Recombinant Erwinia asparaginase (JZP458) in acute lymphoblastic leukemia: results from the phase 2/3 AALL1931 study.

AALL1931, a phase 2/3 study conducted in collaboration with the Children's Oncology Group, investigated the efficacy and safety of JZP458 (asparaginase erwinia chrysanthemi [recombinant]-rywn), a recombinant Erwinia asparaginase derived from a novel expression platform, in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma who developed hypersensitivity/silent inactivation to Escherichia coli-derived asparaginases. Each dose of a pegylated E coli-derived asparaginase remaining in patients' treatment plan was substituted by 6 doses of intramuscular (IM) JZP458 on Monday/Wednesday/Friday (MWF). Three regimens were evaluated: cohort 1a, 25 mg/m2 MWF; cohort 1b, 37.5 mg/m2 MWF; and cohort 1c, 25/25/50 mg/m2 MWF. Efficacy was evaluated by the proportion of patients maintaining adequate nadir serum asparaginase activity (NSAA ≥0.1 IU/mL) at 72 hours and at 48 hours during the first treatment course. A total of 167 patients were enrolled: cohort 1a (n = 33), cohort 1b (n = 83), and cohort 1c (n = 51). Mean serum asparaginase activity levels (IU/mL) at 72 hours were cohort 1a, 0.16, cohort 1b, 0.33, and cohort 1c, 0.47, and at 48 hours were 0.45, 0.88, and 0.66, respectively. The proportion of patients achieving NSAA ≥0.1 IU/mL at 72 and 48 hours in cohort 1c was 90% (44/49) and 96% (47/49), respectively. Simulated data from a population pharmacokinetic model matched the observed data well. Grade 3/4 treatment-related adverse events occurred in 86 of 167 (51%) patients; those leading to discontinuation included pancreatitis (6%), allergic reactions (5%), increased alanine aminotransferase (1%), and hyperammonemia (1%). Results demonstrate that IM JZP458 at 25/25/50 mg/m2 MWF is efficacious and has a safety profile consistent with other asparaginases. This trial was registered at www.clinicaltrials.gov as #NCT04145531.

A Phase 2 Trial of KIR-Mismatched Unrelated Donor Transplantation Using in Vivo T Cell Depletion with Antithymocyte Globulin in Acute Myelogenous Leukemia: Children's Oncology Group AAML05P1 Study.

Patients with acute myelogenous leukemia (AML) who undergo killer immunoglobulin-like receptor (KIR)-mismatched haploidentical hematopoietic stem cell transplantation (HSCT) have improved survival. Children's Oncology Group AAML05P1 is a prospective phase 2 trial of unrelated donor (URD) HSCT in which KIR typing of donors was available to the treating physician at donor selection, aiming to determine feasibility (defined as the ability to obtain donor samples from URDs and obtain KIR data before transplantation) of prospective selection of KIR-mismatched donors and effect on outcomes. Patients age ≤30 years with high-risk AML at presentation or relapsed AML were eligible; the study accrued 90 evaluable patients. After enrollment, as many as 5 potential URD samples were KIR-typed (including gene expression) in a central laboratory and results reported to the treating physician, who made the final donor selection. Cases were categorized as KIR-matched or KIR-mismatched using different published strategies. Overall survival (OS), disease-free survival (DFS), and relapse did not differ significantly by KIR mismatch status. Acute graft-versus-host disease (GVHD) was significantly lower in recipients of KIR-mismatched stem cells (35% versus 60%; P = .027). We examined DFS according to time to natural killer (NK) receptor recovery after HSCT. NK p44 recovery was significantly associated with KIR mismatch and with decreased DFS and increased relapse risk in multivariate Cox analysis (P = .006 and .009, respectively). We show that prospective selection of URD according to KIR type was feasible, acute GVHD was reduced, but survival did not differ using any model of KIR mismatch. However, the study enrolled mostly matched transplants, so ligand-ligand mismatch was rare, and thus the sample size was insufficient to determine potential benefit according to this model. Cord blood recipients demonstrated a trend toward improved DFS with KIR mismatch, but the study was not powered to detect a difference in this small subset of patients. Our data suggest that recovery of NK receptor expression might influence DFS after HSCT.

Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer.

