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RRx-001 is a cysteine-directed anticancer alkylating agent with activity in a Phase II study in platinum refractory small cell lung cancer. Here, we describe the design of REPLATINUM, an open-label, Phase III trial. 120 patients with previously platinum-treated small cell lung cancer in third line will be randomized 1:1 to receive RRx-001 followed by four cycles of a platinum doublet, and then alternating cycles of RRx-001 and single agent platinum until progression versus four cycles of a platinum doublet. At radiologic progression on the platinum doublet, patients may cross over to the RRx-001 arm. Primary objective: to demonstrate superior progression-free survival in the RRx-001 population. Secondary objectives: to demonstrate superiority for overall survival and objective response rate. Clinical Trial registration: NCT03699956

Although the vignette method is widely used in psychology, it is often implemented without the key feature of iterative decision making that can affect the eventual outcome of the vignettes. This Tutorial provides an explanation of how to use Twine, an interactive narrative platform, to create vignettes with iterative decision making. Twine is an especially useful tool for experiments involving branching narratives, spatial navigation, and resource allocation. We provide code for creating exemplar experiments in social and cognitive psychology, as well as behavioral economics, and explain how to integrate Twine projects with survey-management platforms, such as Qualtrics. After following this Tutorial, researchers will be able to use Twine in their experiments to update the classic vignette method by incorporating iterative decision-making tasks.

e20594 Background: RRx-001 is a small molecule immunotherapeutic in Phase 3 for the treatment of SCLC that is associated with M2-M1 tumor associated macrophage (TAM) repolarization with CD47 downregulation, vascular normalization and reversal of chemoresistance. In a controlled, multicenter clinical trial called REPLATINUM that was prematurely halted due to COVID-19, data from 17 patients with third line or beyond SCLC was analyzed. Moving forward, REPLATINUM(restarted) has added SARS-CoV-2 exclusion criteria. Our aim was to explore the efficacy of RRx-001 in REPLATINUM and to assess the statistical assumptions of the REPLATINUM(restarted) trial in order to inform future clinical development in SCLC. Methods: Patients in REPLATINUM were randomized to receive 1 of 2 arms: 1) carboplatin AUC 5 IV on day 1 or cisplatin 60 mg/m2 IV on day 1 plus etoposide 100 mg/m2 IV on days 1 through 3 every 21 days for up to 4 cycles or 2) 4 mg of RRx-001 administered sequentially with 4 cycles of a platinum doublet (cisplatin or carboplatin plus etoposide as outlined above). Progression Free Survival (PFS) was the primary efficacy endpoint based on a blinded independent central review (BICR). Results: The trial was suspended prematurely after 17 patients had been enrolled due to widespread COVID-19 exposure with the plan to restart the trial. The decision to restart the trial has provided an opportunity to examine the data for preliminary evidence of treatment efficacy. At the time that the REPLATINUM trial was halted, there were 11 patients enrolled on the control arm and 6 on the investigational arm. The BICR assessed median PFS was approximately 7.1 months for RRx-001 + platinum doublet and 3.5 months for the platinum doublet alone based on the truncated database. The BICR assessed PFS hazard ratio was approximately 0.5. OS medians were approximately 8.2 and 6.3 months for RRx-001 + platinum doublet and platinum doublet alone, respectively. Additionally, patients on the RRx-001 + platinum doublet-treated experimental arm experienced less toxicity than patients on the platinum doublet-treated control arm. Conclusions: Despite the small sample size, preliminary results from REPLATINUM suggest a trend toward a favorable primary outcome and improved safety in RRx-001-treated patients and support the validity of the statistical assumptions that underlie the REPLATINUM(restarted) trial. Pivotal evidence will emerge from REPLATINUM(restarted), which is imminently recommencing. Clinical trial information: NCT03699956.

