Intention-to-treat Cohort Research Articles

Safety and efficacy of hCDR1 (Edratide) in patients with active systemic lupus erythematosus: results of phase II study

ObjectiveTo evaluate the safety and efficacy of hCDR1 (Edratide) in patients with systemic lupus erythematosus (SLE).MethodsPatients (n=340) with SLE ≥4 ACR criteria (4–11, mean 7) with active disease (SLEDAI-2K of...

598P - Cetuximab Plus Mfolfox-6 As First-Line Therapy for Patients with Kras Wild-Type Unresectable Colorectal Liver-Limited Metastases: an Open, Non-Randomized, Multicenter Phase Ii Clinical Trial (Clime Study)

ABSTRACT Aim: This study aims to observe whether the addition of cetuximab(cet) further increases the curative resection rate and improves long-term survival for patients(pts) with KRAS wide-type unresectable colorectal liver limited metastases in China. Methods: Pts were planned to receive cetuximab (500 mg/m2 q2w) plus mFOLFOX-6 including Oxaliplatin 85 mg/m2 plus CF 400 mg/m2 and 5-FU as a 400 mg/m2 bolus followed by 2400 mg/m2 infusion over 46 hours on day 1, repeated every 2 weeks until metastatic leision became resectable or for a maximum of 9 cycles. The primary endpoint was R0 resection rate in intention to treat (ITT) cohort. The second endpoint included objective response rate (ORR), progression-free survival (PFS), over survival (OS) and safety. Per protocol (PP) cohort were defined as pts without major protocol violation and whose tumours were assessed for hepatectomy feasibility by a multidisciplinary team. Results: Between Dec. 2010 and Nov. 2013, 204 pts were screened from 17 centers in China. 130 (63.7%) pts had KRAS exon 2 wild-type tumors. In the ITT cohort (100 cases), the ORR was 61% (95% CI 50.7%, 70.6%), for PP cohort (71 cases), the ORR was 70.4% (95% CI 58.4%, 80.7%). 39 (39%) pts were technically resectable but 34 pts went through surgical treatment. R0 resections were achieved in 27 cases (27%, 95%CI 18.6%, 36.8%), R0/R1 resection and/or radiofrequency ablation were achieved in 33 cases. The ORRs of resectable (39 cases) and unresectable (61 cases) pts were 74.4%, 52.5%, respectively. The median PFS was 10.6m in ITT cohort (95% CI 6.9, 14.7). 90 pts experienced adverse events, mainly including rash (any Gr 68%, Gr 3/4 5%), neutropenia (43%) and malaise (20%). 7 SAEs were reported and 3 pts died. Two pts died during pre-operative chemotherapy from intestinal obstruction and respiratory/cardiac arrest. The other patient died from leukocyte inhibitory and septic shock, and that a causal relationship of study drug cannot be excluded. Conclusions: With interim analyses combination therapy comprising cetuximab and mFOLFOX-6 was well tolerated with acceptable ORR, R0 resection rates and PFS. Disclosure: All authors have declared no conflicts of interest.

Initial clinical experience with the Coherex FlatStent™ and FlatStent™ EF PFO closure system for in‐tunnel PFO closure: Results of the Coherex‐EU study

