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Background Single patient Investigational New Drug (IND) applications are one mechanism through which experimental therapies are accessed for children with cancer. The landscape of use, outcomes, and toxicity from single patient INDs remains unknown in pediatric oncology. Methods We performed a retrospective analysis of all single patient INDs requested and prescribed at a single institution between 1/1/2007 and 5/1/2019. We report aggregate data from the US Food and Drug Administration (FDA) on single patient IND applications over the final two years of the study (2017–2019). We report an overview of all IND applications, as well as clinical descriptions of patients, treatments, outcomes, and toxicity. Results Over the 2‐year period, the FDA approved all 171 submitted single patient IND requests for pediatric oncology. We identified 56 requests from our center during the 12‐year study period, and all were approved (median time from FDA submission to approval: 1 day (range 0–12)). 71% of requests were based on disease histology. Lack of pediatric clinical trial (65%) was the most common reason for use. 48 approved requests were ultimately administered. The median duration of treatment was 84 days (range: 4–1590), with 3 patients remaining on treatment at time of analysis. Only 7% discontinued treatment due to toxicity. Three‐year overall survival was 50% (95% CI, 35–64). Conclusions Single patient INDs in pediatric oncology were universally approved in our national and single‐center analysis. In our cohort, single patient INDs were primarily utilized based on disease histology, rather than genomics, for agents that lacked a clinical trial., Single patient Investigational New Drug (IND) applications in pediatric oncology are universally approved in a timely fashion in our analysis. Single patient IND therapy is pursued for a range of reasons, with few patients discontinuing therapy due to toxicity.

PURPOSE Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 11-001 assessed efficacy and toxicity of calaspargase pegol (calaspargase), a novel pegylated asparaginase formulation with longer half-life, compared with the standard formulation pegaspargase. METHODS Patients age 1 to ≤ 21 years with newly diagnosed ALL or lymphoblastic lymphoma were randomly assigned to intravenous pegaspargase or calaspargase, 2,500 IU/m2/dose. Patients received one induction dose. Beginning week 7, pegaspargase was administered every 2 week for 15 doses and calaspargase every 3 week for 10 doses (30 weeks). Serum asparaginase activity (SAA) (≥ 0.1 IU/mL considered therapeutic) was assessed 4, 11, 18, and 25 days after the induction dose and before each postinduction dose. RESULTS Between 2012 and 2015, 239 eligible patients enrolled (230 ALL, nine lymphoblastic lymphoma); 120 were assigned to pegaspargase and 119 to calaspargase. After the induction dose, SAA was ≥ 0.1 IU/mL in ≥ 95% of patients on both arms 18 days after dosing. At day 25, more patients had SAA ≥ 0.1 IU/mL with calaspargase (88% v 17%; P ˂ .001). Postinduction, median nadir SAAs were similar (≥ 1.0 IU/mL) for both arms. Of 230 evaluable patients, 99% of pegaspargase and 95% of calaspargase patients achieved complete remission ( P = .12), with no difference in frequency of high end-induction minimal residual disease among evaluable patients with B acute lymphoblastic leukemia (B-ALL). There were no differences in frequencies of asparaginase allergy, pancreatitis, thrombosis, or hyperbilirubinemia. With 5.3 years median follow-up, 5-year event-free survival for pegaspargase was 84.9% (SE ± 3.4%) and 88.1% (± SE 3.0%) for calaspargase ( P = .65). CONCLUSION Every 3-week calaspargase had similar nadir SAA, toxicity, and survival outcomes compared with every 2-week pegaspargase. The high nadir SAA observed for both preparations suggest dosing strategies can be further optimized.

