GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom/Impact Scale (GODDESS©): psychometric properties and clinically meaningful thresholds as assessed in the Phase 3 DeFi randomized controlled clinical trial.

PURPOSE: The GODDESS© tool was developed to assess Desmoid Tumor/Aggressive Fibromatosis (DT/AF) symptom severity and impact on patients' lives. This study evaluated GODDESS©'s cross-sectional and longitudinal measurement properties. METHODS: The Phase 3, randomized placebo-controlled, DeFi study (NCT03785964) of nirogacestat in DT/AF was used to assess GODDESS©'s reliability, construct validity, responsiveness, and estimate of meaningful change thresholds (MCTs). Other patient-reported outcome (PRO) measures included Patient Global Impression of Severity (PGIS) in DT/AF symptoms, EORTC QLQ-C30, Brief Pain Inventory Short Form, and PROMIS Physical Function short-form 10a v2.0 plus 3 items. RESULTS: DeFi participants (N = 142) had a median age of 34 years (range: 18-76) and were mostly female (64.8%), with extra-abdominal (76.8%) or intra-abdominal tumors (23.2%). The GODDESS© symptom/impact scales showed internal consistency at baseline, cycles 4 and 7 (Cronbach's α > 0.70) and test-retest reliability (intra-class correlation coefficient > 0.85). GODDESS© scales correlated moderately to highly with PRO measures capturing similar content and differentiated among PGIS and Eastern Cooperative Oncology Group groups. GODDESS© scales detected improvement over time. For the total symptom score, a 1.30-point decrease was estimated as the within-person MCT and a 1.00-point decrease as the between-group MCT. For the physical functioning impact score, estimated within- and between-group MCTs were 0.60-point and 0.50-point decreases, respectively. Few participants exhibited symptom worsening. CONCLUSION: GODDESS© was found to be reliable, valid, responsive, and interpretable as a clinical trial endpoint in the pooled sample of DT/AF patients. Estimated MCTs can be used to define responders and assess group-level differences in future, unblinded, efficacy analyses. TRIAL REGISTRATION NUMBER AND REGISTRATION DATE: NCT03785964; December 24, 2018.

Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.

BACKGROUND: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments. METHODS: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival. RESULTS: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%). CONCLUSIONS: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.).

The epidemiology of desmoid tumors in Denmark.

INTRODUCTION/AIM: The epidemiology, demographic, clinical, treatment, and healthcare resource utilization (HRU) characteristics of desmoid tumor (DT) patients treated at two sarcoma centers in Denmark is described. METHODS: Using Danish health registers, we studied DT patients treated at two sarcoma centers between 2009 and 2018. For each patient, ten persons from the general population were randomly matched on birth year, sex, and region of residence. RESULTS: Of the 179 DT patients identified, 76% were female and the median patient age was 38 years at diagnosis (interquartile range: 31-50). An average annual incidence of DTs over the study period was 3.2 per 1000,000 individuals with the observed annual incidence of DTs ranging from 2.2 (2011) to 4.3 (2017) per 1000,000 individuals. No notable linear time trend in incidence was observed. Anatomical DT sites included extra-abdominal (49%), abdominal wall (40%), and intra-abdominal or retroperitoneal areas (8%). In total, 56% of patients were initially treated surgically. However, while 75% of patients diagnosed with DT between 2009 and 2014 were initially treated surgically, this was true for only 32% of patients diagnosed with DT between 2015 and 2018. A total of 56% of DT patients used chemotherapeutic agents, tyrosine kinase inhibitors, NSAIDs, opioids, antidepressants, or steroids at some point during the three years before their DT diagnoses. In contrast, 70% of surgically treated and 63% of non-surgically treated patients used one of these drugs in the subsequent three years, including NSAIDs (45% surgical vs. 33% non-surgical), opioids (39% surgical vs. 27% non-surgical), and steroids (22% surgical vs. 18% non-surgical). The average number of inpatient and outpatient visits, days of hospitalization, and additional surgical procedures were higher among DT patients than the comparison cohort. CONCLUSION: DTs are rare but have a large impact on patients' health, HRU, and medication utilization.

Corrigendum: A Comprehensive Safety Trial of Chimeric Antibody 14.18 With GM-CSF, IL-2, and Isotretinoin in High-Risk Neuroblastoma Patients Following Myeloablative Therapy: Children's Oncology Group Study ANBL0931.

[This corrects the article DOI: 10.3389/fimmu.2018.01355.].

A Comprehensive Safety Trial of Chimeric Antibody 14.18 With GM-CSF, IL-2, and Isotretinoin in High-Risk Neuroblastoma Patients Following Myeloablative Therapy: Children's Oncology Group Study ANBL0931.

