ALBERT

Description: Background: A new subcutaneous formulation of rituximab (RSC) has been developed which offers reduced treatment burden for patients compared to intravenous rituximab (RIV) as well as resource savings at the treatment facility. Additionally, availability of RSC would potentially allow patients to be treated primarily IV-free with orally administered partner therapies. The Phase 3 SABRINA study (NCT01200758) investigated induction RIV or RSC plus chemotherapy followed by maintenance RIV or RSC in patients with follicular lymphoma (FL). Pharmacokinetic non-inferiority was previously reported for RSC (1400mg) compared with RIV (375mg/m2) as well as comparable efficacy and safety (Davies et al. Lancet Oncol 2014;15:343-52; Davies, et al. Haematologica 2015;100:P687). Here we present updated efficacy and safety results including overall response rates (ORR) at the end of maintenance and time to event (progression-free [PFS], overall [OS], and event-free [EFS] survival) data with a median follow-up of 37 months. Methods: Patients with treatment-naïve CD20+ grade 1-3a FL (n=410) were randomized to receive RIV or RSC, stratified by FL International Prognostic Index score, chemotherapy regimen, and region. All patients received RIV 375mg/m2 in Cycle 1; for Cycles 2-8, patients received RIV 375mg/m2 or RSC 1400mg every 3 weeks. Patients received ≤8 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or 8 cycles of CVP (cyclophosphamide, vincristine and prednisone). During maintenance, patients received RIV or RSC every 8 weeks for 2 years. Non-serious adverse events (AEs) were reported for 28 days following the last dose of rituximab. Serious AEs (SAEs) were recorded for 1 year post-treatment or until the start of new anti-lymphoma treatment. SAEs considered possibly related to study treatment were recorded indefinitely. Results: Based on investigator assessments for the intent-to-treat population (RIV n=205; RSC n=205), ORR at the end of maintenance was comparable between treatment arms: (78.1%, 95% CI [71.3, 83.9] for RIV vs. 77.9%, 95% CI [71.0, 83.9] for RSC) (Table 1). Analyses of the time-to-event endpoints PFS (HR, 0.84, 95% CI [0.57, 1.23]) (Fig.1), EFS (HR, 0.91, 95% CI [0.64, 1.31), and OS (HR, 0.81, 95% CI [0.42, 1.57) showed no differences in efficacy for the SC vs. the IV formulation. In total, 407 patients received ≥1 dose of rituximab (safety population). Six RSC patients discontinued treatment after Cycle 1 (RIV in both arms) and were included in the RIV safety population (RIV n=210; RSC n=197); 86% of patients started maintenance (RIV n=178, 85%; RSC n=172, 87%). Overall, there were similar incidences of patients with ≥1 AE (95% vs. 96%), grade ≥3 AEs (55% and 56%), and SAEs (34% and 37%) for RIV vs. RSC, respectively (Table 2). The most frequent AEs reported overall (RIV vs. RSC) were neutropenia (27% vs. 32%), nausea (22% vs. 31%), constipation (26% vs. 25%), cough (13% vs. 23%), and fatigue (18% vs. 20%). The most frequently reported AEs during the maintenance phase of the study were upper respiratory tract infection (7% vs. 11%) and cough (11% vs. 12%) for RIV vs. RSC, respectively. Overall, AEs associated with B-cell depletion, including neutropenia, febrile neutropenia, and grade ≥3 infections, were balanced between the SC and IV treatment arms. The change in route of administration led to an expected higher incidence of local cutaneous reactions in the RSC arm (2% RIV vs. 23% RSC) with injection site erythema, injection site pain, and rash being most frequently reported. All reported events, except for 1 AE of injection site rash in the RSC arm at Cycle 2, were of mild or moderate intensity (grade ≤2). Incidence of local cutaneous reactions decreased over subsequent treatment cycles. At data cut-off, 36 deaths had been reported: 20 (9.8%) in the RIV arm and 16 (7.8%) in the RSC arm. Conclusions: Overall, there were no new clinically relevant safety signals observed with RSC and the safety profile was comparable to that of RIV. Response rates as well as PFS and OS data for rituximab SC were comparable to rituximab IV and indicate that the anti-lymphoma activity of rituximab is not impaired when given subcutaneously. The availability of RSC administration over approximately 6 minutes has positive implications for patient and healthcare professional convenience, as well as healthcare resource savings, without compromising efficacy or safety. Figure 1. Figure 1. Disclosures Davies: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel to scientific conferences, Research Funding; GSK: Research Funding; Karyopharma: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodation, expenses, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Research Funding. Leppä:Roche: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda Pharmaceuticals: Consultancy, Honoraria, Other: Travel expenses; Janssen: Consultancy, Research Funding; Mundipharma: Research Funding; CTI Bio Pharma: Consultancy; Bayer: Other: Travel expenses, Research Funding. Cotting:Roche: Employment, Equity Ownership. Veenstra:Roche: Employment. Zharkov:Roche: Employment. Dixon:Roche Products Limited: Employment, Equity Ownership. Barrett:Roche Products Ltd.: Employment, Equity Ownership. Macdonald:Roche: Consultancy, Honoraria; Lundbeck Canada: Consultancy, Honoraria; Gilead: Consultancy, Honoraria.