BACKGROUND/OBJECTIVES While outcomes for pediatric T-cell acute lymphoblastic leukemia (T-ALL) are favorable, there are few widely accepted prognostic factors, limiting the ability to risk stratify therapy. DESIGN/METHODS Dana-Farber Cancer Institute (DFCI) Protocols 05-001 and 11-001 enrolled pediatric patients with newly diagnosed B- or T-ALL from 2005 to 2011 and from 2012 to 2015, respectively. Protocol therapy was nearly identical for patients with T-ALL (N = 123), who were all initially assigned to the high-risk arm. End-induction minimal residual disease (MRD) was assessed by reverse transcription polymerase chain reaction (RT-PCR) or next-generation sequencing (NGS), but was not used to modify postinduction therapy. Early T-cell precursor (ETP) status was determined by flow cytometry. Cases with sufficient diagnostic DNA were retrospectively evaluated by targeted NGS of known genetic drivers of T-ALL, including Notch, PI3K, and Ras pathway genes. RESULTS The 5-year event-free survival (EFS) and overall survival (OS) for patients with T-ALL was 81% (95% CI, 73-87%) and 90% (95% CI, 83-94%), respectively. ETP phenotype was associated with failure to achieve complete remission, but not with inferior OS. Low end-induction MRD (

Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001 tested a new risk stratification system in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL). At study entry, B-ALL patients were classified as standard risk (SR) or high risk (HR) based on age, white blood cell (WBC) count, and central nervous system status. After achieving complete remission (CR), patients with high end-induction minimal residual disease (MRD) (≥10−3 by polymerase chain reaction analysis of patient-specific antigen receptor rearrangements) and/or adverse cytogenetics (KMT2A rearrangement or hypodiploidy) were reclassified as very high risk (VHR) and received intensified therapy. IKZF1 deletion status was retrospectively evaluated by multiplex ligation-dependent probe amplification. Between 2005 and 2011, 678 Philadelphia chromosome-negative B-ALL patients aged 1 to 18 years enrolled; 651 achieved CR and 648 received a final risk group. Among all 678 patients, 5-year event-free survival (EFS) was 87% (95% confidence interval [CI], 84-89) and overall survival 93% (95% CI, 90-94). Five-year disease-free survival of SR patients (N = 407) was 94% (95% CI, 91-96), HR (N = 176) was 84% (95% CI, 77-88), and VHR (N = 65) was 79% (95% CI, 67-87). IKZF1 deletion was present in 62 of 385 (16%) assessed patients and was associated with inferior 5-year EFS (63%; 95% CI, 49%-74% vs 88%; 95% CI, 84%-91%; P < .001), and higher 5-year cumulative incidence of relapse, including among those with low MRD (24% vs 8%, P = .001). In multivariable analysis, age ≥15 years, WBC ≥50 × 109/L, IKZF1 deletion, and MRD ≥10−4 was each associated with inferior outcome. In conclusion, risk-stratified therapy on DFCI 05-001 resulted in favorable outcomes for B-ALL patients, including those with VHR features. IKZF1 deletion was an independent predictor of inferior outcome. This trial was registered at www.clinicaltrials.gov as #{"type":"clinical-trial","attrs":{"text":"NCT00400946","term_id":"NCT00400946"}}NCT00400946.

