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The coronavirus disease (COVID-19) pandemic has substantially impacted psychological health in the U.S and has disproportionately impacted underresourced individuals. Despite the higher need for mental health services during this time, service availability and access were disrupted due to increased demand, social distancing recommendations, and stay-at-home orders. Thus, it is crucial to understand factors that predict the desire for psychological services for underresourced individuals. The present study examined factors at multiple levels of Bronfenbrenner's socioecological model (Bronfenbrenner, 1994) to determine which factors best predicted the desire for mental health services including individual, group, in-person, and online services. The sample consisted of 155 underresourced adults in North Carolina. Participants completed an online survey of mental health symptoms, coping strategies, COVID-19 related stressors, and provided demographic information including ZIP code, which was used to classify urban-central and urban-outlying dwellers. Results from univariate general linear models demonstrated that depression symptoms, venting as a coping strategy, COVID-related stress, and living in more rural regions were all significant predictors of the desire for psychological services. Venting as a predictor of the desire for services may signify a general misunderstanding regarding the purpose of psychotherapy as well as the need for individuals to gain social support and connectedness during a pandemic. This study helps to clarify individual-level and contextual factors that impact the desire for psychological services during a global pandemic. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

In this chapter, the authors introduce research-based strategies to engage beginning teachers in learning as reflexive praxis, a continuous inquiry into teaching. They argue that mastery of such mediational means of reflection as verbal/visual narratives, artmaking, and dialog mediate the development of reflection as a tool-mediated action, reflexive praxis, and support teachers' transformation into agents of their praxis. The discussion concerns the development of teachers' visual narratives, from descriptive to critical, and their ability to engage in critical reflection of their practice. The cycles of verbal narrative, dialog, and visual narrative in a course of artmaking activity scaffolded the development of teachers' reflections from descriptions of the critical event in practice to critical reflection. The chapter includes a detailed protocol for a multi-media triptych activity that can be used by both teachers and teacher educators for developing teachers' reflexive praxis.

8006 Background: Elranatamab (PF-06863135) is a humanized bispecific antibody that targets both BCMA-expressing MM cells and CD3-expressing T cells. MagnetisMM-3 (NCT04649359) is an open-label, multicenter, non-randomized, phase 2 study to evaluate the safety and efficacy of elranatamab monotherapy in pts with R/R MM. Initial safety results are presented. Methods: MagnetisMM-3 enrolled pts who are refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. Pts were assigned to 1 of 2 independent, parallel cohorts: those naïve to BCMA-directed therapies (Cohort A) and those with previous exposure to BCMA-directed antibody-drug conjugates or CAR-T cells (Cohort B). Pts received subcutaneous elranatamab 76 mg QW on a 28-d cycle with a 2-step-up priming dose regimen administered during the first week. Dose modifications were permitted for toxicity. Treatment-emergent adverse events (TEAEs) were graded by CTCAE (v5.0), and cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) by ASTCT criteria. Results: As of the data cutoff on Dec 31, 2021, 60 pts in Cohort A had received ≥1 dose of elranatamab; the last pt’s first dose was ̃2 months prior to the cutoff. Median age was 69.0 y (range, 44−89), 48.3% were male, 63.3% were white, 18.3% were Asian and 11.7% were Black/African American. At baseline, 60.0% of pts had an ECOG performance status 1−2 and pts had received a median of 5 (range, 2−12) prior therapies. Median duration of elranatamab treatment was 9.57 wks (range, 0.1−46.1); median relative dose intensity was 87.4% (range, 23.1−101.4). TEAEs were reported in 100% (Grade [G] 3/4, 75.0%) of pts. Most common (≥30%) hematologic TEAEs were neutropenia (36.7% [G3/4, 35.0%]), anemia (36.7% [G3/4, 30.0%]) and thrombocytopenia (30.0% [G3/4, 21.7%]). Among pts who received the 2-step-up priming regimen (n = 56), CRS and ICANS, respectively, were reported in 58.9% (G3/4, 0%) and 3.6% (G3/4: 0%); of those pts, 57.6% (n = 19/33) and 100% (n = 2/2) received tocilizumab and/or steroids. Most common (≥30%) non-hematologic TEAE, other than CRS/ICANS, was fatigue (31.7% [G3/4, 3.3%]). Infections were reported in 46.7% (G3/4: 18.3%) of pts; most frequently reported were upper respiratory tract infections (11.7% [G3/4: 0%]). Discontinuations due to adverse events were reported in 5.0% of pts. No pts permanently discontinued treatment due to CRS or ICANS. There were 10 deaths; causes were MM progression (n = 8), septic shock (n = 1) and unknown (n = 1). Data will be updated at the time of presentation to include ̃90 pts. Conclusions: Preliminary results of MagnetisMM-3 in pts with R/R MM and no prior BCMA-targeted treatment suggest that 76 mg QW elranatamab with a 2-step-up priming regimen is well tolerated, with no G ≥3 CRS or ICANS observed. Clinical trial information: NCT04649359.

