Co-primary Objectives Research Articles

Immunogenicity, reactogenicity and safety of 2 doses of an adjuvanted herpes zoster subunit vaccine administered 2, 6 or 12 months apart in older adults: Results of a phase III, randomized, open-label, multicenter study

BackgroundIn phase III trials, 2 doses of a herpes zoster (HZ) subunit vaccine (HZ/su; 50 µg varicella-zoster virus glycoprotein E [gE] and AS01B Adjuvant System) administered 2-months apart in older adults (≥50 and ≥70 years) demonstrated >90% efficacy in preventing HZ and had a clinically acceptable safety profile. Here we report immunogenicity, reactogenicity and safety following administration of 2 HZ/su doses at intervals longer than 2 months. MethodsIn this Phase III, open-label trial conducted in the US and Estonia, 354 adults ≥50 years were randomized 1:1:1 to receive 2 HZ/su doses 2, 6, or 12 months apart. gE-specific humoral immune responses were evaluated at pre-vaccination, 1 and 12 months post-dose 2. Co-primary objectives were to compare immune responses to HZ/su 1 month post-dose 2 when given 6-months or 12-months apart to those administered 2-months apart. For each participant, safety information was collected from dose 1 to 12 months post-dose 2. Results346 participants completed the study and 343 were included in the according-to-protocol cohort for immunogenicity. One month post-dose 2, vaccine response rates were 96.5% (97.5% confidence interval [CI]: 90.4; 99.2) and 94.5% (97.5% CI: 87.6; 98.3) for the 0, 6- and 0, 12-month schedules, respectively, both schedules meeting the pre-defined criterion. Non-inferiority of anti-gE geometric mean concentrations was demonstrated for HZ/su administered on 0, 6-month compared to a 0, 2-month schedule; however, HZ/su administered on a 0, 12-month schedule did not meet the non-inferiority criterion. Injection site pain was the most commonly reported solicited adverse event (AE). 26 participants each reported at least 1 serious AE; none were assessed as related to vaccination. ConclusionsImmune responses to HZ/su administered at 0, 6-month were non-inferior to those elicited by a 0, 2-month schedule. HZ/su exhibited a clinically acceptable safety profile for all dosing intervals.Clinical Trials Registration: Clinicaltrials.gov (NCT01751165).

MS 17.02 MAGRIT

MS 17.02 MAGRIT

Combined data of intravaginal prasterone against vulvovaginal atrophy of menopause.

To analyze the effects of intravaginal prasterone obtained in the three randomized clinical studies performed in postmenopausal women suffering from moderate to severe (MS) dyspareunia due to vulvovaginal atrophy (VVA). In three independent 12-week prospective, randomized, double-blind, and placebo-controlled clinical studies, the effect of daily intravaginal 0.50% (6.5 mg) prasterone was examined on four co-primary objectives in women having MS pain during sexual activity (dyspareunia), identified as their most bothersome symptom (MBS) of VVA at baseline. In 436 women treated with 0.50% prasterone and 260 women who received placebo, an average 35.1% decrease over placebo in the percentage of parabasal cells (P < 0.0001), an average 7.7% increase in the percentage of superficial cells (P < 0.0001), and a mean 0.72 pH unit decrease in vaginal pH (P < 0.0001) were observed. The severity score of most bothersome symptom dyspareunia was decreased by a 0.46 unit (49%) (P < 0.0001 over placebo), whereas the severity score of MS vaginal dryness decreased by 0.31 unit (P < 0.0001 over placebo). A very positive evaluation was obtained on the acceptability of the technique of administration of the insert, whereas the male partners reported a very positive evaluation of the changes observed in their sexual partner. The efficacy data demonstrate highly positive effects on all the symptoms and signs of vulvovaginal atrophy with no significant drug-related side effects in line with the physiology of menopause and intracrinology.

Immunogenicity and Safety of an Adjuvanted Herpes Zoster Subunit Candidate Vaccine in Adults with Hematologic Malignancies: A Phase III, Randomized Clinical Trial

BackgroundHematologic malignancy (HM) patients receiving immunosuppressive cancer therapy (ICT) are at increased risk of herpes zoster (HZ). Currently, no HZ vaccine is indicated for immunocompromised patients. The HZ subunit vaccine candidate (HZ/su), containing recombinant varicella zoster virus glycoprotein E and AS01B Adjuvant System, showed >90% efficacy and an acceptable safety profile in immunocompetent adults in all age groups ≥50 years. Here we report HZ/su immunogenicity and safety in HM adults ≥18 years of age who completed or are undergoing ICT.MethodsIn this phase III, observer-blind, multicenter study (NCT01767467), participants were randomized 1:1 to receive HZ/su or placebo (2 doses, 1–2 months apart) ≥10 days pre- or post-ICT. Humoral and cell-mediated immunogenicity (CMI) were assessed. The co-primary immunogenicity objectives were to evaluate HZ/su vaccine response rate and compare the immune response to HZ/su and placebo in participants excluding those with non-Hodgkin B-cell lymphoma (NHBCL) or chronic lymphocytic leukemia (CLL) at 1 month post-dose 2 (M2). Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days after each dose, respectively. Serious AEs (SAEs), disease-related events and potential immune-mediated diseases (pIMDs) were recorded throughout the study. Partial safety results up to 6 months post-dose 2 are shown (partially blinded, ongoing study).ResultsOf 562 participants (283 HZ/su 283; placebo 279), (mean age 57.3 [HZ/su 56.8; placebo 57.8] years), 415 were included in the according-to-protocol (ATP) cohort for humoral immunogenicity and 132 in the ATP sub-cohort for CMI. M2 immune responses were higher in the HZ/su group (Table 1). Both co-primary immunogenicity objectives were met (Figure 1). The most frequent local and general solicited AEs were pain and fatigue, reported by 48.2% and 47.8% of all participants (per-group data remain blinded). The frequency of unsolicited AEs, SAEs and pIMDs in the 2 groups was similar (Table 2).ConclusionHZ/su induced robust humoral and cellular immune responses at M2 in HM adults excluding NHBCL and CLL, who completed or are undergoing ICT. No safety concerns were observed up to 6 months post-dose 2.FundingGlaxoSmithKline Biologicals SADisclosures L. Oostvogels, GSK group of companies: Employee and Shareholder, Salary and Shares