Introduction: Hypersensitivity reactions with asparaginase occur frequently in pediatric patients (pts) with acute lymphoblastic leukemia (ALL). The standard approach for pts with reaction to E.coli-derived asparaginase is to switch to Erwinia asparaginase, given concern that clinical reactions reflect presence of neutralizing antibodies; however, Erwinia requires more frequent dosing and is often unavailable. Therapeutic drug monitoring allows for discrimination between pts with pegaspargase hypersensitivity who have sub-therapeutic asparaginase activity and those still able to derive therapeutic benefit from pegaspargase. We prospectively piloted re-challenging pts with pegaspargase after initial Grade 2 hypersensitivity to this agent, with premedication at re-challenge and assessment of serum asparaginase activity (SAA). Methods: Pts aged 1 to < 22 years with newly diagnosed ALL were eligible for DFCI 16-001. Pts received 1 dose of intravenous pegaspargase during Induction, and every 2 weeks for 15 total doses in Post-Induction phases, without routine premedication. Pts were monitored during/after pegaspargase for allergy, with CTCAE version 4.0 event grading. Those with ≥Grade 3 allergy discontinued pegaspargase and were switched to Erwinia. Those with Grade 2 allergic reaction were eligible for pegaspargase re-challenge with pre-medication (acetaminophen, diphenhydramine, and hydrocortisone, or per institutional standard) and slower infusion rate. If < 50% of the intended dose had been administered when reaction occurred, re-challenge was within 1-7 days of initial reaction. If ≥ 50% of the intended dose had been given, re-challenge was at next planned pegaspargase dose. SAA was measured 1-hour, 7-days, and 14-days after the re-challenge infusion (if dose completed). If 1-hour or 7-day level ≥ 0.1 IU/mL, and 14-day level ≥ 0.025 IU/mL, SAA was considered adequate, and the pt continued to receive pegaspargase with premedication. Pts with an inadequate SAA level, or with new ≥ Grade 2 allergic reaction with the re-challenge dose were considered to have failed re-challenge and were changed to Erwinia (or enrolled on a clinical trial of recombinant crisantaspase, an alternative Erwinia preparation). Results: Between 3/2017- 7/2020, 317 eligible pts enrolled. Overall, 81 of 299 (27%) total evaluable pts experienced a first allergic reaction to pegaspargase, 68 pts with Grade 2 reaction, 13 with Grade ≥3. During Induction, 17 of 299 (6%) evaluable pts had allergic reaction to pegaspargase; all Grade 2. Of the 17 Grade 2 reactions, 13 pts (76%) underwent re-challenge in Induction, 9 (69%) re-challenges successful and 4 failed. Post-Induction, 64 of 241 evaluable pts (27%) had a first allergic reaction; 51 Grade 2 and 13 Grade ≥3. Thirty-six of 51 (71%) pts with Grade 2 allergy during Post-Induction underwent re-challenge, as did 1 additional pt with allergy during Induction who was re-challenged with first Post-Induction pegaspargase dose (per protocol guideline, due to receiving ≥50% of Induction dose). Among these re-challenges, 16 were successful, 21 failed. Overall, 25 of 50 (50%) pts who were re-challenged after Grade 2 reaction had a successful challenge and were able to continue pegaspargase. Among the 25 pts with failed re-challenge, 6 pts (24%) had inadequate SAA alone as cause of failure, 17 pts (68%) had an allergic reaction with the re-challenge dose, and 2 (8%) additional patients had both allergic reaction and documented inadequate SAA. Three pts who were successfully re-challenged had a subsequent allergic reaction to pegaspargase. Among the 22 pts who experienced another allergic reaction with pegaspargase (at re-challenge or subsequent dose), 19 pts (86%) experienced Grade 2, and 3 pts experienced Grade 3 reaction. Conclusion: Fifty percent of pts with a Grade 2 reaction to pegaspargase were able to tolerate and achieve adequate SAA when re-challenged with premedication. For those who did react with or after re-challenge, reactions were not more severe. The re-challenge approach limits premedication exposure only to a minority of pts with a history of prior reaction and substantially decreases the number of pts needing to switch to Erwinia asparaginase, which can be challenging to deliver due to administration schedule and drug shortage. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board.