Background: Multiple myeloma (MM) is a hematological B-cell malignancy that remains incurable for most patients. Almost all patients, including those who initially respond to treatment, are expected to relapse and subsequently cycle through multiple lines of treatment. The addition of proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies has improved patient outcomes; however, survival of patients after these agents is very poor and highlights an unmet medical need in the relapsed/refractory MM population. Elranatamab (PF-06863135) is a humanized bi-specific antibody that targets both BCMA-expressing MM cells and CD3-expressing T cells, with binding resulting in T-cell mediated cytotoxicity. Elranatamab preclinical studies have demonstrated anti-tumor activity and delayed tumor progression. A Phase 1 study, MagnetisMM-1 (ClinicalTrials.gov ID: NCT03269136), with the aim of characterizing the efficacy, safety, pharmacokinetics, and pharmacodynamics of elranatamab as single agent and in combination with immunomodulatory agents for patients with relapsed/refractory MM is ongoing. Study Design and Methods: MagnetisMM-3 is an open-label, multicenter, non-randomized, Phase 2 study to evaluate the efficacy and safety of elranatamab monotherapy in patients with relapsed/refractory MM who are refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody (ClinicalTrials.gov ID: NCT04649359). Approximately 150 patients will be enrolled to one of two independent parallel cohorts: those naïve to BCMA-directed therapies (Cohort A) and those with previous exposure to BCMA-directed therapy (Cohort B). The primary endpoint is objective response rate, according to International Myeloma Working Group [IMWG] response criteria. Secondary endpoints include duration of response, cumulative complete response (CR) rate, duration of cumulative CR, progression-free survival, time to response, minimal residual disease negativity rate, overall survival, safety, plasma concentrations, and immunogenicity of elranatamab. Key inclusion criteria are age ≥18 years, MM diagnosis according to IMWG criteria and with measurable disease based on IMWG criteria as defined by at least 1 of the following: Serum M-protein ≥0.5 g/dL by SPEP, Urinary M-protein excretion ≥200 mg/24 hours by UPEP; Serum immunoglobulin free light chain ≥10 mg/dL (≥100 mg/L) and abnormal serum immunoglobulin kappa to lambda free light chain ratio (1.65). Eligible patients should also have ECOG performance status ≤2, be refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody and be relapsed/refractory to their last treatment regimen. Key exclusion criteria are smoldering MM, active plasma cell leukemia, amyloidosis, POEMS syndrome, active, uncontrolled bacterial, fungal or viral infections, stem cell transplant within 12 weeks of enrollment, any other active malignancy within 3 years prior to enrollment (except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ), or having received previous administration of an investigational drug within 30 days or 5 half-lives (whichever is longer) of the first dose of elranatamab. This study is, or is planned to be, open at centers in the USA, Australia, Canada, Belgium, France, Germany, Japan, Poland, Spain, and the UK. Disclosures Lesokhin: Genetech: Research Funding; Serametrix, Inc: Patents & Royalties; pfizer: Consultancy, Research Funding; Behringer Ingelheim: Honoraria; Trillium Therapeutics: Consultancy; bristol myers squibb: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding. Iida: Ono: Honoraria, Research Funding; Glaxo SmithKlein: Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Research Funding; Amgen: Research Funding. Ma: Pfizer Inc: Current Employment, Current equity holder in publicly-traded company. Sullivan: Pfizer Inc: Current Employment, Current equity holder in publicly-traded company. Raab: Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees.