Description: Abstract 1629 Rituximab and chemotherapy induction followed by maintenance rituximab is the backbone of therapy for FL. IV rituximab administration can take several hours; therefore, a SC formulation has been developed which may shorten administration times and increase convenience for pts. Achieving clinically effective rituximab serum concentrations is essential for optimal activity (Yin et al, ASCO 2010, abstract e13108). Therefore, achieving non-inferior Ctrough levels with SC compared with IV dosing is expected to provide comparable efficacy. BO22334 (NCT01200758) is a two-stage, phase III, international, randomized, controlled, open-label study of SC vs IV rituximab combined with up to 8 cycles of CHOP or 8 cycles of CVP chemotherapy followed by maintenance in pts with previously untreated FL. Pts were scheduled to receive 8 cycles of rituximab, regardless of the number of chemotherapy cycles. In the SC arm, rituximab was administered IV (375 mg/m2) for the first cycle, with following cycles administered SC (1400 mg). Stage 1 aimed to confirm that the SC rituximab dose of 1400 mg (dose based on phase I study BP22333; Salar et al, EHA 2012, abstract 0794), resulted in non-inferior Ctrough rituximab levels compared with the 375 mg/m2 IV dose when given as 3-weekly induction therapy combined with chemotherapy. The stage 1 primary endpoint was non-inferiority of the Ctrough,SC:Ctrough,IV ratio (limit for non-inferiority was Ctrough ratio 〉 0.8) at Cycle 7 of induction. Secondary endpoints included comparisons of SC vs IV: area under the serum concentration–time curve (AUC); end of induction ORR; CR (CR/CRu); and safety. Previously untreated pts with histologically confirmed CD20-positive grade 1, 2, or 3a FL requiring treatment (N = 127) were randomized 1:1 to SC (n = 63) or IV (n = 64) rituximab, stratified by Follicular Lymphoma International Prognostic Index score, chemotherapy, and region. Allocation to R-CHOP or R-CVP was at the investigator's discretion; 40 pts in each arm (63%) received CHOP chemotherapy and the remaining pts (37%) received CVP chemotherapy. The primary PK endpoint was met with a geometric mean of 134.6 μg/mL for the rituximab SC arm (n = 48) and 83.1 μg/mL for the rituximab IV arm (n = 54) resulting in an SC:IV ratio of 1.62 (90% confidence interval [CI]: 1.36, 1.94). The Ctrough achieved with SC rituximab was therefore concluded to be non-inferior to IV administration. The geometric mean ratio of AUCSC:AUCIV (1.378 [90% CI: 1.241, 1.530]) was also non-inferior. After a median follow-up of approximately 9 months, the overall safety profile was as would be expected for IV administration, with no new or unexpected adverse events (AEs). In the SC and IV arms AEs were experienced by 92% (n = 57) and 88% of pts (n = 57), respectively. Grade 3/4 AE were observed in 47% of pts in the SC arm and 46% in the IV arm. The only grade 3/4 AE occurring in 〉 10% of pts was neutropenia (26% in the SC arm, 22% in the IV arm) which was not associated with increased infection rate (grade 3/4 infections and infestations: 5% SC vs 9% IV). Total administration-related reactions (ARRs; any events occurring during/within 24 hours of drug administration that were considered treatment-related by the study investigator) were higher in the SC vs IV arm (50% vs 32%) with the majority being grade 1/2; there were no grade 4 ARRs. Individual ARRs (all grades) occurring in ≥5% of pts in the SC vs IV arms were: erythema (8% vs 3%), pruritus (6% vs 3%), chills (3% vs 6%), injection site erythema (10% vs 0%), and vomiting (3% vs 6%). Investigator-assessed ORR was 90.5% (95% CI: 80.4, 96.4) in the SC arm and 84.4% (95% CI: 73.1, 92.2) in the IV arm. Complete response (CR/CRu) rates were 46.0% (29/63 pts, 95% CI: 33.4, 59.1) for the SC arm and 29.7% (19/64 pts, 95% CI: 18.9, 42.4) for the IV arm. Stable and progressive disease rates were similar in each arm. An independent review of response assessments is planned. Data demonstrate PK non-inferiority and comparable efficacy for SC (1400 mg) compared with IV (375 mg/m2) rituximab administration, with similar ORR and CR rates in the rituximab SC and IV arms. Overall, SC and IV rituximab AE profiles were similar; ARRs were mostly of mild/moderate