Phase 2, two-group, two-stage, open-label study of avelumab in patients with microsatellite stable, microsatellite instable and POLE-mutated recurrent or persistent endometrial cancer.

TPS5615 Background: The Cancer Genome Atlas project identified 2 groups of hypermutated endometrial cancers (ECs): an ultramutated group that harbored mutations in the exonuclease domain of polymerase e ( POLE), and a hypermutated group with microsatellite instability (MSI), the majority of which harbored MLH1 promoter methylation. We (Howitt, JAMA Onc 2015) and others have shown that POLE and MSI ECs are associated with higher number of predicted neoepitopes and tumor infiltrating lymphocytes, which is counterbalanced by overexpression of PD-1/PD-L1, suggesting that they may be excellent candidates for PD-1/PD-L1 blockade. Anti-PD-1 therapy has also demonstrated promising activity in mismatch repair deficient colorectal cancers and collectively in non-colorectal cancers (Le, NEJM 2015). Methods: This is an open-label, two-cohort, two-stage, phase 2 trial, of avelumab, a fully human IgG1 antibody directed against PD-L1, in two cohorts: i) a MSI/ POLE cohort including ECs with immunohistochemical (IHC) complete loss of expression of at least one of the mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE and ii) a MSS cohort including ECs with normal IHC expression of all MMR proteins. Key eligibility criteria include measurable disease, no upper limit of prior therapies, and any EC histology. Co-primary objectives include objective response rate and rate of progression-free survival at 6 months. Avelumab is administered at 10 mg/kg as 1-hour IV infusion every 2 weeks until disease progression or unacceptable toxicity; therapy may continue at the investigator’s discretion while awaiting radiologic confirmation of disease progression 4 weeks later. Maximum target enrollment is 70 patients (35 for each cohort). In the first stage, 16 patients will be enrolled in each cohort; if there are at least two objective responses or two patients progression-free at 6 months, accrual will continue to the second stage where 19 more patients will be enrolled for each cohort. Thus far, 16 patients have been enrolled, 13 on the MSS cohort and 3 on the MSI/ POLE cohort. Clinical trial information: NCT02912572.

Gemox versus surveillance following surgery of localized biliary tract cancer: Results of the PRODIGE 12-ACCORD 18 (UNICANCER GI) phase III trial.

225 Background: No standard post-surgery adjuvant treatment is currently recommended in localized biliary tract cancer (BTC). Gemcitabine combined with platinum is the standard chemotherapy for advanced BTC. The aim of this phase III randomized trial was to assess whether GEMOX would increase relapse-free survival (RFS) while maintaining health-related quality of life (HrQoL). Methods: We performed a multicenter randomized phase III trial. Patients were randomized, within 3 months of R0 or R1 resection of a localized BTC (intra-hepatic, perihilar, extra-hepatic cholangiocarcinoma or gallbladder cancer), to receive either GEMOX 85 for 12 cycles (Experimental Arm A) or surveillance (Standard Arm B). Co-primary objectives were RFS and HrQoL. 190 patients and 126 RFS events were required to show an increase of median RFS from 18 to 30 months. Results: Between July 2009 and February 2014, 196 patients were included in 33 French centers. Baseline characteristics were balanced, with similar primary sites, R0 resection rates were 86.2% (Arm A) vs 87.9% (Arm B), lymph node invasion present in 37.2% vs 36.4%. In Arm A, a median of 12 cycles was delivered (mean: 9.3, range: 0-12). Maximal grade of adverse events were grade 3 in 57.5% vs 22.2%, and grade 4 in 17.0% vs 9.1%. During treatment one patient died in each arm. The main grade ≥ 3 adverse events in the year following inclusion were peripheral neuropathy (50.0% vs 1.1%), and neutropenia (22.3% vs 0%). Median follow-up was 44.3 months, with 54 and 64 RFS events in arms A vs B. There was no significant difference in RFS between the arms (log-rank p = 0.31), with a hazard ratio of 0.83 [95% CI: 0.58-1.19], p = 0.31 (futility boundaries were crossed). Median RFS was 30.4 [95% CI: 15.4-45.8] vs 22.0 months [95%CI: 13.6-38.3] in arms A &amp; B respectively, and 4-years RFS was 39.3% [95%CI: 28.4%-50.0%] vs 33.2% [95%CI: 23.1-43.7%]. Global Health HrQoL scores were not different at 12 months (70.8 vs 83.3, p = 0.18) and at 24 months (75.0 vs 83.3, p = 0.50). Conclusions: Adjuvant chemotherapy in BTC with GEMOX was feasible and associated with expected toxicities and no deterioration of HrQoL. There was no significant difference in RFS between GEMOX and surveillance. Clinical trial information: NCT01313377.