Neuroendocrine tumors (NETs) are grouped together as a single class on the basis of histologic appearance, immunoreactivity for the neuroendocrine markers chromogranin A and synaptophysin, and potential secretion of hormones, neurotransmitters, neuromodulators and neuropeptides. Nevertheless, despite these common characteristics, NETs differ widely in terms of their natural histories: high-grade NETs are clinically aggressive and, like small cell lung cancer, which they most closely resemble, tend to respond to cisplatin and etoposide. In contrast, low-grade NETs, which as a rule progress and behave indolently, do not. In either case, the treatment strategy, apart from potentially curative surgical resection, is very poorly defined. This report describes the case of a 28-year-old white male with a diagnosis of high-grade NET of undetermined primary site metastatic to the lymph nodes, skin and paraspinal soft tissues, treated with the experimental anticancer agent RRx-001, in the context of a phase II clinical trial called TRIPLE THREAT (NCT02489903); serial sampling of tumor material through repeat biopsies demonstrated an intratumoral inflammatory response, including the amplification of infiltrating T cells, which correlated with clinical and symptomatic benefit. This case suggests that pseudoprogression or RRx-001-induced enlargement of tumor lesions, which has been previously described for several RRx-001-treated patients, is the result of tumoral lymphocyte infiltration.

e15119 Background: RRx-001 is a minimally toxic small molecule that downregulates CD47 via Myc inhibition and repolarizes tumor-associated macrophages (TAMs). A phase 1 pilot study was undertaken to determine the safety and feasibility of RRx-001 and nivolumab in patients with advanced traditionally non-immunogenic cancers and no standard options. Methods: This single arm, open-label pilot study (NCT02518958) was designed to evaluate the safety profile of RRx-001 + nivolumab in patients with advanced malignancies. A 3+3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. RRx-001 is infused once weekly while nivolumab is given at 3mg/kg once every 2 weeks. RRx-001 starting dose was 2 mg IV weekly with 4 dose level escalations up to 16 mg IV weekly. From January 2015 to November 2015, 12 patients received treatment for 4 cycles (total 12 weeks) with the combination due to unavailability of nivolumab, which was not supplied to the Sponsor. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events occurring within 16 weeks of the first dose of RRx-001 + nivolumab were characterized according to CTCAE v4.03. Results: 12 patients received > 1 dose of RRx-001 and nivolumab. One discontinuation occurred due to pneumonitis and one to voluntary withdrawal after a post-procedural infection. There were no dose-limiting toxicities. The main adverse event related to RRx-001 was pain on infusion (33.3%). The main adverse event related to the combination was pseudoprogression (larger tumors in symptomatically improved patients) (25%). The most common immune-related treatment-emergent AEs were pneumonitis (8.3%), and hypothyroidism (8.3%). Objective response rate at 12 weeks was 25% and the disease control rate (DCR) consisting of > SD was 67% by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 25% of the patients progressed on the combination. Conclusions: RRx-001 + nivolumab was well-tolerated with preliminary evidence of anti-cancer activity in non-immunogenic cancers. Further analyses with a larger sample size are required to confirm activity. Clinical trial information: NCT02518958 .

e16031 Background: RRx-001 is a downregulator of CD-47 and SIRP-alpha, which demonstrated a clinically meaningful improvement in OS and PFS vs. regorafenib when dosed sequentially with irinotecan in a 3rd/4th line colorectal cancer randomized trial called ROCKET (NCT02096354). Recently, RRx-001 has been shown to downregulate PD-L1 on circulating tumor cells. This phase 1 trial named PAYLOAD (NCT02801097) was performed to assess the safety and tolerability of the combination of RRx-001 and irinotecan and to determine a recommended phase II dose (RP2D). Methods: Eligible patients (pts) had adequate organ and bone marrow functions and an ECOG of 0-2 and evaluable refractory advanced solid tumors. RRx-001 was administered once per week for 3 weeks and thereafter once every two weeks. RRx-001 was administered as a 10-15 min IV infusion with irinotecan, which began on Week 4 and which was also given every other week, staggered with RRx-001 . Dose escalation followed a standard 3 + 3 design with co-escalation of RRx-001 and irinotecan as follows: 1: Irinotecan 120 mg/m2 + RRx-001, 0.5 mg 2: Irinotecan 120 mg/m2 + RRx-001, 2 mg 3: Irinotecan 120 mg/m2 + RRx-001, 4 mg 4: Irinotecan 150 mg/m2 + RRx-001, 4 mg Radiological imaging was performed every 8 weeks. Results: 12 pts; 1 gallbladder, 1 ampullary carcinoma, 1 cholangiocarcinoma, 5 colon, 1 GE junction, 2 pancreatic and 2 rectal cancers were enrolled from January 2018 to November 2018. 1 and 18 doses (median: 6 doses) of the combination of RRx-001 and irinotecan were received. The median number of prior treatments was 4 (range 1-5). There were 2 Grade 3 events, leukopenia and anemia, judged not related to RRx-001 but related to irinotecan, 1 Grade 4 event, leukopenia, judged not related to RRx-001 but related to irinotecan and 1 Grade 5 event, neutropenic enterocolitis, also judged not related to RRx-001 but related to irinotecan. No dose-limiting toxicities were identified. The median overall survival was ~ 6.5 months. Conclusions: Alternating weekly infusions of 150 mg/m2 of irinotecan and 4 mg of RRx-001 were well tolerated. No Grade 2 or above diarrhea was observed with irinotecan treatment, which suggests that RRx-001 may protect against gastrointestinal (GI) toxicities, since RRx-001 has also demonstrated anti- oral mucositis and anti-diarrheal properties in other studies.This dose level is the recommended phase 2 dose for future trials. Clinical trial information: NCT02801097 .