BACKGROUND: Standard chemotherapy is associated with low response rates and short progression-free survival among patients with pretreated metastatic triple-negative breast cancer. Sacituzumab govitecan-hziy is an antibody-drug conjugate that combines a humanized monoclonal antibody, which targets the human trophoblast cell-surface antigen 2 (Trop-2), with SN-38, which is conjugated to the antibody by a cleavable linker. Sacituzumab govitecan-hziy enables delivery of high concentrations of SN-38 to tumors. METHODS: We conducted a phase 1/2 single-group, multicenter trial involving patients with advanced epithelial cancers who received sacituzumab govitecan-hziy intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxic effects. A total of 108 patients received sacituzumab govitecan-hziy at a dose of 10 mg per kilogram of body weight after receiving at least two previous anticancer therapies for metastatic triple-negative breast cancer. The end points included safety; the objective response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), which was assessed locally; the duration of response; the clinical benefit rate (defined as a complete or partial response or stable disease for at least 6 months); progression-free survival; and overall survival. Post hoc analyses determined the response rate and duration, which were assessed by blinded independent central review. RESULTS: The 108 patients with triple-negative breast cancer had received a median of 3 previous therapies (range, 2 to 10). Four deaths occurred during treatment; 3 patients (2.8%) discontinued treatment because of adverse events. Grade 3 or 4 adverse events (in ≥10% of the patients) included anemia and neutropenia; 10 patients (9.3%) had febrile neutropenia. The response rate (3 complete and 33 partial responses) was 33.3% (95% confidence interval [CI], 24.6 to 43.1), and the median duration of response was 7.7 months (95% CI, 4.9 to 10.8); as assessed by independent central review, these values were 34.3% and 9.1 months, respectively. The clinical benefit rate was 45.4%. Median progression-free survival was 5.5 months (95% CI, 4.1 to 6.3), and overall survival was 13.0 months (95% CI, 11.2 to 13.7). CONCLUSIONS: Sacituzumab govitecan-hziy was associated with durable objective responses in patients with heavily pretreated metastatic triple-negative breast cancer. Myelotoxic effects were the main adverse reactions. (Funded by Immunomedics; IMMU-132-01 ClinicalTrials.gov number, NCT01631552.).

A phase 1 study of oral ridaforolimus in pediatric patients with advanced solid tumors.

PURPOSE: Ridaforolimus is an investigational, potent, selective mTOR inhibitor. This study was conducted to determine the recommended phase 2 dose (RP2D), maximum tolerated dose, safety, pharmacokinetics, and antitumor activity of oral ridaforolimus in children with advanced solid tumors. EXPERIMENTAL DESIGN: In this phase 1, multicenter, open-label study in children aged 6 to <18 years with advanced solid tumors, ridaforolimus was administered orally for 5 consecutive days/week in 28-day cycles until progression, unacceptable toxicity, or consent withdrawal. Dose started at 22 mg/m2 and increased to 28 mg/m2 and 33 mg/m2, followed by expansion at the RP2D. RESULTS: Twenty patients were treated; 18 were evaluable for dose-limiting toxicities. One dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in 1 patient at 33 mg/m2. Dose escalation concluded at 33 mg/m2; the maximum tolerated dose was not determined. The most common treatment-related adverse events (frequency ≥40%) were manageable grade 1-2 stomatitis, thrombocytopenia, hypertriglyceridemia, increased alanine aminotransferase, fatigue, hypercholesterolemia, anemia, and increased aspartate aminotransferase. Ridaforolimus exposure at 28 mg/m2 and 33 mg/m2 exceeded adult target levels. The RP2D for oral ridaforolimus in children was defined as 33 mg/m2. Four patients received at least 4 cycles; 2 with pineoblastoma and diffuse intrinsic pontine glioma had stable disease for 12 and 46 cycles, respectively. CONCLUSIONS: Ridaforolimus is orally bioavailable and well tolerated in children with advanced solid tumors. The RP2D (33 mg/m2, 5 days/week) exceeds the adult RP2D. The favorable toxicity and pharmacokinetic profiles may allow for combination therapy, a promising therapeutic option in pediatric malignancies.

Blood Aspergillus RNA is a promising alternative biomarker for invasive aspergillosis.