Purpose: A phase 3 randomized study (COG ANBL0032) demonstrated significantly improved outcome by adding immunotherapy with ch14.18 antibody to isotretinoin as post-consolidation therapy for high-risk neuroblastoma (NB). This study, ANBL0931, was designed to collect FDA-required safety/toxicity data to support FDA registration of ch14.18. Experimental design: Newly diagnosed high-risk NB patients who achieved at least a partial response to induction therapy and received myeloablative consolidation with stem cell rescue were enrolled to receive six courses of isotretinoin with five concomitant cycles of ch14.18 combined with GM-CSF or IL2. Ch14.18 infusion time was 10-20 h per dose. Blood was collected for cytokine analysis and its association with toxicities and outcome. Results: Of 105 patients enrolled, five patients developed protocol-defined unacceptable toxicities. The most common grade ≥ 3 non-hematologic toxicities of immunotherapy for cycles 1-5, respectively, were neuropathic pain (41, 28, 22, 31, 24%), hypotension (10, 17, 4, 14, 8%), allergic reactions (ARs) (3, 10, 5, 7, 2%), capillary leak syndrome (1, 4, 0, 2, 0%), and fever (21, 59, 6, 32, 5%). The 3-year event-free survival and overall survival were 67.6 ± 4.8% and 79.1 ± 4.2%, respectively. AR during course 1 was associated with elevated serum levels of IL-1Ra and IFNγ, while severe hypotension during this course was associated with low IL5 and nitrate. Higher pretreatment CXCL9 level was associated with poorer event-free survival (EFS). Conclusion: This study has confirmed the significant, but manageable treatment-related toxicities of this immunotherapy and identified possible cytokine biomarkers associated with select toxicities and outcome. EFS and OS appear similar to that previously reported on ANBL0032.

Comparative pharmacokinetics, safety, and tolerability of two sources of ch14.18 in pediatric patients with high-risk neuroblastoma following myeloablative therapy.

PURPOSE: Dinutuximab (Unituxin™; ch14.18), a monoclonal antibody against disialoganglioside, improved survival as part of post-consolidation therapy for high-risk neuroblastoma. United Therapeutics Corporation (UTC) assumed ch14.18 production from the National Cancer Institute (NCI); this study evaluates pharmacokinetic comparability, safety, and tolerability of UTC and NCI products. METHODS: In this randomized, two-sequence crossover study, 28 patients aged ≤8 years with high-risk neuroblastoma received equivalent ch14.18-UTC or ch14.18-NCI doses. Despite comparable protein content, nominal doses differed: 17.5 mg/m(2)/day (ch14.18-UTC) and 25 mg/m(2)/day (ch14.18-NCI). Patients received one product during therapy cycles 1 and 2, the other during cycles 3-5. Ch14.18 pharmacokinetic profile characterization used population modeling (NONMEM(®) version 7.2). A two-compartment model with first-order distribution and elimination processes described pharmacokinetic data. Estimated product parameters were normalized to UTC nominal dose. For pharmacokinetic comparability, the final model was used to estimate exposure ratios (UTC/NCI) and associated 90 % confidence intervals (CIs) for area under the curve from time zero to infinity (AUCinf) and maximum concentration (C max). All comparisons were based on a standardized single-dose regimen (17.5 mg/m(2) over 10 h). RESULTS: Final-model pharmacokinetic parameters were similar to previously published ch14.18-NCI parameters and comparable for UTC and NCI products. Products' systemic exposures were comparable, with 90 % CIs around ratios for AUCinf (0.96; 90 % CI 0.88-1.04) and C max (1.04; 90 % CI 0.98-1.11) within standard bioequivalence bounds (90 % CI 0.80-1.25). Products' adverse events were similar and consistent with those previously reported. CONCLUSIONS: Equivalent actual ch14.18-UTC and ch14.18-NCI doses produced comparable exposures, with no notable safety or tolerability differences.

Pharmacokinetics of the chimeric anti-GD2 antibody, ch14.18, in children with high-risk neuroblastoma.

