-70).

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Predictors of anti-VEGF drug-induced hypertension using different hypertension criteria: a secondary analysis of the COMPARZ study

Therapeutic Advances in Medical Oncology ◽

10.1177/1758834018755090 ◽

2018 ◽

Vol 10 ◽

pp. 175883401875509 ◽

Cited By ~ 2

Author(s):

Arduino A. Mangoni ◽

Ganessan Kichenadasse ◽

Andrew Rowland ◽

Michael J. Sorich

Keyword(s):

Antihypertensive Drugs ◽

Karnofsky Performance Status ◽

Phase Iii ◽

Drug Induced ◽

Specific Patient ◽

Post Hoc Analysis ◽

Anti Vegf ◽

Induced Hypertension ◽

Grade 3 ◽

Post Hoc

Background: There is inconsistency in the criteria used to define anti-vascular endothelial growth factor (VEGF) drug-induced hypertension (AVEGF-HT) in published studies. It is unknown whether specific patient characteristics similarly predict AVEGF-HT using different criteria. Methods: We assessed the associations between clinical and demographic factors ( n = 22) and AVEGF-HT, using six criteria based on predefined on-treatment blood pressure (BP) thresholds or absolute BP elevations versus baseline, in a post hoc analysis of a phase III trial of 1102 patients with renal cell carcinoma (RCC) randomized to pazopanib or sunitinib (COMPARZ study). Results: The cumulative incidence of AVEGF-HT at any time while on treatment ranged between 14.8% [criterion: grade ⩾3 toxicity, National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0] and 58.8% (criterion: absolute systolic BP increase ⩾20 mmHg versus baseline). After adjusting for anti-VEGF treatment and baseline BP, the number of significant ( p < 0.05) predictors ranged between one (criterion: absolute systolic BP increase ⩾20 mmHg, on-treatment systolic BP ⩾140 mmHg and diastolic BP ⩾90 mmHg) and nine (criterion: grade ⩾3 toxicity, NCI CTCAE v3.0). Age, use of antidiabetic drugs and use of antihypertensive drugs each significantly predicted four AVEGF-HT criteria. By contrast, sex, smoking, heart rate, proteinuria, Karnofsky performance status, and use of thiazide diuretics did not predict any criterion. Conclusions: There was a significant variability in the incidence, number and type of predictors of AVEGF-HT, using six different criteria, in a post hoc analysis of the COMPARZ study. The use of specific criteria might affect the assessment of the interaction between anti-VEGF drugs, AVEGF-HT and cancer outcomes.

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