A critical challenge for the successful application of antifungal therapies for invasive aspergillosis (IA) is a lack of reliable biomarkers to assess early treatment response. Patients with proven or probable IA were prospectively enrolled, and serial blood samples were collected at 8 specified time points during 12-week antifungal therapy. Total nucleic acid was extracted from 2.5 ml blood and tested for Aspergillus-specific RNA by a pan-Aspergillus real-time nucleic acid sequence-based amplification (NASBA) assay. Serum 1, 3-ß-D-glucan (BG) and galactomannan (GM) were measured in parallel. Clinical outcome was evaluated at 6 and 12 weeks. Overall, 48/328 (14.6%) blood samples from 29/46 (63%) patients had positive NASBA detection at baseline and/or some point during the study. Positive NASBA results during the first 4 and 6 weeks of treatment are significantly associated with the 12-week outcome. Blood RNA load change during weeks 4-6 may be informative to predict outcome at 12 weeks. While independent of serum GM, the kinetic change of circulating Aspergillus RNA appears to be well correlated with that of BG on some patient individuals. Monitoring blood Aspergillus RNA during the first 4-6 weeks of antifungal treatment may help assess therapeutic response. Combination of circulating Aspergillus RNA and BG may be a useful adjunct to assess response.

Phase 1 study of dalotuzumab monotherapy and ridaforolimus-dalotuzumab combination therapy in paediatric patients with advanced solid tumours.

AIM: Dalotuzumab is a highly specific, humanised immunoglobulin G1 monoclonal antibody against insulin-like growth factor receptor 1. This multicenter phase 1 study (NCT01431547) explored the safety and pharmacokinetics of dalotuzumab monotherapy (part 1) and the combination of dalotuzumab with the mammalian target of rapamycin inhibitor ridaforolimus (part 2) in paediatric patients with advanced solid tumours. METHODS: Dalotuzumab was administered intravenously every 3 weeks starting at 900 mg/m(2) and escalating to 1200 and 1500 mg/m(2). Combination therapy included intravenous dalotuzumab at the defined single-agent recommended phase 2 dose (RP2D) and oral ridaforolimus 28 mg/m(2) daily (days 1-5), repeated weekly. Pharmacokinetic studies were performed to evaluate the mean serum trough dalotuzumab concentration, which guided the RP2D. RESULTS: Twenty-four patients were enrolled (part 1, n = 20; part 2, n = 4). No dose-limiting toxicities were observed in patients receiving dalotuzumab alone. One patient experienced dose-limiting stomatitis in the combination arm. Pharmacokinetic data showed dose-dependent increases in exposure (area under the curve from zero to infinity [AUC0-∞]) (87,900, 164,000, and 186,000 h*mg/ml for the 900, 1200, and 1500 mg/m(2) dose levels, respectively), maximum serum concentration (Cmax) (392, 643, and 870 mg/ml), and serum trough concentration (Ctrough) (67.1, 71.6, and 101 mg/ml). The mean half-life was 265, 394, and 310 h, respectively. Dalotuzumab pharmacokinetics were not affected by coadministration with ridaforolimus. One of six patients with Ewing sarcoma had confirmed partial response to dalotuzumab monotherapy at 900 mg/m(2). Time to response was 41 d, and progression occurred at 126 d. CONCLUSION: Dalotuzumab was well tolerated in paediatric patients with advanced solid malignancies. The RP2D of dalotuzumab is 900 mg/m(2) (ClinicalTrials.gov identifier: NCT01431547, Protocol PN062).

Correlation between Circulating Fungal Biomarkers and Clinical Outcome in Invasive Aspergillosis.

Objective means are needed to predict and assess clinical response in patients treated for invasive aspergillosis (IA). We examined whether early changes in serum galactomannan (GM) and/or ß-D-glucan (BDG) can predict clinical outcomes. Patients with proven or probable IA were prospectively enrolled, and serial GM and BDG levels and GM optical density indices (GMI) were calculated twice weekly for 6 weeks following initiation of standard-of-care antifungal therapy. Changes in these biomarkers during the first 2 and 6 weeks of treatment were analyzed for associations with clinical response and survival at weeks 6 and 12. Among 47 patients with IA, 53.2% (25/47) and 65.9% (27/41) had clinical response by weeks 6 and 12, respectively. Changes in biomarkers during the first 2 weeks were associated with clinical response at 6 weeks (GMI, P = 0.03) and 12 weeks (GM+BDG composite, P = 0.05; GM, P = 0.04; GMI, P = 0.02). Changes in biomarkers during the first 6 weeks were also associated with clinical response at 6 weeks (GM, P = 0.05; GMI, P = 0.03) and 12 weeks (BDG+GM, P = 0.02; GM, P = 0.02; GMI, P = 0.01). Overall survival rates at 6 weeks and 12 weeks were 87.2% (41/47) and 79.1% (34/43), respectively. Decreasing biomarkers in the first 2 weeks were associated with survival at 6 weeks (BDG+GM, P = 0.03; BDG, P = 0.01; GM, P = 0.03) and at 12 weeks (BDG+GM, P = 0.01; BDG, P = 0.03; GM, P = 0.01; GMI, P = 0.007). Similar correlations occurred for biomarkers measured over 6 weeks. Patients with negative baseline GMI and/or persistently negative GMI during the first 2 weeks were more likely to have CR and survival. These results suggest that changes of biomarkers may be informative to predict and/or assess response to therapy and survival in patients treated for IA.

Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors.

PURPOSE: This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0.005-10 mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: No dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56+ weeks' duration, respectively. Three patients with melanoma experienced partial responses. Fifteen patients with various malignancies experienced stable disease. One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation, following prolonged corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies. Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based translational models with a focus on intratumor exposure prediction suggested robust clinical activity would be observed at doses ≥2 mg/kg every 3 weeks. CONCLUSIONS: Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.

Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial.

BACKGROUND: The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma. METHODS: In an open-label, international, multicentre expansion cohort of a phase 1 trial, patients (aged ≥18 years) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were randomly assigned with a computer-generated allocation schedule (1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. Primary endpoint was overall response rate (ORR) assessed with the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was done on the full-analysis set (all treated patients with measurable disease at baseline). This study is registered with ClinicalTrials.gov, number NCT01295827. FINDINGS: 173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). Median follow-up duration was 8 months. ORR was 26% at both doses--21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%, 95% CI -14 to 13; p=0·96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient. INTERPRETATION: The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options. FUNDING: Merck Sharp and Dohme.

Repeatability of quantitative FDG-PET/CT and contrast-enhanced CT in recurrent ovarian carcinoma: test-retest measurements for tumor FDG uptake, diameter, and volume.

PURPOSE: Repeatability of baseline FDG-PET/CT measurements has not been tested in ovarian cancer. This dual-center, prospective study assessed variation in tumor 2[18F]fluoro-2-deoxy-D-glucose (FDG) uptake, tumor diameter, and tumor volume from sequential FDG-PET/CT and contrast-enhanced computed tomography (CECT) in patients with recurrent platinum-sensitive ovarian cancer. EXPERIMENTAL DESIGN: Patients underwent two pretreatment baseline FDG-PET/CT (n = 21) and CECT (n = 20) at two clinical sites with different PET/CT instruments. Patients were included if they had at least one target lesion in the abdomen with a standardized uptake value (SUV) maximum (SUVmax) of ≥ 2.5 and a long axis diameter of ≥ 15 mm. Two independent reading methods were used to evaluate repeatability of tumor diameter and SUV uptake: on site and at an imaging clinical research organization (CRO). Tumor volume reads were only performed by CRO. In each reading set, target lesions were independently measured on sequential imaging. RESULTS: Median time between FDG-PET/CT was two days (range 1-7). For site reads, concordance correlation coefficients (CCC) for SUVmean, SUVmax, and tumor diameter were 0.95, 0.94, and 0.99, respectively. Repeatability coefficients were 16.3%, 17.3%, and 8.8% for SUVmean, SUVmax, and tumor diameter, respectively. Similar results were observed for CRO reads. Tumor volume CCC was 0.99 with a repeatability coefficient of 28.1%. CONCLUSIONS: There was excellent test-retest repeatability for FDG-PET/CT quantitative measurements across two sites and two independent reading methods. Cutoff values for determining change in SUVmean, SUVmax, and tumor volume establish limits to determine metabolic and/or volumetric response to treatment in platinum-sensitive relapsed ovarian cancer.

(11)C-MK-8278 PET as a tool for pharmacodynamic brain occupancy of histamine 3 receptor inverse agonists.