intensity. Stage 1 pts are continuing to receive maintenance treatment with SC or IV rituximab. Stage 2 of the study has opened recruitment of an additional 280 pts who will be randomized to receive SC (1400 mg) or IV rituximab. Disclosures: Davies: Roche: Consultancy, Honoraria, Research Funding. Off Label Use: Pharmacokinetics (PK), safety and overall response rate (ORR) achieved with subcutaneous (SC) administration of rituximab in combination with chemotherapy were comparable to those achieved with intravenous (IV) administration in patients (pts) with follicular lymphoma (FL) in the first-line setting. Siritanaratkul:Roche: Research Funding. Solal-Céligny:Roche, France: Consultancy, Honoraria, Research Funding. Boehnke:F. Hoffmann-La Roche: Employment. Berge:Roche: Employment. McIntyre:Roche: Employment. Barrett:Roche: Employment. Macdonald:Roche, Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Abstract 1390 Introduction: Levels of minimal residual disease (MRD) have been shown to correlate with PFS in previously untreated patients with CLL (CLL8, Boettcher et al. Leukemia, 2009). Patients who remain MRD positive after treatment have a higher risk of relapse. Eradication of MRD is therefore a desirable clinical endpoint of treatment. We were interested to assess this correlation in REACH, a randomized international clinical study in previously treated CLL patients, randomized 1:1 for treatment with rituximab, fludarabine and cyclophosphamide© R-FC (276 patients) or FC alone (276 patients); (Robak et al. JCO 2010). Methods: While MRD quantification by flow cytometry requires an identifiable stable phenotype and fresh blood samples, PCR based methods can be performed centrally on frozen samples. We have therefore developed a Realtime Quantitative (RQ) PCR method, using patient-specific IgVH (immunoglobulin variable heavy chain) gene rearrangements as targets. Briefly, genomic DNA was isolated from CD19 sorted B-cells. ASO (allele-specific oligonucleotide) primers were designed matching the hypervariable N-D-N region of the patient-specific leukemic clone and used with reverse consensus primers and hydrolysis probes annealing to the family-specific joining region of the IGH rearrangement (Brüggemann et al., Leukemia, 2004). Maximum sensitivity and quantitative range were defined for every RQ-PCR. Patients were categorized as molecular responders (MRD negative) if there was no detectable clonal IgH rearrangement, using a sensitivity cut-off of 1×10-4. Molecular response was assessed at the time of CR confirmation and 6 months later (if CR was maintained). Results: Among the 103 patients who achieved CR during the study, 86 patients had at least one MRD assessment in peripheral blood, 92 patients in bone marrow. Since many patients had a CR confirmation at different time points during the follow-up period, we initially analyzed the MRD levels only in patients who had achieved confirmed complete response at end of treatment +/−3 month (“EOT - period”). The rate of MRD negativity in blood (22 pts: 5(15) FC, 6(7)R-FC) at EOT was 33% for patients treated with FC, and 86% for patients treated with R-FC (p=0.06); In bone marrow at the EOT (61 patients: 5(27) FC, 20(34) R-FC) the rates were 19% and 59%, respectively (p= 0,02), indicating higher efficacy of the Rituximab containing regimen in eradication of residual disease; This is in line with the previously reported results using FACS analysis of MRD in the CLL8 trial; the differences in the detection rate in blood versus bone-marrow, suggest a higher sensitivity for detection of MRD in bone marrow. We therefore compared the levels of MRD negativity in samples from blood and bone marrow in patients where both samples were taken at the same time point. Results were concordant in 8/9 patients, one patient had a positive result in bone marrow with no detectable signal in blood. This supports the notion that assessment of MRD in bone marrow of CLL patients may be more sensitive than assessment in blood only. However, for a definitive statement larger sample size would be needed. We then correlated MRD status at EOT, regardless of treatment arm, with PFS: In line with previous reports, there was a clear trend to longer PFS in patients who had reached MRD negativity (median PFS not reached), while patients with residual disease had shorter PFS; however, due to small sample numbers, statistical significance could not be reached. We also analyzed the correlation of MRD negativity reached at any time during and after treatment with PFS, bearing in mind that this sample set is inherently biased, since patients with early progression will be lost from the analysis; the results are consistent with the EOT findings. Summary: ASO IgVH RQ-PCR is a powerful method to detect residual levels of disease in CLL patients with clinical complete response and undetectable MRD correlates with longer PFS. Among patients in REACH achieving clinical CR on either study arm, a higher percentage achieved MRD negativity on the R-FC arm, consistent with the increased efficacy shown for the Rituximab treatment arm by the REACH clinical data. Disclosures: Mundt: Roche: Employment. Smith:Roche: Employment. Lin:Genentech: Employment. Barrett:Roche: Employment. Hurst:Genentech: Employment. Geisler:Roche: Research Funding, Speakers Bureau. Hiddemann:Roche: Research Funding.

Description: In many ways, intercollegiate athletics represents the ‘sustainable’ front porch of higher education. The high-visibility, high-impact nature of elite-level college athletics make athletic departments a central player in the sustainable development journey. However, not all athletic departments respond to this responsibility, nor are all responses uniformly successful. According to national reporting frameworks, an increasing number of universities in the United States are choosing to involve their athletic departments in university-level sustainability governance structures, but the benefits and limitations of this remain unclear. Using the theory of loosely coupled systems, and more specifically, the voice of compensations (which views loose coupling as an unsatisfactory state), the purpose of this paper is to explore perceptions of athletic department engagement in shared sustainability governance, and, thus, a whole-of-institution approach. Semi-structured interviews with sustainability office personnel were conducted and analyzed, and the findings imply that shared sustainability governance has the potential to focus the attention of athletic departments toward sustainability, as well as to reaffirm shared values. Yet, to maximize the impact of athletic departments toward the sustainable development goals of a university, sustainability office personnel suggest the deployment of additional change levers, in a multi-dimensional fashion, as supplementary coupling mechanisms. These would include more rigorous sustainability goals (top-down), continued collaboration on ‘low-hanging fruit’ initiatives (lateral), student-athlete engagement (bottom-up), and the development of an internal sustainability framework (inside-out).

Description: Sport stadia are political objects that carry an environmental cost. The purpose of this research is to add to previous literature by theorizing the political process of stadium construction in a way that accounts for how environmental issues are introduced into the political process and, therefore, offers a more accurate lens through which to interpret how sustainable stadia are constructed. We conducted a case study of SC Freiburg’s carbon-neutral stadium construction process to theorize the object-oriented politics of sport facility construction. SC Freiburg is a German football club, playing in the Bundesliga. To examine the case, we employed a key informant interview and document analysis using Nexis Uni searches, local newspaper articles, official city documents, and social media websites. The case study of SC Freiburg’s carbon neutral stadium construction process showed that environmental concerns were included through a political process that incorporated the interests of a diverse public of human and nonhuman actors (while excluding some actors whose interests could not be reconciled) to produce a sustainable matter of fact. Additionally, we propose a pragmatic definition of stadium sustainability and suggest that environmental activists should make sure that both human and nonhuman actors with sustainability concerns are included in the stadium’s material public.