Maternal immunisation with trivalent inactivated influenza vaccine for prevention of influenza in infants in Mali: a prospective, active-controlled, observer-blind, randomised phase 4 trial

SummaryBackgroundDespite the heightened risk of serious influenza during infancy, vaccination is not recommended in infants younger than 6 months. We aimed to assess the safety, immunogenicity, and efficacy of maternal immunisation with trivalent inactivated influenza vaccine for protection of infants against a first episode of laboratory-confirmed influenza.MethodsWe did this prospective, active-controlled, observer-blind, randomised phase 4 trial at six referral centres and community health centres in Bamako, Mali. Third-trimester pregnant women (≥28 weeks' gestation) were randomly assigned (1:1), via a computer-generated, centre-specific list with alternate block sizes of six or 12, to receive either trivalent inactivated influenza vaccine or quadrivalent meningococcal vaccine. Study personnel administering vaccines were not masked to treatment allocation, but allocation was concealed from clinicians, laboratory personnel, and participants. Infants were visited weekly until age 6 months to detect influenza-like illness; laboratory-confirmed influenza diagnosed with RT-PCR. We assessed two coprimary objectives: vaccine efficacy against laboratory-confirmed influenza in infants born to women immunised any time prepartum (intention-to-treat population), and vaccine efficacy in infants born to women immunised at least 14 days prepartum (per-protocol population). The primary outcome was the occurrence of a first case of laboratory-confirmed influenza by age 6 months. This trial is registered with ClinicalTrials.gov, number NCT01430689.FindingsWe did this trial from Sept 12, 2011, to Jan 28, 2014. Between Sept 12, 2011, and April 18, 2013, we randomly assigned 4193 women to receive trivalent inactivated influenza vaccine (n=2108) or quadrivalent meningococcal vaccine (n=2085). There were 4105 livebirths; 1797 (87%) of 2064 infants in the trivalent inactivated influenza vaccine group and 1793 (88%) of 2041 infants in the quadrivalent meningococcal vaccine group were followed up until age 6 months. We recorded 5279 influenza-like illness episodes in 2789 (68%) infants, of which 131 (2%) episodes were laboratory-confirmed influenza. 129 (98%) cases of laboratory-confirmed influenza were first episodes (n=77 in the quadrivalent meningococcal vaccine group vs n=52 in the trivalent inactivated influenza vaccine group). In the intention-to-treat population, overall infant vaccine efficacy was 33·1% (95% CI 3·7–53·9); in the per-protocol population, vaccine efficacy was 37·3% (7·6–57·8). Vaccine efficacy remained robust during the first 4 months of follow-up (67·9% [95% CI 35·1–85·3] by intention to treat and 70·2% [35·7–87·6] by per protocol), before diminishing during the fifth month (57·3% [30·6–74·4] and 60·7 [33·8–77·5], respectively). Adverse event rates in women and infants were similar among groups. Pain at the injection site was more common in women given quadrivalent meningococcal vaccine than in those given trivalent inactivated influenza vaccine (n=253 vs n=132; p<0·0001), although 354 [92%] reactions were mild. Obstetrical and non-obstetrical serious adverse events were reported in 60 (3%) women in the quadrivalent meningococcal vaccine group and 61 (3%) women in the trivalent inactivated influenza vaccine group. Presumed neonatal infection was more common in infants in the trivalent inactivated influenza vaccine group than in those in the quadrivalent meningococcal vaccine group (n=60 vs n=37; p=0·02). No serious adverse events were related to vaccination.InterpretationVaccination of pregnant women with trivalent inactivated influenza vaccine in Mali—a poorly resourced country with high infant mortality—was technically and logistically feasible and protected infants from laboratory-confirmed influenza for 4 months. With adequate financing to procure the vaccine, implementation will parallel the access to antenatal care and immunisation coverage of pregnant women with tetanus toxoid.FundingBill & Melinda Gates Foundation.

Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial

Fewer than half of the patients with completely resected non-small-cell lung cancer (NSCLC) are cured. Since the introduction of adjuvant chemotherapy in 2004, no substantial progress has been made in adjuvant treatment. We aimed to assess the efficacy of the MAGE-A3 cancer immunotherapeutic in surgically resected NSCLC. In this randomised, double-blind, placebo-controlled trial, we recruited patients aged at least 18 years with completely resected stage IB, II, and IIIA MAGE-A3-positive NSCLC who did or did not receive adjuvant chemotherapy from 443 centres in 34 countries (Europe, the Americas, and Asia Pacific). Patients were randomly assigned (2:1) to receive 13 intramuscular injections of recMAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic) or placebo during 27 months. Randomisation and treatment allocation at the investigator site was done centrally via internet with stratification for chemotherapy versus no chemotherapy. Participants, investigators, and those assessing outcomes were masked to group assignment. A minimisation algorithm accounted for the number of chemotherapy cycles received, disease stage, lymph node sampling procedure, performance status score, and lifetime smoking status. The primary endpoint was broken up into three co-primary objectives: disease-free survival in the overall population, the no-chemotherapy population, and patients with a potentially predictive gene signature. The final analyses included the total treated population (all patients who had received at least one treatment dose). This trial is registered with ClinicalTrials.gov, number NCT00480025. Between Oct 18, 2007, and July 17, 2012, we screened 13 849 patients for MAGE-A3 expression; 12 820 had a valid sample and of these, 4210 (33%) had a MAGE-A3-positive tumour. 2312 of these patients met all eligibility criteria and were randomly assigned to treatment: 1515 received MAGE-A3 and 757 received placebo and 40 were randomly assigned but never started treatment. 784 patients in the MAGE-A3 group also received chemotherapy, as did 392 in the placebo group. Median follow-up was 38·1 months (IQR 27·9-48·4) in the MAGE-A3 group and 39·5 months (27·9-50·4) in the placebo group. In the overall population, median disease-free survival was 60·5 months (95% CI 57·2-not reached) for the MAGE-A3 immunotherapeutic group and 57·9 months (55·7-not reached) for the placebo group (hazard ratio [HR] 1·02, 95% CI 0·89-1·18; p=0·74). Of the patients who did not receive chemotherapy, median disease-free survival was 58·0 months (95% CI 56·6-not reached) in those in the MAGE-A3 group and 56·9 months (44·4-not reached) in the placebo group (HR 0·97, 95% CI 0·80-1·18; p=0·76). Because of the absence of treatment effect, we could not identify a gene signature predictive of clinical benefit to MAGE-A3 immunotherapeutic. The frequency of grade 3 or worse adverse events was similar between treatment groups (246 [16%] of 1515 patients in the MAGE-A3 group and 122 [16%] of 757 in the placebo group). The most frequently reported grade 3 or higher adverse events were infections and infestations (37 [2%] in the MAGE-A3 group and 19 [3%] in the placebo group), vascular disorders (30 [2%] vs 17 [3%]), and neoplasm (benign, malignant, and unspecified (29 [2%] vs 16 [2%]). Adjuvant treatment with the MAGE-A3 immunotherapeutic did not increase disease-free survival compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC. Based on our results, further development of the MAGE-A3 immunotherapeutic for use in NSCLC has been stopped. GlaxoSmithKline Biologicals SA.

Abstract P5-08-18: Biomarker (BM) results from MERiDiAN, a double-blind placebo (PLA)-controlled randomized phase 3 trial of 1st-line paclitaxel (PAC) with or without bevacizumab (BEV) for HER2-negative metastatic breast cancer (mBC)

Abstract Background: In the MERiDiAN trial, progression-free survival (PFS) was significantly improved with the addition of BEV to 1st-line PAC for mBC in both the ITT population and the subgroup with high baseline plasma (p) vascular endothelial growth factor (VEGF)-A, meeting both co-primary objectives. However, a predictive effect of pVEGF-A was not seen (PFS pVEGF-A-by-treatment interaction p=0.46; secondary endpoint). We report exploratory analyses of additional candidate BMs. Methods: Patients (pts) with HER2-negative mBC previously untreated with chemotherapy for mBC were randomized to receive PAC (90 mg/m2, days 1, 8 &amp; 15 q4w) combined with either PLA or BEV 10 mg/kg q2w until disease progression or unacceptable toxicity. Plasma, blood and archival tumor sampling was mandatory. The BM-evaluable population (BEP) comprised all ITT pts with a baseline sample for ≥1 BM. Prespecified exploratory BM analyses included: tumor (t) CD31 (marker of microvascular density) and tVEGF-A (molecular target of BEV) by immunohistochemistry; tPAM50 gene expression; and pVEGF receptor (R)-2 by ELISA. For CD31, tVEGF-A and pVEGFR-2 analyses, the BEP was dichotomized using the median of each BM as the cutoff between low and high subgroups. BEV effect on PFS was assessed within these subgroups (unstratified analyses). Similar subgroup analyses were done for each tPAM50 molecular subtype. No adjustment was made for multiplicity of testing as the analyses were exploratory. Results: The BEP included 467 (97%) of the 481 randomized pts. There was no correlation between CD31, tVEGF-A and pVEGFR-2. Correlations between BMs and PFS are shown below. The hazard ratio (HR) point estimate for BEV effect was lower in luminal B (0.59) than luminal A (0.96) or other smaller tPAM50 subgroups, but 95% CIs overlapped. pVEGFR-2 showed borderline significance for predictive potential using the median (10.2 ng/mL) as the cutoff. In further exploratory analyses using the 1st quartile (Q1; 8.7 ng/mL) as the cutoff, the PFS HR was 1.19 (95% CI 0.75–1.89) in the low (≤Q1) subgroup vs 0.60 (95% CI 0.46–0.79) in the high (&amp;gt;Q1) subgroup (interaction p=0.01). BMSubgroupNo. of events/ptsMedian PFS, mosPFS HR (95% Wald CI)Interaction p-value PAC–PLAPAC–BEVPAC–PLAPAC–BEV tPAM50 (N=421)Luminal A65/10367/10610.911.20.96 (0.68-1.35)Not applicable Luminal B46/6332/569.011.00.59 (0.38-0.93) HER2 enriched8/119/105.58.30.88 (0.33-2.32) Basal like29/3727/355.68.50.67 (0.39-1.14) tCD31 (N=410)Low69/9969/1067.610.80.71 (0.51-0.99)0.40 High78/11164/949.211.00.87 (0.62-1.22) tVEGF-A (N=434)Low78/10777/1107.411.00.68 (0.49-0.93)0.23 High76/11165/1069.210.90.89 (0.64-1.24) pVEGFR-2 (N=436)Low70/10773/1119.210.60.90 (0.64-1.25)0.06 High83/10968/1097.912.20.58 (0.42-0.81) Conclusions: Of the 4 candidate BMs explored here, potential predictive value was suggested only for pVEGFR-2. Correlations between pVEGFR-2 levels and outcome have been observed in previous retrospective analyses of breast cancer trials. However, similar levels in healthy donors and breast cancer pts, as well as the narrow dynamic range, may limit the utility of pVEGFR-2 as a potential predictive BM for BEV efficacy. Citation Format: Das Thakur M, Bais C, Estay I, Vaidyanathan R, O'Shaughnessy J, Cameron D, Hubeaux S, Quah C, Miles D. Biomarker (BM) results from MERiDiAN, a double-blind placebo (PLA)-controlled randomized phase 3 trial of 1st-line paclitaxel (PAC) with or without bevacizumab (BEV) for HER2-negative metastatic breast cancer (mBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-18.