9062 Background: In a Phase 2 trial called QUADRUPLE THREAT (QT) (NCT02489903), where 2nd line+ small cell lung cancer (SCLC) patients were treated with RRx-001 and a platinum doublet, the programmed death-ligand 1 (PD-L1) status of circulating tumor cells (CTCs) in 14 patient samples was evaluated. Methods: 26 consented patients received weekly RRx-001 4 mg followed by a reintroduced platinum doublet; epithelial cell adhesion molecule (EPCAM+) CTCs from 10 ml of blood on two consecutive timepoints cycle 1 day 1 and cycle 3 day 8 (cycle duration = 1 week) were detected by EpCAM-based immunomagnetic capture and flow cytometric analysis. CTCs were further characterized for protein expression of PD-L1. Tumor response was classified as partial or complete response based on the response evaluation criteria in solid tumors (RECISTv1.1) measured every 6 weeks. Results: The analyzed clinical data set comprised 14 RECIST-evaluable patients. 50% were females (7/14) and the median age (years) at baseline was 64.5 (Min = 48.5, Max = 84.2, SD = 10.3). The logistic model McFadden goodness of fit score (0 to 100) is 0.477, which is a strong correlation value. The logistic model analyzing the association of CTC PD-L1 expression at two timepoints and response had an approximate 92.8% accuracy in its prediction of clinical benefit (SD/PR/CR). Accuracy is defined in the standard way as 1- (False positive rate + False negative rate). The estimated ROC displayed in Figure 1 suggests a ROC AUC of 0.93 (95% CI: 0.78, 0.99), an excellent measure of performance. Conclusions: Reduction of PD-L1 expression was correlated with good clinical outcome after RRx-001 + platinum doublet treatment. PD-L1 expression reduction in favor of RRx-001 RECIST clinical benefit was clinically significant as compared to non-responders with progressive disease (PD). In the ongoing SCLC Phase 3 study called REPLATINUM (NCT03699956), analyses are planned to correlate response and survival with expression of CD47 and PD-L1 on CTCs. Clinical trial information: NCT02489903.

This article presents the design and empirical investigation of the "RePlay Health" game ( www.replayhealth.com/ ), a novel "role-playing sport" derived from a complex, data-driven, computational simulation of healthcare dynamics. By immersing players in a fictional world in which they take on the role of characters facing specific behavioral and environmental risk factors, the "RePlay Health" game models the impact of health and healthcare policy on individual-level livelihood and community-level productivity.A randomized experiment tested the efficacy of the game for inspiring shifts in thinking about public health and healthcare policy. This study compared the impact of actively playing the game versus passively spectating: 31 young adults were assigned to one of these two roles. Participants completed pretest and posttest measures of their subjective ranking of healthcare policies and attributions for health outcomes.Active players (compared with spectators) reported significantly higher prioritizations (from pretest to posttest) in their subjective ranking of several health policies modeled by the game, such as "improving postdischarge care" and "increasing access to healthy foods." Furthermore, players, but not spectators, were significantly more likely following gameplay to identify environmental or systemic factors as potential causes of health problems.The fact that significant results emerged with a 1-week gap between gameplay and measurement demonstrates that the game could exert a lasting impact on attitudes and perceptions. More broadly, this work illustrates the value of incorporating experiential components, such as narrative, embodiment, and role-playing, in designing efficacious games for health.