In the early 1980s, Sandra Bowdler established a firm foundation for the assessment of archaeological significance and urged the integration of archaeological and Aboriginal values in site assessment, listing and management. This paper describes developments in the integration of archaeological and Aboriginal heritage values, using recent work by Lilley and Williams as an example. The paper then goes on to question whether this progress is reflected in the relatively newly introduced National Heritage listing process (which replaced the Register of the National Estate), taking the listing of rock art on the Dampier Archipelago in Western Australia as a case study.The paper analyses the values for which the Dampier Archipelago was listed, and the implications of this listing. It concludes that in this case, in large part because of the workings of the Environment Protection and Biodiversity Conservation Act 1999, archaeological and Aboriginal values have become separated. It concludes that some of ...

This study evaluated the safety and efficacy of inotuzumab ozogamicin (INO), a targeted humanized anti-CD22 antibody conjugated to calicheamicin, plus rituximab (R-INO) every 3 weeks, up to six cycles, followed by high dose therapy and autologous stem cell transplant (HDT-aSCT) in patients with high-risk relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The primary endpoint was overall response (OR) rate after three cycles of R-INO. Sixty-three patients were enrolled. Common grade 3/4 adverse events during R-INO treatment were thrombocytopenia, lymphopenia and neutropenia. OR rate after three cycles of R-INO was 28.6% (95% confidence interval: 17.9-41.4). Eighteen patients underwent HDT-aSCT; 2-year progression-free survival (PFS) for these patients was 61.1%. Serious infections and hepatic toxicity following aSCT occurred in 33% and 22%, respectively. One- and 2-year PFS rates for all enrolled patients were 28.9% and 25.3%, respectively (median, 3.0 months). R-INO had lower than expected activity as a salvage regimen for transplant eligible patients with DLBCL.

SUMMARY This discussion-intensive workshop featured a panel of five librarians who have worked both in libraries and in the commercial environment sharing their diverse experiences. The panelists provided brief overviews of their careers to date, then spoke in greater depth about what they look for in a job, what has motivated them to move from libraries to the commercial sector or vice versa, and what they have learned in the process.

This investigation assessed the effectiveness of coaching active reasoning of students with learning disabilities. Sixty-three fourth- and fifth-grade students with learning disabilities were assigned at random to one of three treatment conditions: coaching, provided explanation, or no explanation control. In the coaching condition, students were provided factual information followed by a sequence of questions designed to help them construct explanations for the information. In the provided explanation condition, students were concurrently provided both the factual information and the associated explanations. Students in the no explanation control condition received only the target information. Results indicated that students in the coaching condition outperformed students in the two comparison conditions on immediate and 1-week delayed tests of both factual information and explanations. Further, it was found that a variety of levels of coaching support was required to lead students to construct their own explanations. Implications for future research and instruction for students with learning disabilities are discussed.

In May 1995, a landmark conference on the management of archaeological sites in the Mediterranean region was organized by the J. Paul Getty Trust. The following report on the conference is in two parts: Nicholas Stanley Price, a member of the conference organizing committee, describes its format and programme, and then Sharon Sullivan, an invited keynote speaker, provides some reflections on the conference from an Australian perspective.

This study evaluated the effectiveness of promoting relational thinking, using “elaborative interrogation” techniques, to facilitate the content acquisition of elementary school students with mild disabilities. Three conditions were used: control, experimenter-provided explanation, and student-generated explanation. Results indicated that both explanation groups significantly outperformed the control group on recall of facts, as well as explanations. Students coached in relational thinking statistically outperformed those in the control condition and descriptively outperformed students in the experimenter-provided explanation condition on immediate recall. Students in the student-generated explanation condition statistically outperformed both groups in delayed factual recall.

This investigation sought to determine whether elaborative interrogation techniques would facilitate recall of information relevant to, but not included in, mnemonic and representational pictures. Fifty-three adolescents with learning disabilities or mild mental retardation were taught information about nine reasons for dinosaur extinction, ranked in order of plausibility. In the direct teaching condition, students were provided with each ordered reason and an explanation for why that reason may have resulted in dinosaur extinction. In the elaborative interrogation condition, students were provided with each ordered reason and prompted and questioned to provide an explanation for each. In the mnemonic elaborative interrogation condition, students were provided with mnemonic peg-words to facilitate recall of the ordered reasons for dinosaur extinction and also coached and prompted to provide explanations. Students' recall of ordered reasons was higher in the mnemonic elaborative interrogation condition, and students in the two elaborative interrogation conditions recalled more explanations than did students in the direct teaching condition. Further, students in both elaborative interrogation conditions more accurately linked reasons with explanations for those reasons. Findings are discussed with respect to previous findings of mnemonic instruction. Implications for teaching students with mild cognitive disabilities are provided.