The Coherex-EU Study evaluated the safety and efficacy of PFO closure utilizing novel in-tunnel PFO closure devices. Transcatheter closure of patent foramen ovale (PFO) followed the development of transcatheter closure devices designed to patch atrial septal defects (ASDs). The Coherex FlatStent™ and FlatStent™ EF devices were designed specifically to treat PFO anatomy. A total of 95 patients with a clinical indication for PFO closure were enrolled in a prospective, multicenter first in man study at six clinical sites. Thirty-six patients received the first-generation FlatStent study device, and 57 patients received the second-generation FlatStent EF study device, which was modified based on clinical experience during the first 38 cases. Two patients enrolled to receive the first generation did not receive a device. At 6 months post-procedure, 45% (17/38) of the intention-to-treat (ITT) cohort receiving the first-generation FlatStent device had complete closure, 26% (10/38) had a trivial residual shunt, and 29% (11/38) had a moderate to large residual shunt. In the ITT cohort receiving the second-generation FlatStent EF device, 76% (43/57) had complete closure, 12% (7/57) had a trivial shunt, and 12% had a moderate to large shunt. Five major adverse events occurred, all without sequelae. This initial study of the Coherex FlatStent/FlatStent EF PFO Closure System demonstrated the potential for in-tunnel PFO closure. The in-tunnel Coherex FlatStent EF may offer an alternative to septal repair devices for PFO closure in appropriately selected patients; however, further investigation will be necessary to establish the best use of this device.

A Matched Comparison of Cyclophosphamide, Bortezomib and Dexamethasone (CVD) Versus Cyclophosphamide, Thalidomide and Dexamethasone (CTD) in the Treatment of Mayo Cardiac Stage III Patients with AL Amyloidosis.

AbstractAbstract 2966 Introduction:Poor survival in AL amyloidosis is largely driven by outcomes in patients with advanced cardiac disease. To date, the Mayo cardiac staging system is the most widely used tool to identify these high risk patients. For stage III patients few treatment options exist to modify the natural history of this disease with up to 50% dying within the first 6 months. Moreover, there are currently no studies comparing different regimens in the novel agent era specifically addressing this group. Here we present a matched comparison examining response and survival endpoints after upfront treatment in Mayo stage III patients using either Cyclophosphamide, Bortezomib and Dexamethasone (CVD) or Cyclophosphamide, Thalidomide and Dexamethasone (CTD), the current standard of care for this disease in the United Kingdom. Patients and Methods:The primary cohort comprises 78 patients (39 in each arm) referred to the National Amyloidosis Centre in London between 2008–2012. All patients had cardiac involvement by the 2005 consensus criteria and all were Mayo stage III. The CVD cohort reflects all patients seen at the NAC with Mayo stage III disease treated with this regimen upfront. Based on baseline NT-proBNP (>8000ng/L) and dFLC (>180mg/L) the patients were then matched with a recent cohort treated with CTD as first line therapy. The CVD and CTD regimens were recommended as previously described (1,2). Dose modifications were at the discretion of the treating haematologist. Both conventional haematologic responses and dFLC responses were examined (3,4). Overall survival (OS) was calculated by the Kaplan-Meier method and calculated from the start of treatment until death or last follow-up. To correct for the influence of early deaths on response rates a landmark analysis was performed in patients surviving at least 3 months from treatment (n=21 (CVD) and n=30 (CTD)). Results:In the intention-to-treat (ITT) cohort response rates are comparable although there was a trend to higher CR rates with the CVD regimen (table 1). On an ITT basis, there was no statistically significant difference in the 1-year OS (59.4% vs 46.2% for CVD and CTD respectively, p = 0.9, figure 1a). A high rate of early deaths is noted. 23.7% of CVD and 13.1% of CTD patients died within 6 weeks (p = 0.24). 36.8% of CVD and 23.7% of CTD patients died within 3 months (p = 0.22). In the landmark analysis upfront therapy with CVD correlated with an improved 1-year OS (94% vs 62.1%, p = 0.01, figure 1 b). This may be partly driven by the increased CR rate in the CVD cohort compared to those receiving CTD (47% vs 24% respectively, p = 0.03, table 1). Conclusion:Compared with CTD, treatment with CVD was not associated with a reduction in the high rate of early deaths often seen in patients with Mayo cardiac stage III disease. However, these data suggest that survival of patients treated with CVD upfront may be superior among those who remain alive after the first 3 months, consistent with the higher CR rates achieved. While it did not reach statistical significance the high rate of early deaths indicates that further optimisation and better supportive care strategies are required during the early stages of treatment especially with CVD. Ongoing phase III trials are currently underway to address these issues in a prospective manner. [Display omitted] The ITT cohort is shown in (A) and the landmark cohort is shown in (B). Solid and dashed lines reflect CVD and CTD treated patients respectively. [Display omitted] Disclosures:Wechalekar:Janssen-Cilag: Honoraria.