UNLABELLED: The histamine 3 (H3) receptor is a presynaptic autoreceptor in the central nervous system that regulates the synthesis and release of histamine and modulates the release of other major neurotransmitters. H3 receptor inverse agonists (IAs) may be efficacious in the treatment of various central nervous system disorders, including excessive daytime sleepiness, attention deficit hyperactivity disorder, Alzheimer disease, ethanol addiction, and obesity. METHODS: Using PET and a novel high-affinity and selective radioligand (11)C-MK-8278, we studied the tracer biodistribution, quantification, and brain H3 receptor occupancy (RO) of MK-0249 and MK-3134, 2 potential IA drugs targeting cerebral H3 receptors, in 6 healthy male subjects (age, 19-40 y). The relationship among H3 IA dose, time on target, and peripheral pharmacokinetics was further investigated in 15 healthy male volunteers (age, 18-40 y) with up to 3 PET scans and 3 subjects per dose level. RESULTS: The mean effective dose for (11)C-MK-8278 was 5.4 ± 1.1 µSv/MBq. Human brain kinetics showed rapid high uptake and fast washout. Binding potential values can be assessed using the pons as a reference region, with a test-retest repeatability of 7%. Drug RO data showed low interindividual variability per dose (mean RO SD, 2.1%), and a targeted 90% RO can be reached for both IAs at clinically feasible doses. CONCLUSION: (11)C-MK-8278 is a useful novel PET radioligand for determination of human cerebral H3 receptor binding and allows highly reproducible in vivo brain occupancy of H3-targeting drugs, hereby enabling the evaluation of novel compounds in early development to select doses and schedules.

The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. METHODS: In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov, NCT00749502. FINDINGS: Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients [48%]), nausea (42 [42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8-46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% [95% CI 19-64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7-93]) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. INTERPRETATION: A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. FUNDING: Merck Sharp and Dohme.

Improving publication rates of biomarker results from cancer trials.

Mandatory nondiagnostic biopsies for biomarker research pose risk and inconvenience to patients with cancer that should be justified by the knowledge gained. This commentary reflects on the publication by Freeman and Kimmelman, which points to a potentially low publication rate of biomarker results from cancer clinical trials requiring nondiagnostic biopsies.

Repeatability of edited lactate and other metabolites in astrocytoma at 3T.

PURPOSE: To assess the repeatability of measurement of lactate and other metabolites in tumors using magnetic resonance spectroscopy (MRS). MATERIALS AND METHODS: MRS with spectral editing for lactate was performed on 10 patients with astrocytoma (two Grade III, eight Grade IV) using an 8-channel receive coil at 3T. Lactate, lipid, choline, creatine, and N-acetyl aspartate (NAA) signals were measured in regions of tumor and contralateral white matter. Metabolites were quantified relative to unsuppressed water using LCModel fitting software. RESULTS: The within-patient coefficients of variation were ≈16% (tumor lactate), 6%-8% (tumor choline and contralateral choline, creatine, and NAA), and 22% (tumor lipid). As expected due to their low concentration in normal tissue, lactate and lipid were not reliably detected in white matter but were found at high levels in most tumors. NAA and creatine were lower in tumors than in normal white matter, and choline varied between above- and below-normal values. No consistent short-term variation in metabolite levels was observed, despite differences in the time elapsed since administration of contrast agent. CONCLUSION: MRS appears repeatable enough to provide longitudinal measures of metabolite content in tumors and contralateral tissue in the brain in vivo.

AAML03P1, a pilot study of the safety of gemtuzumab ozogamicin in combination with chemotherapy for newly diagnosed childhood acute myeloid leukemia: a report from the Children's Oncology Group.

BACKGROUND: The development of antigen-targeted therapies may provide additional options to improve outcomes in children with acute myeloid leukemia (AML). The Children's Oncology Group AAML03P1 trial sought to determine the safety of adding 2 doses of gemtuzumab ozogamicin, a humanized anti-CD33 antibody-targeted agent, to intensive chemotherapy during remission induction and postremission intensification for children with de novo AML. METHODS: AAML03P1 enrolled 350 children with previously untreated AML. Patients with a matched family donor received 3 courses of chemotherapy followed by hematopoietic stem cell transplantation; those without a matched family donor received 5 courses of chemotherapy. Gemtuzumab ozogamicin 3 mg/m(2)/dose was administered on Day 6 of Course 1 and Day 7 of Course 4. RESULTS: Toxicities observed in all courses of therapy were typical of AML chemotherapy regimens, with infection being most common. Patients achieved a complete remission rate of 83% after 1 course and 87% after 2 courses. The mortality rate was 1.5% after the first gemtuzumab ozogamicin-containing induction course and 2.6% after 2 induction courses. The 3-year event-free survival and overall survival rates were 53 ± 6% and 66 ± 5%, respectively. CONCLUSIONS: This trial determined that it is safe and feasible to include gemtuzumab ozogamicin in combination with intensive chemotherapy. The survival rates compare favorably with the recently published results of clinical trials worldwide.