Prophylaxis is increasingly prescribed in treatment of haemophilia and its benefit is believed to be most significant for the youngest patients as haemophilic arthropathy may be prevented if prophylaxis is initiated prior to recurrent haemarthroses. While clinical prophylaxis data are readily available for haemophilia A, analogous data for haemophilia B are relatively limited. A prospective clinical study of recombinant factor IX (BeneFIX; rFIX), designed to allow investigator prescribed prophylaxis according to customary practices, was conducted in children

Thirty-nine seventh- and eighth-grade students with learning disabilities received verbal and spatial information about eighteenth-century North American battles under two conditions. In the control condition, learners were provided a map depicting locations of battles, accompanied by descriptive/decorative pictures. Mnemonic condition learners received the same map with the exception that pictures accompanying place names represented reconstructed keywords of those names. In both conditions, pictures were colored red if they represented British victories, blue if they represented American victories. After a training session and a 90-second filler activity, students were asked to locate each battle on an unlabeled map and indicate which side had won the battle. Analysis of results indicated that mnemonic condition students significantly outperformed controls on measures of spatial relocation and correct matching of place name with victor. Effects were especially pronounced on the measure of spatial relocation, in which an effect size of over two standard deviations was obtained. Implications for research and practice are discussed.

Abstract 2718 Background: Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to cytotoxic calicheamicin. In a prior study, INO combined with rituximab (INO+R) had an overall response rate (ORR) of 78% in patients (pts) with relapsed diffuse large B-cell lymphoma (DLBCL) who were not candidates for high-dose therapy and autologous stem cell transplant (HDT-aSCT). An ORR of ∼20% was seen in pts with refractory aggressive lymphoma. Objectives: Safety and activity of INO+R followed by HDT-aSCT in relapsed/refractory DLBCL pts. Primary endpoint: ORR. Secondary endpoints: successful peripheral blood stem cell (PBSC) collection, aSCT rate, progression free survival (PFS), and overall survival (OS). Patients, Treatment: CD20+/CD22+ B cell DLBCL, HDT-aSCT eligible, ≥2 adverse prognostic factors (prior R exposure, early relapse/persistent disease with prior therapy, sIPI ≥2). R 375 mg/m2 on day (d) 1, INO 1.8 mg/m2 on d 2 every 21 d, up to 6 cycles; PBSC mobilization with G-CSF (+/− plerixafor injection) on d ≥8, cycle 2. Chemo-priming if insufficient PBSC collected by G-CSF and after response observed. INO+R responders with >2×106 CD34+ cells/kg proceed to HDT-aSCT. Results: 63 pts were enrolled; 61 received INO+R in this ongoing trial. Median age was 60 y (range 19–75 y); 46% had 1 prior therapy, 41% had 2, and 11% had ≥3. Pts had adverse prognostic factors: 100% prior R treatment; 78% sIPI ≥2 (range 0–4); 25% had no response to most recent prior therapy, 60% responded with early relapse/failure (12 mo, early relapse/failure (2×106 CD34+PBSC/kg (range 2.1–7.1 ×106/kg): 7 mobilized with G-CSF, 6 with G-CSF + plerixafor, 3 with G-CSF + chemo-priming (2 also received plerixafor). Five pts collected 12 mo had longer PFS than those with early relapse/failure or no response (median 12.8, 2.1, 2.7 mo, respectively). Pts who underwent HDT-aSCT had 6- and 12-mo PFS rates of 79% and 35%, respectively (median 10 mo); median OS not reached. Common adverse events during INO+R treatment: thrombocytopenia (68%), nausea (46%), lymphopenia (41%), increased aspartate aminotransferase (38%), fatigue (38%), neutropenia (30%), pyrexia (29%), and vomiting (24%). Two pts had veno-occlusive disease, each occurred after HDT-aSCT: 1 recovered without intervention, the other did not recover, ultimately dying from CMV complications (above). In addition, 26 other deaths occurred: 22 due to PD, 2 due to infection after HDT-aSCT (1 neutropenic sepsis pre-engraftment, 1 sepsis post-engraftment), 1 due to neutropenic sepsis (death 77 d after last INO dose), and 1 attributed to complications of pre-existing chronic obstructive pulmonary disease (death 101 d after last INO dose). Conclusion: In this selected high-risk population with relapsed/refractory DLBCL, INO+R shows activity and a 12-mo PFS rate of 35% after aSCT. The safety profile was most notable for some toxicities (hematologic, infectious, and hepatic) after aSCT. Further follow-up is required to assess long-term impact after aSCT. Disclosures: Wagner-Johnston: Sanofi Aventis: Consultancy. Goy:Pfizer Inc: Honoraria, Research Funding. Rodriguez:Pfizer Inc: Research Funding; Genentech: Research Funding; Ortho-Biotech: Research Funding. Hamlin:Seattle Genetics: Consultancy, Honoraria, Research Funding; Calistoga: Consultancy; Spectrum: Consultancy; Pfizer Inc: Research Funding. Thieblemont:Assistance Publique - Hôpitaux de Paris: Employment; Institut National du Cancer - INCa [French National Cancer Institute]: Research Funding. Suh:Wyeth advisory member: Consultancy. Jiang:Pfizer Inc: Consultancy, Employment. Sullivan:Pfizer Inc: Employment. Vandendries:Pfizer Inc: Employment, Equity Ownership. Gisselbrecht:Pfizer Inc: Research Funding; Baxter: Consultancy, Honoraria; Allos: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding.