Efficacy and Safety of Pregabalin in the Treatment of Patients With Painful Diabetic Peripheral Neuropathy and Pain on Walking.

This randomized, double-blind, placebo-controlled, multicenter, 2-period crossover study (two 6-week treatment periods separated by a 2-week washout period) evaluated the efficacy and safety of pregabalin (150 to 300 mg/d) for treatment of pain and pain on walking in patients with painful diabetic peripheral neuropathy (DPN) who experienced pain while walking. Co-primary efficacy endpoints were: (1) mean pain score (last 7 daily pain diary scores, 0 to 10 numeric rating scale at end of each treatment period) and (2) DPN pain on walking (0 to 10 numeric rating scale immediately after walking 50 feet [15.2 m] on flat surface). Secondary endpoints included other pain parameters, patient-reported sleep, health-related quality of life, and safety measures. Two hundred three patients were treated (pregabalin, n=198; placebo, n=186), with no statistically significant treatment difference for pregabalin versus placebo in the co-primary efficacy endpoints, mean DPN pain (P=0.0656) and mean DPN pain on walking (P=0.412). A carryover effect was observed. Analysis of co-primary endpoints for period 1 showed significant treatment difference for DPN pain (P=0.034) and DPN pain on walking (P=0.001). Treatment with pregabalin resulted in significant improvements versus placebo on prespecified patient global impression of change (end of period 1; P=0.002), and sleep interference rating scale (end of period 2; P=0.011). Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 13 (6.6%) pregabalin patients versus 5 (2.7%) placebo patients. Failure to meet the co-primary objectives may be related to carryover effect from period 1 to period 2, lower pregabalin dose (150 to 300 mg/d), and/or placebo response in painful DPN.

Treatment Rationale and Study Design for the JUNIPER Study: A Randomized Phase III Study of Abemaciclib With Best Supportive Care Versus Erlotinib With Best Supportive Care in Patients With Stage IV Non–Small-Cell Lung Cancer With a Detectable KRAS Mutation Whose Disease Has Progressed After Platinum-Based Chemotherapy

This clinical trial summary provides the background and rationale for the JUNIPER study (NCT02152631). JUNIPER is a randomized study of abemaciclib (200 mg orally every 12 hours) with best supportive care (BSC) versus erlotinib (150 mg orally every 24 hours) with BSC in patients with stage IV non–small-cell lung cancer (NSCLC) whose tumors have detectable Kirsten rat sarcoma (KRAS) mutations and whose disease has progressed after platinum-based chemotherapy and 1 other previous therapy, or who are not eligible for further chemotherapy. Approximately 550 patients will be randomized in a 3:2 ratio and stratified according to number of previous chemotherapy regimens (1 vs. 2), Eastern Cooperative Oncology Group performance status (0 vs. 1), sex (male vs. female), and KRAS mutation (G12C vs. others). Erlotinib was chosen as the control arm, because it is the only agent indicated for second- and third-line therapy in advanced NSCLC. Treatment will continue until disease progression or unacceptable toxicity occurs, with assessments every 28 days, followed by short-term and long-term follow-up. The coprimary efficacy objectives of this study are progression-free survival (PFS) and overall survival (OS); secondary objectives are overall response rate, changes in patient-reported pain and disease-related symptoms, changes in health status, resource utilization, safety and tolerability, and pharmacokinetics/pharmacodynamics. This design has 80% power to detect OS hazard ratio (HR) of 0.75 (type I error 0.045) and PFS HR of 0.67 (type I error 0.005). If the coprimary objectives (OS and PFS) are achieved, this study will provide a new alternative third-line treatment option for patients with NSCLC whose tumors have detectable KRAS mutations.