With a growing body of work demonstrating the power of games to transform players' attitudes, behaviors, and cognitions, it is crucial to understand the potentially divergent experiences and outcomes afforded by digital and non-digital platforms. In a recent study, we found that transferring a public health game from a non-digital to a digital format profoundly impacted players' behaviors and the game's impact. Specifically, players of the digital version of the game, despite it being a nearly identical translation, exhibited a more rapid play pace and discussed strategies and consequences less frequently and with less depth. As a result of this discrepancy, players of the non-digital version of the game exhibited significantly higher post-game systems thinking performance and more positive valuations of vaccination, whereas players of the digital game did not. We propose several explanations for this finding, including follow-up work demonstrating the impact of platform on basic cognitive processes, that elucidate critical distinctions between digital and non-digital experiences.

With an increasing reliance on crowdsourcing games as data-gathering tools, it is imperative to understand how to motivate and sustain high levels of voluntary contribution. To this end, the present work directly compared the impact of various "emphasis frames," highlighting distinct intrinsic motivational factors, used to describe an online game in which players provide descriptive metadata "tags" for digitized images. An initial study showed that, compared to frames emphasizing personal enjoyment or altruistic motivations, a frame emphasizing a "growing community of players" solicited significantly fewer contributions. A second study tested the hypothesis that this lower level of contribution resulted from social loafing (the tendency to exert less effort in collective tasks in which contributions are anonymous and pooled). Results revealed that, compared to a no-frame control condition, a frame emphasizing the preponderance of other players reduced contribution levels and game replay likelihood, whereas a frame emphasizing the scarcity of fellow players increased contribution and replay levels. Various strategies for counteracting social loafing in crowdsourcing contexts are discussed.

As an exceedingly recalcitrant and highly aggressive tumor type without Food and Drug Administration-approved treatment or a known cure, the prognosis of recurrent extensive stage platinum-resistant/refractory small cell lung cancer (SCLC) is worse than other types of lung cancer, and many other tumor types, given a response rate of less than 10% and an overall survival of less than six months. It was broadly classified into three groups based on the initial response to cisplatin/etoposide therapy, platinum-refractory, platinum-resistant, and platinum-sensitive, extensive stage SCLC inevitably relapses, at which point the only standard options are to rechallenge with the first-line chemotherapeutic regimen in the case of sensitive disease or to start the topoisomerase I inhibitor, topotecan. Sensitive disease is defined by a response to the first-line therapy and a treatment-free interval of at least 90 days, while the definitions of refractory and resistant disease, respectively, are nonresponse to the first-line treatment or relapse within 90 days. As an important predictor of response to the second-line treatment, the clinical cutoff of three months (or two months in some cases) for resistant and sensitive disease, which along with performance status prognostically separates patients into high- and low-risk categories, dictates subsequent management. This case report presents a resistant SCLC patient enrolled on a Phase II clinical trial called QUADRUPLE THREAT (formerly TRIPLE THREAT, NCT02489903) who responded to reintroduced platinum doublets after sequential priming with the resistance-reversing epi-immunotherapeutic agent, RRx-001. In the QUADRUPLE THREAT clinical trial, both during priming with RRx-001 and during sequential treatment with platinum doublets, the patient maintained a good quality of life and performance status.

2516Background: Differential response to tamoxifen observed in patients (pts) with hormone receptor-positive cancer may be due to variations in tamoxifen metabolism from CYP2D6 genetic polymorphism...

2587Background: Wee1 tyrosine kinase promotes G2 cell cycle arrest following DNA damage via inactivating phosphorylation of cyclin-dependent kinase 1. We are conducting a phase I study of the oral ...

TPS3128Background: Interleukin-15 is a stimulatory cytokine. Recombinant human IL-15 (rhIL-15), a nonglycosylated single-chain peptide, increased circulating CD8+T-cells, NK cells and inflammatory ...

2549Background: Ataxia-telangiectasia-related (ATR) protein kinase is central to the repair of damaged DNA through the homologous recombination (HR) pathway, activating phosphorylation cascades tha...