Summary Background l-asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia, and is usually administered intramuscularly. Pegylated Escherichia coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than the native Escherichia coli ( E coli ) preparation, and can be more feasibly administered intravenously. The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05-001 (DFCI 05-001) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E coli l-asparaginase in children with newly diagnosed acute lymphoblastic leukaemia. Methods DFCI 05-001 enrolled patients aged 1–18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada. Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy. Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a randomised comparison of intravenous PEG-asparaginase (15 doses of 2500 IU/m 2 every 2 weeks) or intramuscular native E coli l-asparaginase (30 doses of 25 000 IU/m 2 weekly), beginning at week 7 after study entry. Randomisation (1:1) was unmasked, and was done by a statistician-generated allocation sequence using a permuted blocks algorithm (block size of 4), stratified by final risk group. The primary endpoint of the randomised comparison was the overall frequency of asparaginase-related toxicities (defined as allergy, pancreatitis, and thrombotic or bleeding complications). Predefined secondary endpoints were disease-free survival, serum asparaginase activity, and quality of life during therapy as assessed by PedsQL surveys. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00400946. Findings Between April 22, 2005, and Feb 12, 2010, 551 eligible patients were enrolled. 526 patients achieved complete remission after induction, of whom 463 were randomly assigned to receive intramuscular native E coli l-asparaginase (n=231) or intravenous PEG-asparaginase (n=232). The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities (65 [28%] of 232 patients in the intravenous PEG-asparaginase group vs 59 [26%] of 231 patients in the intramuscular native E coli l-asparaginase group, p=0·60), or in the individual frequency of allergy (p=0·36), pancreatitis (p=0·55), or thrombotic or bleeding complications (p=0·26). Median follow-up was 6·0 years (IQR 5·0–7·1). 5-year disease-free survival was 90% (95% CI 86–94) for patients assigned to intravenous PEG-asparaginase and 89% (85–93) for those assigned to intramuscular native E coli l-asparaginase (p=0·58). The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E coli l-asparaginase. Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E coli l-asparaginase group than in the intravenous PEG-asparaginase group. Scores for other domains were similar between the groups. The most common grade 3 or worse adverse events were bacterial or fungal infections (47 [20%] of 232 in the intravenous PEG-asparaginase group vs 51 [22%] of 231 patients in the intramuscular E coli l-asparaginase group) and asparaginase-related allergic reactions (14 [6%] vs 6 [3%]). Interpretation Intravenous PEG-asparaginase was not more toxic than, was similarly efficacious to, and was associated with decreased anxiety compared with intramuscular native E coli l-asparaginase, supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia. Funding National Cancer Institute and Enzon Pharmaceuticals.

10006 Background: DFCI ALL Consortium Protocol 11-001 assessed the efficacy and toxicity of Calaspargase pegol (SC-PEG), a novel pegylated asparaginase (ASP) formulation with longer half-life, compared with standard pegaspargase (SS-PEG). Methods: Patients (pts) aged 1-21 years with newly diagnosed acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) were eligible. At study entry, pts were randomly assigned to receive either intravenous SS-PEG or SC-PEG, 2500 IU/m2/dose. Pts received 1 dose during the first treatment month. Beginning week 7, SS-PEG was administered every 2 weeks for 15 doses, SC-PEG every 3 weeks for 10 doses (30 weeks). Serum asparaginase activity (SAA) (considered therapeutic at ≥ 0.1 IU/mL) was assessed 4, 11, 18, and 25 days after the induction dose and before each post-induction dose. End-induction minimal residual disease (MRD) was assessed in ALL pts by IGH/TCR PCR. Results: Between 2012-2015, 239 eligible pts enrolled (230 ALL, 9 LL); 120 assigned to SS-PEG, 119 to SC-PEG. After dose 1, SAA remained ≥ 0.1 IU/mL in ≥ 95% of pts on both arms through day 18. Median SAA was higher (0.319 IU/mL vs 0.056 IU/mL) and more pts had therapeutic SAA (88% vs 17%, p˂0.001) with SC-PEG vs SS-PEG 25 days after dose 1. Post-induction, median nadir SAA (NSAA) were similar ( > 1.0 IU/mL) for both arms. There was no difference in rates of ASP-allergy, pancreatitis, thrombosis, hyperbilirubinemia, osteonecrosis, or infection. Of 230 evaluable pts, 99% of SS-PEG and 95% of SC-PEG pts achieved complete remission (p = 0.12). For B ALL pts, there was no difference in frequency of high end-induction MRD (10.3% SS-PEG, 9.5% SC-PEG, p = 1.0). With 4-year median follow-up, 4-year event-free survival (EFS) (90% confidence interval) for SS-PEG was 90.2% (84.3, 93.9), 87.7% (81.5, 91.9) for SC-PEG (p = 0.78); overall survival (OS) was 95.6% (91.0, 97.9) for SS-PEG, 94.8% (90.0, 97.3) for SC-PEG (p = 0.74). Conclusions: Every 3-week SC-PEG had similar EFS, OS, safety profile, and NSAA compared with every 2-week SS-PEG. The high NSAA observed for both preparations suggest dosing strategies can be further optimized. These data informed FDA approval of SC-PEG for pediatric pts. Clinical trial information: NCT01574274.