Abstract 2883 Background: Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 antibody conjugated to calicheamicin, a cytotoxic agent. CMC-544 targets CD22, which is expressed in the majority of B-cell non-Hodgkin lymphomas (NHL). CMC-544 alone and in combination with rituximab has demonstrated efficacy and tolerability in relapsed/refractory NHL patients including diffuse large B-cell lymphoma (DLBCL) patients who were ineligible for high-dose therapy and autologous stem cell transplant (HDT-aSCT). This trial is evaluating the safety and preliminary efficacy of CMC-544 plus rituximab (CMC-544+R) followed by HDT-aSCT. Objectives: Assess the safety and activity of CMC-544+R prior to HDT-aSCT in relapsed/refractory DLBCL patients using overall response rate (ORR), rate of successful peripheral blood stem cell (PBSC) collection, and aSCT rate as endpoints. Patients: Patients are eligible for this ongoing trial if they have CD20+/CD22+ B-cell DLBCL, have received 1 or 2 therapies, have at least 2 adverse prognostic factors (prior rituximab exposure, early (1), and are judged eligible for HDT-aSCT. Rituximab (375 mg/m2) is given on day 1, then CMC-544 (1.8 mg/m2) on day 2 every 21 days for up to 6 cycles; PBSC mobilization with G-CSF (+/− plerixafor injection [Mozobil®]) begins no earlier than day 8 of cycle 2. Chemo-primed mobilization (with cyclophosphamide [C] or etoposide [E]) is allowed if insufficient PBSCs are collected by G-CSF and is initiated only after disease response is observed. Patients responding to CMC-544+R and with sufficient PBSCs (>2×106 CD34+ cells/kg) proceed to HDT-aSCT. Results: To date, 34 patients have been treated with CMC-544+R. Median age is 62 y (range: 19–75); 74% male; 50% had 1 prior chemotherapy regimen, 38% had 2, and 9% had ≥ 3. Most common adverse events during CMC-544+R treatment were: thrombocytopenia (38%), neutropenia (21%), lymphopenia (21%), nausea (27%), fatigue (29%), and increased aspartate aminotransferase (21%). Three deaths have been reported: 2 due to disease progression at days 76 and 126 after last dose of CMC-544; and 1 after HDT-aSCT. There have been no reports of veno-occlusive disease. To date, 19 patients have postbaseline disease assessment(s), with adverse prognostic factors as follows: 100% prior treatment with rituximab; 79% with sIPI >1 (range, 2–4); 37% had no response to their most recent prior therapy, 53% responded but had early relapse or required initiation of new anti-cancer treatment (CMC-544+R) 12 months). Additionally, all had prior treatment with both anthracyclines and alkylating agents. For these 19 patients (each with ≥ 2 adverse prognostic factors) and who received a median of 2 cycles, a best ORR of 21% was observed (2 complete and 2 partial responses); 26% showed stable disease, and 53% had disease progression. Of the 4 responders, 1 had no response to prior R-ICE, 1 had early relapse (~ 6 months) after prior R-CHOP, 1 relapsed 12 months after prior aSCT, and 1 had a complete response to R-DHAP 5 years prior to study treatment. To date, 7 patients have had PBSC collections: of these, 5 had successful collections (3 with G-CSF plus plerixafor, 1 with G-CSF alone, 1 with G-CSF plus chemo-priming); 2 patients, receiving G-CSF alone, did not have successful collections. Three patients have had both a response to CMC-544+R and sufficient PBSCs allowing HDT-aSCT: 1 patient had successful carmustine/E/cytarabine/C (BEAC)-aSCT (neutrophil, platelet recovery 11 and 29 days after aSCT, respectively); 1 patient did not have complete platelet recovery after busulfan/E/melphalan (M)-aSCT with 4.35×106 CD34+ cells/kg (platelet levels were as low as 19,000/μL ~60 days after aSCT, and transfusions were required to sustain levels ≥20,000/μL); and 1 patient, a 74-y old male, expired 39 days after BEAM-aSCT from neutropenic sepsis with multiorgan failure. Conclusion: In this patient population, CMC-544+R has a safety profile similar as previously reported. The preliminary ORR observed is notable given the poor prognosis of these patients. Current results suggest that successful PBSC mobilizations following CMC-544+R are possible. Additional