This paper provides an overview of creating games for change from within an academic context, focusing specifically on the development of educational computer games for middle school girls. The essay addresses larger issues such as the cultural importance of computer games, the difficulty in categorizing a diverse user group such as “girls,” and the ways in which one could design game goals to promote diverse play and learning styles. Through such alternate design strategies, both media makers and students can incorporate significant social intervention into media work.

TPS2609 Background: The DNA damage response (DDR) pathway is a key element of cellular integrity. Platinum compounds form covalent bonds with purine bases causing DNA cross-links that stall replication forks halting transcription. Poly (ADP-ribose)polymerase-1 (PARP-1) plays a pivotal role in DDR and base-excision repair. Ataxia-telangiectasia-related (ATR) protein kinase is also central to DDR and homologous recombination, activating a series of phosphorylation cascades culminating in cell cycle arrest to allow time for DNA repair. Veliparib (ABT-888) is a PARP 1/2 inhibitor (PARPi) with clinical evidence of antitumor activity in combination with cisplatin in BRCA mutation carriers (Rodler et al, Cancer Res. 2011). VX-970 is a potent ATR inhibitor, with antitumor activity across a range of cell lines in combination with DNA damaging agents, including cisplatin (Huntoon et al, Cancer Res. 2013). In this trial, we will evaluate whether the combination of veliparib + VX-970 impairs DNA repair, inducing a “BRCA null”-like phenotype leading to potentiation of the antitumor activity of cisplatin. Methods: Open label phase I trial of the veliparib+VX-970+cisplatin combination, following a 3+3 design, with dose limiting toxicities defined during cycle 1. Estimated enrollment: 24 patients (pts); Dana Farber and MD Anderson planned as additional sites. Drug administration over a 21-day cycle: VX- intravenously (IV) on Days 2 and 9; Veliparib orally twice daily (q12 hours ± 1 hour) Days 1-3 and 8-10; cisplatin 40 mg/m2 IV Day 1 (with Day 8 added from DL3 onwards). Pts must be ≥ 18 years of age; have histologically confirmed solid tumors that have progressed on standard of care therapy known to prolong survival or without known standard, ECOG PS ≤2, and life expectancy ≥3 months. Pts with treated brain metastasis with stable disease ≥4 weeks without requiring steroids or anti-seizure medication are eligible. Exclusion criteria include a prolonged QTc interval, and sensory/motor neuropathy ≥grade 2 by CTCAE v.4. At this time, cohort 3 has enrolled 1 of 3 planned pts. Assessment of DDR and apoptosis biomarkers at the maximally tolerated dose using a validated and quantitative immunofluorescence assay is planned. Clinical trial information: NCT02723864.

2558 Background: Indenoisoquinolines (ID) are non-camptothecin inhibitors of topoisomerase (TOP1) identified following a COMPARE analysis of the National Cancer Institute’s (NCI) in vitro anticancer drug discovery screen. IDs have improved characteristics over camptothecin top1 inhibitors, with better chemical stability (lacking the labile hydroxylactone E-ring) producing stable DNA breaks that are resistant to reversal of the trapped DNA-TOP1 cleavage complex and at different DNA sequence sites to camptothecins (Kohlhagen et al. Mol Pharmacol. 2005). IDs have shown more activity against camptothecin-resistant cell lines and mouse models, as well as in cells overexpressing the ATP-binding cassette (ABC) transporters, and multidrug resistance (MDR-1/ABCB1) genes. A parallel first-in-human Phase I study conducted at the NCI of LMP400 in patients with refractory solid tumors and lymphomas showed this molecule to be well tolerated (Kummar et al, Cancer Chemother Pharmacol. 2016). A trial of LMP776 (NSC725776), has completed accrual. Primary Objectives: define the maximum tolerated dose (MTD) of LMP776 and the dose-limiting toxicities (DLTs). Methods: Phase I trial using Design 4 of the Simon accelerated titration designs (Simon et al. JNCI, 1997), with doses escalated based on toxicity during cycle 1. LMP776 was administered via central line QD over 1 hour on days 1–5 q 28-days. Response is defined by RECIST 1.1 on CT. Results: 32 of 34 patients (pts) were evaluable for toxicity and response. Enrollment was expanded at dose level (DL) 2 to 6 pts due to a hypocalcemia DLT, with subsequent enrollment on a 3+3 design. MTD was established at DL7 (12mg/m2, DLT myelosuppression). Common Grade 3/4 adverse events by CTCAE v.4 included anemia (5 pts, 15%), thrombocytopenia (5), lymphopenia (5) and neutropenia (3 pts, 9%). 12 (37%) pts experienced stable disease (SD), with a median of 4 cycles of treatment (range 2-9). 10 (30%) pts with SD remained on study for ≥4 months, with 4 pts on study ≥6 months. Conclusions: LMP776 is overall well tolerated. Explorative correlatives and additional trials are being considered. Clinical trial information: NCT01051635.