Background: This study evaluated sex and family history of alcoholism as moderators of subjective ratings of sleepiness/sleep quality and polysomnography (PSG) following alcohol intoxication in healthy, young adults. Methods: Ninety-three healthy adults [mean age 24.4 ± 2.7 years, 59 women, 29 subjects with a positive family history of alcoholism (FH+)] were recruited. After screening PSG, participants consumed alcohol (sex/weight adjusted dosing) to intoxication [peak breath alcohol concentration (BrAC) of 0.11 ± 0.01 g% for men and women] or matching placebo between 20:30 and 22:00 hours. Sleep was monitored using PSG between 23:00 and 07:00 hours. Participants completed the Stanford Sleepiness Scale and Karolinska Sleepiness Scale at bedtime and on awakening and a validated post-sleep questionnaire. Results: Following alcohol, total sleep time, sleep efficiency, nighttime awakenings, and wake after sleep onset were more disrupted in women than men, with no differences by family history status. Alcohol reduced sleep onset latency, sleep efficiency, and rapid eye movement sleep while increasing wakefulness and slow wave sleep across the entire night compared with placebo. Alcohol also generally increased sleep consolidation in the first half of the night, but decreased it during the second half. Sleepiness ratings were higher following alcohol, particularly in women at bedtime. Morning sleep quality ratings were lower following alcohol than placebo. Conclusions: Alcohol intoxication increases subjective sleepiness and disrupts sleep objectively more in healthy women than in men, with no differences evident by family history of alcoholism status. Evaluating moderators of alcohol effects on sleep may provide insight into the role of sleep in problem drinking.

Aims Marketing that promotes mixing caffeinated 'energy' drinks with alcoholic beverages (e.g. Red Bull with vodka) targets young drinkers and conveys the expectation that caffeine will offset the sedating effects of alcohol and enhance alertness. Such beliefs could result in unwarranted risk taking (e.g. driving while intoxicated). The aim of this study was to assess the acute effects of caffeinated versus non-caffeinated alcoholic beverages on a simulated driving task and attention/reaction time. Design We conducted a 2 × 2 between-groups randomized trial in which participants were randomized to one of four conditions: beer and non-alcoholic beer, with and without caffeine added. Caffeine was added in the same proportion as found in a commercially available caffeinated beer (69 mg/12 oz of beer at 4.8% alc. by vol). Participants Participants were 127 non-dependent, heavy episodic, young adult drinkers (age 21-30) who were college students or recent graduates. The target breath alcohol level was 0.12 g%. Measures Driving performance was assessed with a driving simulator; sustained attention/reaction with the Psychomotor Vigilance Task (PVT). Findings Across the driving and attention/reaction time we found main effects for alcohol, with alcohol significantly impairing driving and sustained attention/reaction time, with mainly large statistical effects; however, the addition of caffeine had no main or interaction effects on performance. Conclusion The addition of caffeine to alcohol does not appear to enhance driving or sustained attention/reaction time performance relative to alcohol alone. Language: en