data from this ongoing trial will be helpful to further assess the safety and efficacy of CMC-544+R prior to HDT-aSCT. Disclosures: Goy: Allos Therapeutics: Consultancy, Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goh:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Ciliag: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweetenham:Pfizer: Research Funding. Powell:Pfizer: Employment, Equity Ownership. Sullivan:Pfizer: Employment, Equity Ownership. Vandendries:Pfizer Inc.: Employment, Equity Ownership. Gisselbrecht:Allos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Clinical trials in patients with hemophilia B have demonstrated considerable inter-patient variability in the pharmacokinetics (PK) of Factor IX (FIX) replacement therapy, including the recovery, an important PK parameter from which individualized clinical dosing decisions are calculated. In clinical trials of plasma-derived and recombinant factor IX replacement therapies, the age of the patient has been demonstrated to affect recovery (younger patients have lower recovery values than older patients), however the specific contribution of age, as well as additional covariates such as body weight and race to PK variability has not been systematically evaluated. We analyzed an extensive database of BeneFIX PK data collected from 8 separate clinical trials conducted over 13 years. A systematic approach involving population PK modeling and simulation was utilized for the first time to estimate the effects of individual-specific covariate factors on PK of BeneFIX in the pooled population that included pediatric and adult patients. A total of 4025 plasma FIX activity PK data sets collected from 191 patients, aged 0 to 69 years were used for the analysis. There were 111 children (£15 years) including 53 infants 15 years) in the pooled data. The majority (84%) of patients were Caucasian. The remaining patients were African American (7%), Hispanic (4%), Asian/Japanese (3%), and other ethnicity (3%). The data were analyzed using nonlinear mixed-effects modeling with the NONMEM software system. Age, weight, and race were examined as covariates for the ability to explain inter-individual variability in the BeneFIX PK. The PK in pediatric and adult patients was described by a two-compartment model with first-order elimination and a zero-order input using the following parameters: clearance (CL), volume of central compartment (V1), volume of peripheral compartment (V2) and inter-compartmental clearance (Q). Population predicted BeneFIX PK parameters, standardized to a 70 kg patient, were 7.46 (standard error; 0.20) mL/hr/kg, 131 (4.4) mL/kg, 71.5 (2.1) mL/kg and 12.1 (1.1) mL/h/kg, for CL, V1, V2 and Q, respectively. The final model was able to simulate data in close agreement with the actual study observations. Variability (%CV) in BeneFIX PK was explained most significantly by allometrically scaled body weight (Figure 1a), while age and race had no discernible effects on BeneFIX PK in the population studied. Observed recovery values were slightly lower in children (£15 years) compared with those in adults (>15 years) since the initial volume of distribution (V1), normalized to body weight, was slightly higher in children than in adults, while the variability in the observed recovery values was comparable between children and adults (Figure 1b). In conclusion, the present analysis, for the first time, systematically describes and quantifies the sources of age-dependent variability of factor IX PK, using BeneFIX data, and provides a better understanding of the importance of body weight in the disposition of BeneFIX. This confirms existing weight-based dosing recommendations and further supports consideration of dosing adjustments that are individualized based on the patient’s body weight in the context of the achieving the desired clinical response, such as recovery. This also may be important in pediatric patients during growth periods associated with significant weight change. Figure 1a. Clearance versus Body weight Figure 1a. Clearance versus Body weight Figure 1b. Recovery versus Body weight Figure 1b. Recovery versus Body weight