Abstract OT2-1-01: Fulvestrant alone versus fulvestrant and everolimus versus fulvestrant, everolimus and anastrozole: A Phase III randomized, placebo-controlled trial in postmenopausal patients with hormone-receptor-positive stage IV breast cancer: SWOG-Clinical Trials Ini

Abstract BACKGROUND: The median survival for women with hormone-receptor-positive (HR+) stage IV metastatic breast cancer (MBC) is 36 months. Strategies to improve outcome for postmenopausal women, include combinations of aromatase inhibitors (AIs) with either the estrogen receptor downregulator fulvestrant, or with the PI3kinase/AKT/mTOR signal inhibitor everolimus, as this pathway has been implicated as a mediator of resistance to endocrine therapies. However,fulvestrant 500 mg has not been tested in combination with everolimus alone, or in combination with everolimus and an AI. SPECIFIC AIMS/TRIAL DESIGN: S1222 (NCT02137837) is a randomized phase III double-blinded, placebo-controlled clinical trial and is currently accruing. Patients receive fulvestrant (500 mg IM every 2 weeks for 3 doses, then monthly) on all arms, everolimus 10 PO daily (Arms 2 and 3, placebo Arm 1), and anastrozole 1 mg daily (Arm 3), or placebo (Arms 2 and 1). The co-primary objectives are to compare progression-free survival (PFS) between fulvestrant and everolimus (Arm 2) vs. fulvestrant (Arm 1), and fulvestrant, everolimus, and anastrozole (Arm 3) vs. fulvestrant (Arm 1). Additional objectives include comparison of PFS between Arms 2 and 3, and overall survival (OS), response and clinical benefit rates, toxicities, feasibility, compliance, and OS among the study arms. Translational research goals are to test molecular determinants of response in circulating tumor cells (CTCs), assess a previously piloted CTC-Endocrine Therapy Index (CTC ETI), perform CTC-Next Generation Sequencing Analysis (CTC-NGS), and NGS on cancer tissue and germ line DNA. ELIGIBILITY CRITERIA: Postmenopausal women with histologically confirmed de novo or newly relapsed stage IV MBC, with HER2-negative and HR-positive (&amp;gt;1% positive nuclear staining) features, with either measurable, or evaluable disease are eligible. Previous neoadjuvant/adjuvant therapy allowed, but adjuvant anti-HR therapy must have been completed ≥ 12 months prior to enrollment. STATISTICAL METHODS/TARGET ACCRUAL: This is a parallel randomized design with equal allocation to the three arms: (1) fulvestrant + placebo for everolimus + placebo for anastrozole; (2) fulvestrant + everolimus + placebo for anastrozole; (3) fulvestrant, everolimus, and anastrozole. PFS is the primary outcome. There are two coprimary hypotheses: (1) Arm 2 versus Arm 1; and (2) Arm 3 versus Arm 1, each will be tested at α = 0.025 (2-sided) .Arm 2 versus Arm 3 is a secondary comparison. Sample size computations are based on accrual of 33 patients per month for 24 months resulting in a computed accrual total of 792. We estimate that the final analysis will occur 24 months after the last patient is accrued, an average followup of 36 months at the time of the final analysis with an expected trial duration of 4 years. *SWOG-CTI manages the non-federally funded components of SWOG under The Hope Foundation. The study is supported by AstraZeneca and Novartis Pharmaceuticals Corp. Citation Format: George Somlo, William Barlow, Halle Moore, Julie Gralow, Anne Schott, Daniel Hayes, Peter Kuhn, James Hicks, Danika Lew, Debu Tripathy, Gabriel Hortobagyl. Fulvestrant alone versus fulvestrant and everolimus versus fulvestrant, everolimus and anastrozole: A Phase III randomized, placebo-controlled trial in postmenopausal patients with hormone-receptor-positive stage IV breast cancer: SWOG-Clinical Trials Ini [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-01.

Design of a large outcome trial for a multivalent human papillomavirus L1 virus-like particle vaccine

BackgroundThe 9-valent human papillomavirus (HPV) (9vHPV) vaccine targets the four HPV types (6/11/16/18) covered by the licensed quadrivalent HPV (qHPV) vaccine and five additional types (31/33/45/52/58). A large outcome trial of 9vHPV vaccine was conducted. MethodsAn active control (qHPV vaccine) was used because a placebo is not ethically acceptable. Since qHPV vaccine is (and 9vHPV vaccine was anticipated to be) highly efficacious against HPV 6/11/16/18, low incidence of HPV 6/11/16/18-associated disease was expected. Consequently, an efficacy comparison of 9vHPV versus qHPV vaccine for HPV 6/11/16/18 would have been prohibitively large in size. Moreover, no minimum antibody level predicting protection against infection or disease is defined for HPV vaccination. As an alternative approach, the two vaccines were compared using immunogenicity bridging for HPV 6/11/16/18 and clinical efficacy for HPV 31/33/45/52/58. ResultsThe two co-primary objectives were to demonstrate: (1) non-inferior anti-HPV 6/11/16/18 antibody response; and (2) superior efficacy in HPV 31/33/45/52/58-related clinical outcome, for 9vHPV vaccine versus qHPV vaccine. For HPV 6/11/16/18, supportive analyses included a non-inferiority assessment of the percent risk reduction (compared to historical placebo) for 9vHPV versus qHPV vaccine. ConclusionsA Phase III study of 9vHPV vaccine was successfully implemented. Experience from this study design may be applicable when developing a multivalent vaccine covering the same serotypes as an existing vaccine plus additional serotypes and there is no immune correlate of protection. Also, this study established that efficacy of a new HPV vaccine may be demonstrated using immunogenicity endpoints, which may open new options in HPV vaccine development.