Background We sought to determine the feasibility of co-administering everolimus with a four-drug reinduction in children and adolescents with acute lymphoblastic leukemia (ALL) experiencing a first marrow relapse. Procedure This phase I study tested everolimus with vincristine, prednisone, pegaspargase and doxorubicin in patients with marrow relapse occurring >18 months after first complete remission (CR). The primary aim was to identify the maximum tolerated dose of everolimus. Three dose levels (DLs) were tested during dose escalation (2, 3, and 5 mg/m2 /day). Additional patients were enrolled at the 3- and 5 mg/m2 /day DLs to further evaluate toxicity (dose expansion). Results Thirteen patients enrolled during dose escalation and nine during dose expansion. During dose escalation, one dose-limiting toxicity occurred (grade 4 hyperbilirubinemia) in six evaluable patients at DL3 (5 mg/m2 /day). The most common grade ≥3 adverse events were febrile neutropenia, infections, transaminitis, hyperbilirubinemia, and hypophosphatemia. Two of the 12 patients treated at DL3 developed Rothia mucilaginosa meningitis. Nineteen patients (86%) achieved a second CR (CR2). Of those, 13 (68%) had a low end-reinduction minimal residual disease (MRD) level (≤10-3 by polymerase chain reaction-based assay). The CR2 rate for patients with B-cell ALL treated at DL3 (n = 12) was 92%; 82% of these patients had low MRD. Conclusions Everolimus combined with four-drug reinduction chemotherapy was generally well tolerated and associated with favorable rates of CR2 and low end-reinduction MRD. The recommended phase 2 dose of everolimus given in combination with a four-drug reinduction is 5 mg/m2 /day. This promising combination should be further evaluated in a larger patient cohort.

Aim To assess the effects of binge drinking on students' next‐day academic test‐taking performance. Design A placebo‐controlled cross‐over design with randomly assigned order of conditions. Participants were randomized to either alcoholic beverage [mean = 0.12 g% breath alcohol concentration (BrAC)] or placebo on the first night and then received the other beverage a week later. The next day, participants were assessed on test‐taking, neurocognitive performance and mood state. Participants A total of 196 college students (≥21 years) recruited from greater Boston. Setting The trial was conducted at the General Clinical Research Center at the Boston Medical Center. Measurements The Graduate Record Examinations© (GREs) and a quiz on a lecture presented the previous day measured test‐taking performance; the Neurobehavioral Evaluation System (NES3) and the Psychomotor Vigilance Test (PVT) measured neurocognitive performance; and the Profile of Mood States (POMS) measured mood. Findings Test‐taking performance was not affected on the morning after alcohol administration, but mood state and attention/reaction‐time were affected. Conclusion Drinking to a level of 0.12 g% BrAC does not affect next‐day test‐taking performance, but does affect some neurocognitive measures and mood state.