How can design (broadly thought) and creative thought in technology, 'make a difference' empirically and conceptually from the point of view of design practice? In the world of social impact design, how do designers know if they have the right approach for the best outcomes? In this talk, Tiltfactor laboratory director and Dartmouth professor Mary Flanagan shares strategies for design, focusing on cooperative interactions and the unintended consequences of designers' actions. Urging designers to ask big questions about where our technology is heading and how we might improve it from a social justice perspective, Flanagan offers actionable approaches to these questions through design examples and case studies of specific projects from her innovative game design work at http://www.Tiltfactor.org.

Purpose: Clinical toxicity associated with 5-fluorouracil (5-FU) is related to the area under the plasma concentration-time curve (AUC). Recently, short-term infusions of 5-FU given over 30 or 60 min have been substituted for conventional "bolus" 5-FU given over 3–5 min in randomized clinical trials, but there are only limited pharmacokinetic data for these altered infusion durations. We therefore wished to determine the pharmacokinetics and toxicity associated with 5-FU given as a 1-h intravenous (i.v.) infusion. Methods: A group of 22 adults with advanced gastrointestinal tract cancers and no prior systemic chemotherapy for advanced disease received interferon α-2a (5 MU/m2 s.c., days 1–7), leucovorin (500 mg/m2 i.v. over 30 min, days 2–6) and 5-FU (370 mg/m2 i.v. over 1 h, days 2–6). The doses of 5-FU and interferon-α were adjusted according to individual tolerance. The pharmacokinetics and clinical toxicity were retrospectively compared with patients receiving the same regimen under the same treatment guidelines except that 5-FU was given over 5 min. Results: The regimen was well tolerated, and 41% of the patients tolerated 5-FU dose escalations to 425–560 mg/m2 per day. Grade 3 or worse diarrhea and fatigue ultimately occurred in 14% of the patients each. Granulocytopenia, mucositis, and diarrhea appeared to be appreciably milder in the present trial compared with our prior phase II experience in colorectal cancer. The peak 5-FU plasma levels and AUC with 370 mg/m2 5-FU given over 1 h were 7.3-fold and 2.4-fold lower than previously measured in 31 patients who received 5-FU over 5 min. Conclusion: Increasing the length of 5-FU infusion to 1 h seemed to substantially reduce the clinical toxicity with this modulated 5-FU regimen, likely due to markedly lower peak 5-FU plasma levels and AUC. Changes in the duration of a short infusion of 5-FU clearly affects the clinical toxicity, but raises the concern of a potentially adverse impact on its antitumor activity. These results suggest the importance of including precise guidelines concerning the time over which 5-FU is given in clinical trials. Having a specified duration of 5-FU infusion is also important if 5-FU dose escalation is considered.

This paper presents insights about design practices that can lead to effective and fun games for learning, gleaned from interviews with experienced game developers. We based our approach on Schon's notion of practitioners evolving shared 'appreciation systems' for discussing and critiquing work, and aimed to gather and share some of game designers' 'appreciation system' for games and learning. The resulting insights provide valuable pointers to other designers in the CHI community crafting game-like experiences.

Young people interact with games, animations, and simulations all of the time. But few of them are able to create interactive media. The obstacle: traditional programming languages are too difficult to learn and understand. This panel brings together a group of researchers, developers, and educators who are aiming to democratize the activity of programming. They are developing a new generation of programming environments that enable children and teens to create their own interactive games, stories, animations, and simulations. Panelists will discuss and critique their programming environments, then set up interactive demonstration stations for focused exploration and small-group discussion. Audience members will also have the opportunity to download the environments onto their own laptops, so that they can experiment in greater depth.