Commentary on “Intermittent versus continuous androgen deprivation in prostate cancer.” Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Kanaga Sundaram S, Small EJ, Dawson NA, Donnelly BJ, Venner PM, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Ely B, Moinpour CM, Vogelzang NJ, Thompson IM Jr, University of Michigan, Division of Hematology/Oncology,

BackgroundCastration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence. MethodsMen with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization. ResultsA total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P=0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events. ConclusionsOur findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.).

Immunogenicity and safety of the candidate RTS,S/AS01 vaccine in young Nigerian children: A randomized, double-blind, lot-to-lot consistency trial

BackgroundFor regulatory approval, consistency in manufacturing of vaccine lots is expected to be demonstrated in confirmatory immunogenicity studies using two-sided equivalence trials. This randomized, double-blind study (NCT01323972) assessed consistency of three RTS,S/AS01 malaria vaccine batches formulated from commercial-scale purified antigen bulk lots in terms of anti-CS-responses induced. MethodsHealthy children aged 5–17 months were randomized (1:1:1:1) to receive RTS,S/AS01 at 0-1-2 months from one of three commercial-scale purified antigen bulk lots (1600 litres-fermentation scale; commercial-scale lots), or a comparator vaccine batch made from pilot-scale purified antigen bulk lot (20 litres-fermentation scale; pilot-scale lot). The co-primary objectives were to first demonstrate consistency of antibody responses against circumsporozoite (CS) protein at one month post-dose 3 for the three commercial-scale lots and second demonstrate non-inferiority of anti-CS antibody responses at one month post-dose 3 for the commercial-scale lots compared to the pilot-scale lot. Safety and reactogenicity were evaluated as secondary endpoints. ResultsOne month post-dose-3, anti-CS antibody geometric mean titres (GMT) for the 3 commercial scale lots were 319.6EU/ml (95% confidence interval (CI): 268.9–379.8), 241.4EU/ml (207.6–280.7), and 302.3EU/ml (259.4–352.3). Consistency for the RTS,S/AS01 commercial-scale lots was demonstrated as the two-sided 95% CI of the anti-CS antibody GMT ratio between each pair of lots was within the range of 0.5–2.0. GMT of the pooled commercial-scale lots (285.8EU/ml (260.7–313.3)) was non-inferior to the pilot-scale lot (271.7EU/ml (228.5–323.1)). Each RTS,S/AS01 lot had an acceptable tolerability profile, with infrequent reports of grade 3 solicited symptoms. No safety signals were identified and no serious adverse events were considered related to vaccination. ConclusionsRTS,S/AS01 lots formulated from commercial-scale purified antigen bulk batches induced a consistent anti-CS antibody response, and the anti-CS GMT of pooled commercial-scale lots was non-inferior to that of a lot formulated from a pilot-scale antigen bulk batch.

Comparison of the safety and immunogenicity of an MF59®-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects

AimAdjuvanted influenza vaccines can overcome the poor antibody response of conventional non-adjuvanted vaccines in the elderly. We evaluated the immunogenicity, safety and clinical effectiveness of an MF59®-adjuvanted trivalent influenza vaccine (aTIV) compared with a non-adjuvanted vaccine (TIV) in subjects ≥65 years old, with or without co-morbidities. MethodsIn 2010–2011, subjects (N=7082) were randomized to receive one dose of aTIV or TIV. Co-primary objectives were to assess lot-to-lot consistency of aTIV, non-inferiority, superiority and immunogenicity 22 days after vaccination. Clinical effectiveness, reactogenicity and serious adverse events were monitored up to Day 366. ResultsThe immunological equivalence of three lots of aTIV was demonstrated. aTIV was not only non-inferior to TIV but also elicited significantly higher antibody responses at Day 22 than TIV against all homologous and heterologous strains, even in subjects with co-morbidities. Superiority was not established. Reactogenicity was higher in the aTIV group, but reactions were mild to moderate and transient. ConclusionsaTIV elicited a significantly higher antibody response than TIV, especially against A/H3N2 strains, although superiority by pre-defined criteria was not formally met. The study demonstrates potential immunological benefits of MF59-adjuvanted influenza vaccines for the elderly.This trial was registered with www.clinicaltrials.gov (NCT01162122).

SoMore trial: Early metabolic response assessment of a sorafenib (SOR) and capecitabine (CAP) combination in chemorefractory metastatic colorectal cancer (mCRC).