BACKGROUND Pediatric patients receiving induction chemotherapy for newly diagnosed acute lymphoblastic leukemia (ALL) are at high risk of developing life-threatening infections. We investigated whether uniform antibacterial guidelines, including mandatory antibacterial prophylaxis in afebrile patients during induction, decreases the incidence of microbiologically documented bacteremia. METHODS Between 2012 and 2015, 230 patients with newly diagnosed ALL (aged 1-21) were enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 11-001 (DFCI 11-001). Induction therapy, regardless of risk group, included vincristine, prednisone, doxorubicin, methotrexate, and PEG-asparaginase. Afebrile patients received fluoroquinolone prophylaxis at the initiation of induction and those presenting with fever received broad-spectrum antibiotics; antibiotics were continued until blood count recovery. Rates of documented bacteremias and fungal infections on DFCI 11-001 were compared to those on the predecessor protocol (DFCI 05-001), which included the same induction phase without antibiotic prophylaxis guidelines. RESULTS Sixty-six (28.7%) patients received fluoroquinolone prophylaxis, the remaining patients received broad-spectrum antibiotics. Twenty-four (36.4%) patients on prophylaxis developed fever and seven (10.6%) developed bacteremia. The overall rate of infection during induction on DFCI 11-001 was lower than on DFCl 05-001 (14.3% vs. 26.3%, P

Background: E.coli L-asparaginase (L-ASP) is an important component of treatment for childhood acute lymphoblastic leukemia (ALL), but the optimal preparation and dosing remain to be determined. Pegaspargase (SS-PEG) is a pegylated L-ASP formulation commonly used in frontline therapy. Calaspargase pegol (SC-PEG) is a novel formulation that uses the same ASP enzyme and PEG moiety as SS-PEG but a different linker molecule that is more hydrolytically stable, leading to a longer half-life. On Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols, patients (pts) typically receive a single dose SS-PEG during induction, and then 15 doses every 2-weeks (wks) during post-induction in order to maintain therapeutic serum asparaginase activity (SAA), defined as ≥ 0.1 IU/mL, for 30 consecutive wks. We hypothesized that SC-PEG could be administered less frequently than SS-PEG during post-induction therapy with a similar SAA and toxicity profile. Methods: Between 2012-2015, pts aged 1-21 years with newly diagnosed ALL or lymphoblastic lymphoma (LL) were eligible to enroll on DFCI ALL Consortium Protocol 11-001. Pts were randomized at study entry to receive either SS-PEG (N=120) or SC-PEG (N=119), each given intravenously (IV) at a dose of 2500 IU/m2. Both groups received a single dose during multi-agent remission induction. Post-induction, pts assigned to SS-PEG received 15 doses every 2-wks and those assigned to SC-PEG received 10 doses every 3-wks along with other risk-stratified chemotherapy. Serum samples were obtained 4, 11, 18 and 25 days after the induction dose to determine SAA and prior to each post-induction dose (2 wks after each SS-PEG and 3 wks after each SC-PEG dose) to determine nadir SAA (NSAA) by a validated biochemical assay. Pts were switched to Erwinia asparaginase for Grade 2 or higher allergy or for silent inactivation (defined as 2 consecutive non-detectable NSAA). Asparaginase was permanently discontinued for pancreatitis and held for thrombosis (but re-started once the clot improved). End-induction minimal residual disease (MRD) was assessed in ALL pts by IGH/TCRPCR assay, with low MRD defined as < 0.001. Results: 239 eligible pts were enrolled (230 ALL and 9 LL). There were no significant differences in presenting characteristics between randomized arms. SAA during induction and NSAA during post-induction are displayed in Figure 1. SAA was similar for the two preparations at 4, 11 and 18 days after the induction dose, with SAA ≥ 0.1 IU/mL in ≥ 95% of pts at these time points on both arms. 25 days after the induction dose, SAA was higher with SC-PEG (median 0.298 IU/mL vs 0.056 for SS-PEG), with significantly more pts on SC-PEG arm with SAA ≥ 0.1 IU/mL (88% vs 15%, p Conclusion: During remission induction, a single dose of SC-PEG (2500 IU/m2) leads to more sustained SAA without excess toxicity or significant difference in the proportion of pts with low end-induction MRD. During post-induction therapy, SC-PEG can be given less frequently (every 3-wks) than SS-PEG (every 2-wks) with similar NSAA and toxicity. The high NSAA observed during post-induction therapy with each preparation suggests that a longer dosing interval and/or reduced dose may be feasible while still maintaining NSAA ≥ 0.1 IU/mL. Longer follow-up is necessary to determine event-free survival by randomized arm. Disclosures No relevant conflicts of interest to declare.