Efficacy of a Bivalent L1 Virus-Like Particle Vaccine in Prevention of Infection With Human Papillomavirus Types 16 and 18 in Young Women: A Randomized Trial

This double-blind, multicenter, randomized, placebo-controlled study was conducted to assess the efficacy of a bivalent human papillomavirus (HPV)-16/18 L1 virus-like particle vaccine in preventing cervical infection with HPV-16/18. The study participants were recruited among healthy women aged 15 to 25 years from 32 healthcare facilities in Brazil, Canada, and the United States. A total of 1113 women enrolled in the study. Enrollees had 6 or fewer lifetime sexual partners, no history of cervical abnormality, and were negative for high-risk HPV types. The subjects were randomized to receive placebo injections or the vaccine that contained 20 μg each of HPV-16 and HPV-18 virus-like particles. Women received 1 0.5-mL dose of vaccine or placebo at enrollment, 1 month, and 6 months. Cervical smears were taken at 6, 12, and 18 months. In addition, participants collected self-administered cervicovaginal samples at enrollment, 6 months, and every 3 months thereafter. Serologic testing for immunogenicity was performed at 0, 1, 6, 12, and 18 months. The women kept a diary of symptoms for 1 week after each injection, and symptoms were evaluated by telephone interview 1 month after each injection. Outcome results at 27 months were available for 81 women in the vaccine group and 59 in the placebo group. Study subject data were analyzed in two different cohorts. One analysis was performed including women who received all 3 injections and who had complete follow-up data. They comprised the ′according-to-protocol′ cohort (ATP). Another analysis was performed using data from the ′intention-to-treat′ cohort (ITT), which consisted of all enrolled participants who had at least one dose of vaccine or placebo and had any data available for analysis. There were 560 subjects randomized to receive vaccine and 553 randomized to receive placebo. The average age was 20 years. The two groups had similar patterns of risk factors for HPV infection. There were no cases of persistent HPV-16/18 among ATP women who received the vaccine. The vaccine was 100% effective against HPV-16, HPV-18, and HPV-16/18 (P < 0.0001). The effectiveness against HPV-18 infection was not significant until 27 months. In comparison, 13 (2.1%) women in the ATP group who received placebo developed a persistent HPV-16 infection, 4 (0.6%) had persistent HPV-18, and 16 (2.6%) had persistent HPV-16/18. In the ITT cohort, there were 4 women in the vaccine group who were positive for persistent HPV-16 (0.5%: efficacy 84.5%, P < 0.0001), 1 positive for persistent HPV-18 (0.1%: efficacy 91.1%, P = 0.003) and 4 with HPV-16/18 (0.5%: efficacy 87.5%, P < .0001). In the ITT placebo group, 25 women (3.2%) were positive for persistent HPV-16, 11 (1.4%) had persistent HPV-18, and 31 (4.0%) persistent HPV-16/18. Among the 560 women who received the vaccine, 2 developed cervical abnormalities associated with HPV types 16 or 18. One had atypical squamous cells of unknown significance (ASGUS) and 1 had a low-grade squamous intraepithelial lesion (LSIL). Of the 553 women who received placebo, 27 developed cervical abnormalities, including 15 ASCUS, 14 LSIL, and 1 high-grade squamous intraepithelial lesion (HSIL). The vaccine had an efficacy of 95.2% against HPV-16 (P < 0.0001), 91.2% against HPV-18 (P = 0.003), and 92.9% against HPV-16/18 (P < 0.0001). Cervical intraepithelial neoplasia (CIN) 1 or 2 was seen in 7 women, including 1 CIN 1 in the vaccine group, and 3 each CIN 1 and CIN 2 in the placebo group.