It would have been difficult to imagine the growth in both the power and role of computers in day-to-day life that has taken place since the 1980 publication of Martin Kay's The Proper Place of Men and Machines in Language Translation. Since that time, the computing power available to ordinary PC users has increased by orders of magnitude and desktop computers have become ubiquitous and indispensable. The Internet and online information services have grown from their beginnings as arcane tools of the computer scientist to large interactive communities with participants from all walks of life and with all levels of computer skills.

Significant work in the CHI community has focused on designing systems that support human values. Designers and engineers have also become increasingly aware of ways in which the artifacts they create can embody political, social, and ethical values. Despite such an awareness, there has been little work towards producing practical methodologies that systematically incorporate values into the design process. Many designers struggle to find a balance between their own values, those of users and other stakeholders, and those of the surrounding culture. In this paper, we present the RAPUNSEL project as a case study of game design in a values-rich context and describe our efforts toward navigating the complexities this entails. Additionally, we present initial steps toward the development of a systematic methodology for discovery, analysis, and integration of values in technology design in the hope that others may both benefit from and build upon this work.

PURPOSE: We conducted a phase I and pharmacologic study of a weekly 96-hour infusion of irinotecan to determine the maximum-tolerated dose, define the toxicity profile, and characterize the clinical pharmacology of irinotecan and its metabolites. PATIENTS AND METHODS: In 26 adult patients with solid tumors, the duration and dose rate of infusion were escalated in new patients until toxicity was observed. RESULTS: In 11 patients who were treated with irinotecan at 12.5 mg/m2/d for 4 days weekly for 2 of 3 weeks, dose-limiting grade 3 diarrhea occurred in three patients and grade 3 thrombocytopenia occurred in two patients. The recommended phase II dose is 10 mg/m2/d for 4 days given weekly for 2 of 3 weeks. At this dose, the steady-state plasma concentration (Css) of total SN-38 (the active metabolite of irinotecan) was 6.42 ± 1.10 nmol/L, and the Css of total irinotecan was 28.60 ± 17.78 nmol/L. No patient experienced grade 3 or 4 neutropenia during any cycle. All other toxicities were mild to moderate. The systemic exposure to SN-38 relative to irinotecan was greater than anticipated, with a molar ratio of the area under the concentration curve (AUC) of SN-38 to irinotecan of 0.24 ± 0.08. One objective response lasting 12 months in duration was observed in a patient with metastatic colon cancer. CONCLUSION: The recommended phase II dose of irinotecan of 10 mg/m2/d for 4 days weekly for 2 of 3 weeks was extremely well tolerated. Further efficacy testing of this pharmacologic strategy of administering intermittent low doses of irinotecan is warranted.

As information technologies become increasingly prevalent in children’s lives, designers must make difficult design decisions regarding both the developmental constraints of the user population (e.g., cognitive capacity, literacy, attention span, etc.) and implications for fundamental human values (e.g., information access, privacy, autonomy, informed consent, psychological welfare, etc.). Whether interacting with digital reference systems (Silverstein, 2005), robotic pets (Kahn, Friedman, Perez-Granados, & Freier, in press), or educational games to teach young girls programming (Flanagan, Howe, & Nissenbaum, 2005), children are continuously constructing knowledge about these information systems and utilizing that knowledge to reflect upon larger domains of life such as the personal-psychological, socialconventional, and moral.

Persuasive games tackling serious issues in a literal, explicit fashion are far less likely to succeed in changing attitudes or behaviors than are games that take the more “stealthy” approach of embedding persuasive messages within a game’s content or context. The “Embedded Design” model, developed by the design and research team at Tiltfactor Laboratory at Dartmouth College, offers novel, evidence-based strategies for including persuasive content in a game in ways that circumvent players’ psychological defenses, triggering a more receptive mindset for internalizing a game’s intended message, and do so without sacrificing players’ enjoyment or the game’s inherent replayability. Such techniques promise to revolutionize the repertoire of techniques that game developers should consider in broaching and presenting serious topics in games. Three original “Embedded Design” strategies are presented here: (1) Intermixing: balancing “on-message” and “off-message” content to render the former less overt or threatening; (2) Obfuscating: using framing devices or genres that divert expectations or focus away from the game’s persuasive intent; and (3) Distancing: employing fiction and metaphor to increase the psychological gap between players’ identities and beliefs, and the game’s characters and persuasive content.