PURPOSE: Ch14.18 improves survival in children with high-risk neuroblastoma but is associated with substantial toxicity. Ch14.18 pharmacokinetics were previously reported to be highly variable and characterized by a higher clearance in children than in adults, and a large volume of distribution. Identifying factors responsible for its variability could lead to alternative dosing strategies that reduce toxicity. METHODS: Plasma sampling was performed prior to, during, and for 25 days after four daily 10-h infusions of 25 mg/m(2) of ch14.18 administered with sargramostim. Ch14.18 concentrations were quantified with an electrochemiluminescence immunoassay, and pharmacokinetic parameters were derived using non-compartmental methods and from fitting a two-compartment model. Human anti-chimeric antibody (HACA) was measured before each course. RESULTS: Fourteen subjects (median age, 4.3 years) were enrolled; seven had sampling on two courses to assess intra-subject variability. Mean peak ch14.18 plasma concentration was 11 µg/mL, and disappearance was biexponential with half-life of 7 days. Mean trough (day 28) concentration was 0.2 µg/mL. Mean AUC0-∞ was 1,380 µg h/mL and was less variable than previously reported (CV 29 %). Intra-patient variability was also minimal, but one subject who developed HACA had a 41 % decrease in AUC 0-tlast from courses 1 to 3. Clearance (2 L/day m(2)) was fourfold higher in children than in adults and appeared to be age dependent. Steady state volume of distribution was 0.4 L/kg. Two-compartment model parameters were used to simulate alternative dosing schedules. CONCLUSIONS: Ch14.18 disposition in children is less variable than previously reported. Clearance is age dependent and more rapid in younger children.

Oregovomab maintenance monoimmunotherapy does not improve outcomes in advanced ovarian cancer.

PURPOSE: This phase III study tested the hypothesis that the CA-125-specific murine monoclonal antibody, oregovomab, administered as a monoimmunotherapy after front-line therapy in a selected ovarian cancer population would prolong time to relapse (TTR) and, ultimately, survival. PATIENTS AND METHODS: Patients with stage III to IV ovarian cancer with preoperatively elevated CA-125 and objectively defined characteristics were randomly assigned 4 to 12 weeks after front-line carboplatin and paclitaxel chemotherapy to maintenance monoimmunotherapy in a fully blinded protocol. Two mg of oregovomab or placebo was infused over 20 minutes at weeks 0, 4, and 8 and then 12 weeks until recurrence or up to year 5. Patients were evaluated with serial imaging and clinical evaluation for evidence of recurrence at quarterly visits. TTR was the primary end point. RESULTS: Three hundred seventy-three patients were accrued at more than 60 centers; 251 patients were assigned to oregovomab and 120 patients were assigned to placebo. The treatment arms were well balanced. There were no differences in the clinical outcomes between treatment groups. Median TTR measured from randomization after completion of chemotherapy for the integrated study was 10.3 months (95% CI, 9.7 to 13.0 months) for oregovomab and 12.9 months (95% CI, 10.1 to 17.4 months) for placebo (P = .29, log-rank test). The treatment was well tolerated. Grade 3 to 4 toxicity was reported in 24.6% of patients in the placebo group and 20.1% of patients in the oregovomab group, respectively. CONCLUSION: Although oregovomab has demonstrated bioactivity, the strategy of monoimmunotherapy is not effective as maintenance therapy after front-line treatment of a favorable subset of patients with advanced ovarian cancer. Future studies of this or other tumor-antigen specific immunization strategies should seek ways to further augment induced immunity.

Role of monoclonal antibodies in tumor-specific immunity.

Monoclonal antibodies, considered to be 'magic bullets' 20 years ago, may finally be realizing their full potential, particularly in the area of oncology, where > 10 monoclonal antibodies are approved for treatment. Monoclonal antibodies are being used to modulate tumor-specific immunity through several approaches: antibodies that direct cytotoxicity against the tumor through cellular or complement-mediated pathways; antibodies that directly modulate immune regulation; antibodies that alter tolerance to tumor antigens; and antibodies that act as antigen mimetics through the anti-idiotype network. Therapeutic progress in these areas is reviewed as well as the potential to combine these approaches with standard therapies.

ICOS-mediated signaling regulates cytokine production by human T cells and provides a unique signal to selectively control the clonal expansion of Th2 helper cells.

The CD28 homologue inducible costimulator (ICOS) has been demonstrated to regulate a number of T cell-dependent immune responses in vivo. However, the expression and functional importance of ICOS during APC-Th cell interaction in the human is not fully understood. Here, we demonstrate that ICOS-mediated signaling plays an important role in the production of selective cytokines during both primary and subsequent Th cell responses upon allospecific or superantigen activation. In contrast, ICOS does not play a role in the differentiation of naive cells into Th1 or Th2 effector cells, nor does it determine the type of effector function of memory cells upon subsequent allogeneic challenge. In addition, our data demonstrate that ICOS provides a novel and unique role in regulating DC-mediated Th2, but not Th1 cell clonal expansion. These data suggest that ICOS-mediated signaling plays a discrete role in the regulation of human T helper cell responses.