Transdermal scopolamine is commonly used by mariners to prevent or treat seasickness. Most studies indicate that scopolamine administered transdermally via an adhesive patch does not impair performance of skills required to navigate a vessel, but trials have not been conducted testing navigation and ship handling under realistic conditions. The aim of this study was to test the effects of transdermal scopolamine on performance using training simulators to assess complex vessel navigation and rough-weather ship handling abilities. A randomized double-blind crossover study assessed 32 Swedish maritime cadets under transdermal scopolamine and placebo conditions on simulated navigation and ship handling performance, sleepiness, and subjective measures of fitness and performance. There were no significant differences on occupational outcomes by medication condition, but sustained reaction time was significantly increased under transdermal scopolamine, relative to placebo. We conclude that the transdermal scopolamine patch does not impair simulated ship handling.

Current treatment regimens for childhood ALL have resulted in long-term event-free survival (EFS) of approximately 80%. On DFCI ALL Consortium Protocol 05-001, patients (pts) with newly diagnosed ALL aged 1-18 years (yrs) who achieved complete remission (CR) were eligible to participate in a randomized comparison of native E.coli asparaginase (ASP) given intramuscularly (IM) and PEG ASP, the polyethylene glycol conjugate of E.coli ASP, given intravenously (IV). The objective was to compare the serum ASP activity (SAA), toxicity, and EFS of the two ASP preparations. An intensified consolidation regimen for VHR pts, including B-ALL pts with high end-induction minimal residual disease (MRD), was also evaluated. Methods All pts received 1 dose of PEG ASP (2500 IU/m2) during the 4-week (wk) multiagent induction phase. After CR was achieved, final risk group was assigned based on age, presenting WBC, CNS status, cytogenetics and end-induction MRD (assessed by PCR). All T-ALL pts were considered HR. Pts were considered VHR if they met one of the following criteria: i) B-ALL with high end-induction MRD; or ii) adverse cytogenetics (MLL gene rearrangement or hypodiploidy). BCR-ABL positive pts began daily imatinib at Day 18 and were allocated to allogeneic transplant in 1st CR. Beginning at wk 7, pts began the consolidation phase including 30 wks of ASP, either IM E.coli ASP 25000 IU/m2 weekly or IV PEG 2500 IU/m2 every 2 wks. In addition, SR pts received every 3-wk cycles with vincristine, dexamethasone, 6MP and low-dose methotrexate (mtx) during consolidation; HR pts received doxorubicin (cumulative dose 300 mg/m2) with dexrazoxane instead of mtx during this phase. VHR pts received 2 additional cycles beginning at week 7 (cyclophosphamide/low-dose araC/6-MP and then high-dose araC/etoposide/dexamethasone), followed by the HR consolidation phase. Continuation phase was identical for all pts. Total duration of therapy was 25 months. Serum samples were obtained every 6 wks just prior to an ASP dose to measure SAA. EFS rates were calculated from date of registration, except for EFS by randomized arm, risk group, and end-induction MRD, which were calculated from time of randomization. Results Between 2005-2010, 551 evaluable pts enrolled, of whom 526 (95%) achieved CR. 463 pts participated in the ASP randomization. Median nadir SAA was significantly higher with IV PEG than with IM E.coli ASP,(Table 1) with more IV PEG-randomized pts achieving nadir SAA ≥ 0.1 IU/mL (p Conclusion Overall EFS on Protocol 05001 compares favorably with previously published outcomes for pediatric ALL. Intensified consolidation improved outcome for B-ALL pts with high end-induction MRD. Relatively favorable outcomes were also observed in other high-risk pt subsets, including older children/adolescents and pts with T-ALL. We have demonstrated that IV PEG is as effective as and no more toxic than weekly IM E.coli ASP in children and adolescents with ALL. Disclosures: Silverman: Sigma Tau Pharmaceuticals: Consultancy. Andrew:Sigma Tau Pharmaceuticals: Consultancy. Neuberg:Synta Pharmaceuticals: Trust owns stock; I am a Trustee Other. Sallan:Sigma Tau Pharmaceuticals: Consultancy.