Prophylaxis is increasingly prescribed in treatment of hemophilia. The therapeutic benefit is believed to be most significant for the youngest patients since hemophilic arthropathy may be prevented if prophylaxis is initiated prior to recurrent hemarthroses. While clinical prophylaxis data is readily available for hemophilia A, analogous data for hemophilia B is limited. A prospective clinical study of recombinant human FIX (rFIX; BeneFIX®) was recently completed in which the efficacy and safety of rFIX were evaluated in children Table 1. Bleeding Rate During Prophylaxis by Infusion Schedule Bleeding Rate (per 30 Days) Infusion Schedule No. Patients Patient Age (years) (median, range) Duration of Prophylaxis (mean ± SD months) Spontaneous Injury Related Total NA = not applicable; No. = number. 1 per week 9 2.5 (0.6-4.3) 8.0 ± 2.7 0.07 0.18 0.25 1−2 per week 1 1.0 (NA) 2.5 ± (NA) 0 0.40 0.40 2 per week 12 3.6 (1.2-4.8) 5.9 ± 1.1 0.03 0.33 0.35 All Schedules 22 2.9 (0.6-4.8) 6.6 ± 2.3 0.05 0.26 0.30

A new formulation (rFIX-R) of BeneFIX has been developed to reduce the possibility of RBC agglutination, a phenomenon associated with the low ionic strength of the reconstituted drug product. The new formulation contains NaCl to increase the ionic strength and the recombinant factor IX concentration is increased for the 1000 IU strength and a new 2000 IU strength by reconstituting all strengths in 5 mL, facilitating the administration of larger doses in decreased volumes. Thirty-four (34) previously treated (≥150 exposure days [EDs]) males (≥12 years) with moderately severe/severe hemophilia B (FIX:C ≤2%) were enrolled and treated in this 2 part study. In the randomized, double-blind, crossover pharmacokinetic (PK) period of the study, the PK characteristics of rFIX-R were compared with those of the currently available formulation of BeneFIX. Subjects received either rFIX-R or BeneFIX as a 75 IU/kg bolus infusion over 10 minutes after a suitable washout. Blood samples were collected at defined times over 72 hours to measure pre-/post-infusion plasma factor IX activity. Subjects then received the alternate treatment following the same procedure. The mean plasma factor IX activity-versus-time profile after the infusion of rFIX-R was essentially identical to that seen with BeneFIX. From the 26 evaluable subjects, the mean PK parameter estimates of factor IX activity establish bioequivalence of the products since the 90% confidence intervals for rFIX-R to BeneFIX ratios of the geometric means of Cmax and AUCs fell within the bioequivalence interval of 80% to 125%. Figure Figure In the open-label treatment period, subjects used rFIX-R for on-demand control of bleeding, routine prophylaxis, and/or surgical prophylaxis for 6- to 12-months to achieve at least 30 EDs. The plasma factor IX activity-versus-time profile was recharacterized after 6 months of rFIX-R treatment and was unchanged compared with the baseline rFIX-R PK profile. Over 1000 infusions (>3,500,000 IU of rFIX-R) have been administered with no serious adverse events related to rFIX-R. No clinically significant adverse events related to rFIX-R have been reported, including FIX inhibitor development, allergic-type manifestations, or thrombotic complications. One subject, with a prior history of frequent RBC agglutination, reported two instances without any associated adverse events. The overall results of this study demonstrate the safety of rFIX-R and the bioequivalence of the new formulation and BeneFIX. Since bioequivalence is the most important surrogate endpoint for efficacy, these data predict a favorable rFIX-R efficacy profile, consistent with that of BeneFIX, but with increased convenience in that larger doses can be administered using decreased volumes relative to BeneFIX.

In the perilous high seas of international trade, girding the corporate ship with patents may be the best defense against piracy of your product or service ideas.

Though I was asked for this contribution because I am a 'state' or 'public' archaeologist, I have no mandate to speak for any other such archaeologists in Australia, nor do I intend to discuss the interpretation or administration of the various acts which throughout most of Australia limit and control the activities of professional archaeologists. I suspect that it is not the actual details of legislation, but the principles of its interpretation which is of most interest and relevance to the first symposium of the AAA

8529 Background: InO is an anti-CD22 antibody conjugated to calicheamicin; R-InO has shown activity in pts with relapsed/refractory aggressive B-NHL in a phase 1/2 study (Fayad, J Clin Oncol 2013; ...