Effect of a novel histamine subtype-3 receptor inverse agonist and modafinil on EEG power spectra during sleep deprivation and recovery sleep in male volunteers.

RATIONALE: Histamine and dopamine contribute to the maintenance of wakefulness. OBJECTIVE: This study aims to conduct an exploratory analysis of the effects of 10 and 50 mg of MK-0249, a novel histamine subtype-3 receptor inverse agonist, and 200 mg of modafinil, a presumed dopaminergic compound, on EEG power spectra during sleep deprivation and subsequent recovery sleep. METHODS: A total of 25 healthy men were recruited to a double-blind, placebo-controlled cross-over design. EEG power spectra, an electrophysiological marker of changes in sleepiness and vigilance, were obtained at the beginning of wake maintenance tests at two-hourly intervals throughout a night and day of sleep deprivation, which is an established model of excessive sleepiness. RESULTS: After placebo, sleep deprivation was associated with enhancements in delta and theta and reductions in alpha and beta activity. Following dosing at 02:00 h, MK-0249 and modafinil reduced delta and theta activity and enhanced alpha and beta activity, compared to placebo. During recovery sleep initiated at 21:00 h, latency to sleep onset and number of awakenings were not different from placebo for any of the active treatments. Wake after sleep onset and stage 1% was increased and total sleep time, SWS% and REM% were reduced after both doses of MK-0249. Compared to placebo, MK-0249, the 50-mg dose in particular, reduced activity in some delta and theta/alpha frequencies and enhanced beta activity during NREM sleep and REM sleep. After modafinil, no changes were observed for power spectra during sleep. CONCLUSION: Both MK-0249 and modafinil exert effects on the EEG which are consistent with wake promotion.

Weighing the risks of G-CSF administration, leukopheresis, and standard marrow harvest: ethical and safety considerations for normal pediatric hematopoietic cell donors.

BACKGROUND: Granulocyte colony stimulating factor (G-CSF) is used for collection of hematopoietic cells in most adult and a smaller but significant percentage of pediatric normal donor harvests. Short and long-term risks of G-CSF administration and leukopheresis are not well understood in the pediatric population. PROCEDURE: Literature review including observations from the IBMTR, NMDP, EBMT, German Donor Registry, and the authors' work. RESULTS: G-CSF causes temporary discomfort in a minority of younger donors. Rare serious side effects of G-CSF have yet to be reported in children. To date, an increase in hematological malignancies after short-term G-CSF use has not been detected in adult donors and no cases have been reported in children. Reported complications of leukopheresis in children are rare and minor, but donors <20 kg may be exposed to allogeneic blood products. Pediatric aged donors vary widely in their ability to assent or consent to the risks of a donation procedure. There are key regulations and ethical imperitives, which must be addressed in deciding which donation procedures are appropriate for minors. CONCLUSIONS: While short term administration of G-CSF and leukopheresis appear to be safe and effective procedures when used to assist in collection of a hematopoietic cell graft from a normal pediatric donor, institutions adding or substituting one or both of these procedures for standard marrow donation must decide whether the donor should be considered a research subject, and if so, whether the new procedures are a minor increase over minimal risk. Because these procedures are being performed on and off study at many pediatric centers, a comprehensive study addressing donor safety could help clarify risks of rare adverse events.

Tissue typing for hematopoietic cell transplantation: newer techniques and newer antigens for which cross-matching is helpful.

Refinements in human leukocyte antigen (HLA) typing techniques for hematopoietic cell transplantation (HCT) have permitted a more precise assessment of donor-recipient histocompatibility, which has impacted transplantation outcomes. More recently, differences in transplant outcomes associated with killer immunoglobulin-like receptor compatibility have emphasized the potential importance of natural killer (NK) cell typing in HCT. This article reviews the current state of the art for HCT donor selection based on both HLA and NK cell typing.

Pulmonary hypertension complicating bone marrow transplantation for idiopathic myelofibrosis.

Idiopathic myelofibrosis is a rare hematologic disorder that is occasionally associated with pulmonary hypertension and has been cured with bone marrow transplantation (BMT). Most cases occur in older adults, but children with similar clinical and pathologic findings have been described. The authors describe a critically ill male infant with idiopathic myelofibrosis and subtle findings suggestive of pulmonary hypertension who was treated with BMT after failing to respond to chemotherapy. After BMT, the patient's clinical course improved in all respects, but he ultimately died of progressive pulmonary hypertension.