524 Background: The SOR-CAP combination has shown clinical activity in several phase I-II trials involving metastatic breast cancer and mCRC patients (pts). SoMore aims to substantiate the combination’s effects in mCRC refractory to all medications and the predictive value of early metabolic response (MR) on survival. Methods: SoMore (EUDRACT 2010-023695-91) has 2 coprimary objectives: 1) to demonstrate an overall survival (OS) rate at 6 months (mths) &gt; 30%, and 2) to compare OS between pts with and without MR. CAP was given at 1700 mg/m²/day (D), 2 weeks out of 3. SOR was administered at 600mg/D for the first cycle, then at 800mg/D until progression or unacceptable toxicity. FDGPET-CT was performed at baseline and before the 2nd cycle. MR analysis was centralized and blinded for the investigators. Results: From February to October 2011, 92 eligible pts were prospectively recruited in 6 Belgian centers: M/F: 54%/46%; ECOG PS 0/1: 55%/45%; median age: 61. A median of 5 treatment cycles were given (0-28+). Grade 3-4 toxic reactions were reported in 61.2%, mainly fatigue (18%), hand-foot skin reaction (14%) and diarrhea (11%), but no toxic death. 6.9% of the pts stopped therapy due to toxicity. 6 mths OS was 71% (95% CI: 61%-79%), significantly &gt;30% (p&lt;0.001). 47% of the 79 pts evaluable for metabolic assessment showed homogeneous MR (HMR) of all metastatic lesions, 32% mixed MR and 21% homogeneous non-MR. Median overall OS and PFS of the intent-to-treat population and of pts with and without HMR are shown in the table below. Hazard ratio for HMR was 0.34 (95% CI, 0.21 to 0.56) p-value &lt;0.001 for PFS and 0.59 (95% CI, 0.37 to 0.96) p-value 0.03 for OS. Conclusions: These data suggest robust efficacy for the SOR-CAP combination in heavily pretreated mCRC, associated with high but manageable toxicity. Early MR assessment, by detecting unresponsive lesions within the whole body tumoral load, is able to capture the pts’ likelihood of benefit, opening the path to personalized medicine. Clinical trial information: NCT01290926. [Table: see text]

Comprehensive geriatric assessment in patients undergoing transcatheter aortic valve implantation–rationale and design of the European CGA-TAVI registry

PurposeAortic stenosis (AS) is the most common valvular abnormality in the elderly population. For inoperable patients or those at high-risk for surgery, transcatheter aortic valve implantation (TAVI) has become an alternative therapeutic option. The aim of the “Comprehensive geriatric assessment for transcatheter aortic valve implantation” (CGA-TAVI) registry is to evaluate the effectiveness of TAVI from the perspective of the geriatrician and to identify patient characteristics and indicators related to complications and clinical benefits for patients with symptomatic severe calcified degenerative AS undergoing TAVI. Materials and methodsThe CGA-TAVI registry is an international, multi-center, prospective, observational registry across Europe with consecutive patient enrolment. The registry will enrol up to 200 patients with AS undergoing TAVI, starting August 2013. CGA-TAVI has two co-primary objectives: (1) Establish predictive value of Comprehensive geriatric assessment (CGA) for mortality and/or hospitalization in TAVI patients. (2) Demonstrate CGA changes within 3 months after TAVI. Secondary objectives are: (1) Establish predictive value of CGA in TAVI patients for all-cause hospitalization, TAVI-related hospitalization, and nursing home admission. (2) Develop a comprehensive score for the assessment of TAVI patient prognosis. ConclusionsThe data obtained from the CGA-TAVI registry will supplement previous results to document the potential value of the effectiveness of TAVI from the perspective of geriatricians and will allow the assessment of the predictive value of CGA for mortality and/or hospitalization in elderly TAVI patients.

Commentary on “Intermittent versus continuous androgen deprivation in prostate cancer.” Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Kanaga Sundaram S, Small EJ, Dawson NA, Donnelly BJ, Venner PM, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Ely B, Moinpour CM, Vogelzang NJ, Thompson IM Jr., University of Michigan, Division of Hematology/Oncology,

BackgroundCastration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence. MethodsMen with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization. ResultsA total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P = 0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events. ConclusionsOur findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life.

EARLY Treatment with azilsartan compared to ACE-inhibitors in anti-hypertensive therapy – rationale and design of the EARLY hypertension registry

BackgroundArterial hypertension is highly prevalent but poorly controlled. Blood pressure (BP) reduction substantially reduces cardiovascular morbidity and mortality. Recent randomized, double-blind clinical trials demonstrated that azilsartan medoxomil (AZM) is more effective in reducing BP than the ubiquitary ACE inhibitor ramipril. Therefore, we aimed to test whether these can be verified under clinical practice conditions.Methods/DesignThe “Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy” (EARLY) registry is a prospective, observational, national, multicenter registry with a follow-up of up to 12 months. It will include up to 5000 patients on AZM or ACE-inhibitor monotherapy in a ratio of 7 to 3. A subgroup of patients will undergo 24-hour BP monitoring. EARLY has two co-primary objectives: 1) Description of the safety profile of azilsartan and 2) achievement of BP targets based on recent national and international guidelines for patients treated with azilsartan in comparison to those treated with ACE-inhibitors. The most important secondary endpoints are the determination of persistence with treatment and the documentation of cardiovascular and renal events. Recruitment commenced in January 2012 and will be completed by February 2013.ConclusionsThe data obtained will supplement previous results from randomized controlled trials to document the potential value of utilizing azilsartan medoxomil in comparison to ACE-inhibitor treatment for target BP achievement in clinical practice.