10003 Background: A subset of children with INRGSS Stage MS neuroblastoma (NBL) may be observed without treatment, while others have rapidly evolving symptoms that can be life-threatening. ANBL1232 ...adapted a previously developed semi-quantitative objective scoring system (OSS) to assign a numeric value to symptoms and laboratory abnormalities. The goal was to standardize monitoring, therapy initiation, and treatment duration in this cohort. Methods: Patients with newly diagnosed Stage MS NBL were eligible for this prospective trial. An OSS score (OSSS) was assigned at enrollment; the total number was based on scoring in 5 systems: gastrointestinal (GI), respiratory, circulatory, renal, and hepatic. Within the 5 systems, individual clinical and laboratory parameters were scored as not present = 0, mild/moderate = 1 Grade 2 CTCAEv4.0 adverse event (AE) or severe = 2 (Grade ≥3 AE). The OSSS was the sum of highest score within each organ system (maximum score: 2 per system, 10 total). Asymptomatic MS patients with an OSSS < 2 who were either < 3 months (mo) of age without hepatomegaly or 3-18 mo of age with favorable biology tumors were eligible for observation without initial treatment. Observed patients underwent monthly physical examinations and laboratory assessments for the first 6 mo following diagnosis. Tumor imaging was performed every 3 mo for 1 year, then every 6-12 mo through 36 mo. An OSSS ≥2 or a protocol-defined increase in primary tumor size prompted initiation of therapy. Results: From July 2014 to February 2021, 89 eligible and evaluable patients with newly diagnosed stage MS NBL enrolled. Among these, 18 (20.2%; 5 male and 13 female) were eligible for observation. Observed patients were older at diagnosis (median age: 2.87 vs. 1.81 mo, p = 0.23) and more likely to have primary tumors without image-defined risk factors (62.5% vs. 30.0%, p = 0.0166) than those assigned to therapy up front. Nearly all observed patients (17/18) had abdominal/adrenal primaries. The initial OSSS was 0 in all observed patients. Median reported observation time was 36 mo (range: 1-36 mo); 13 patients completed all required monthly assessments for the first 6 mo. No patients in the observation cohort required initiation of therapy for an increase in OSSS. One patient with OSSS = 1 at mo 3 had complete GI symptom resolution by mo 5. Conclusions: An OSSS of 0 at diagnosis can aid in identifying a favorable group of patients with stage MS NBL who can be safely observed. No patients in the observation cohort developed evidence of organ dysfunction or OSSS > 1 despite frequent physical examination and comprehensive laboratory testing, suggesting that follow up may be safely liberalized in this population over time. Clinical and laboratory criteria implemented at diagnosis could be used to identify patients requiring prompt treatment. Clinical trial information: NCT02176967 .
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Background: PSMA expression is increased in response to anti-androgen therapies and is a promising therapeutic target for the treatment of prostate cancer (PCa). JNJ-081 is a ...bispecific antibody with one arm binding PSMA on cancer cells and the other binding CD3 on T-cells to promote anti-tumor activity. Methods: This Phase 1 Dose Escalation Study evaluated JNJ-081 in mCRPC participants (pts) who progressed after novel androgen targeting therapy (eg, abiraterone, enzalutamide or apalutamide). Prior chemotherapy was permitted. JNJ-081 was administered initially by intravenous (IV) then by subcutaneous (SC) route. Dose escalation followed a continuous reassessment method based on a Bayesian regression model. The primary endpoint to determine the recommended phase 2 dose (RP2D) was based on safety. Pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary anti-tumor activity were also evaluated. Cytokine release syndrome (CRS) was graded by CTCAE V5. Results: As of 10 May 2021, 39 pts were dosed in 10 cohorts ranging from 0.1 µg/kg to 3 µg/kg IV and from 3 µg/kg to 60 µg/kg SC. Premedications included high dose corticosteroids. Step-up priming was implemented at higher SC doses. Most common treatment-emergent AEs were CRS (65%), fatigue (49%) and nausea (43%). 2 pts developed DLTs of Grade (G) 3 or G4 transaminases increased, 1 each at 30 µg/kg SC and priming with 10 µg/kg SC then 55 µg/kg SC, respectively. Both DLTs were in conjunction with or followed an episode of G2 CRS. SC route as well as step-up priming helped mitigate CRS and infusion-related reaction (IRR) during escalation to higher doses: at 3 µg/kg IV, 4 of 5 pts had G2 CRS or IRR; at 30 µg/kg SC, 3 of 4 pts had G2 CRS; priming with 10 µg/kg then 55 µg/kg SC, 4 of 5 pts had G2 CRS. Injection site reactions (G1 or G2) occurred in 24 of 26 pts treated via SC JNJ-081. No treatment related death was reported. Transient PSA decreases were observed at treatment doses greater than 30 µg/kg SC. Two subjects treated with 55 µg/kg had PSA decreases > 50%. No radiographic responses were observed. PK of JNJ-081 was linear over the dose range of 3-60 µg/kg following SC administration. SC bioavailability was approximately 25%. Anti-drug antibodies (ADA) were detected in 2 of 12 subjects treated by IV administration and 14 of 23 pts treated by SC administration. ADA resulted in loss of exposure in some SC pts. Intrapatient dose escalation in 3 pts did not overcome the reduced exposure after ADA seropositivity. Conclusions: JNJ-081 demonstrated transient decreases in PSA in mCRPC patients. Grade 2 CRS was observed at higher doses and was partially mitigated by SC and step-up dosing. ADA resulting in decreased exposure occurred in the majority of pts treated SC. PSMA remains a potential therapeutic target for T-cell redirection for the treatment of PCa. Clinical trial information: NCT03926013.
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Background: FAP is the most common hereditary adenomatous polyposis syndrome and, if left untreated, will lead to colorectal cancer development in nearly all patients. Chronic inflammation, ...driven in part by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, may promote polyp formation. Enteric-selective inhibition of the JAK/STAT pathway may provide a treatment for FAP. Lorpucitinib is an oral, small molecule, potent pan-JAK inhibitor with favorable enteric-selective properties. Here, we report the efficacy, safety, and pharmacokinetic (PK) results from a phase 1b study of lorpucitinib in patients with FAP (NCT05014360). Methods: Patients aged ≥18 years with ≥6 polyps ≥2 mm in diameter in the rectum or colon with FAP ( APC germline mutation or obligate carrier) received lorpucitinib 75 mg twice daily for 24 weeks. The primary objective was to evaluate the effect of lorpucitinib on colorectal polyp burden at Week 24, assessed by endoscopy at baseline and Week 24. Secondary objectives were safety, PK, and biomarker assessments of lorpucitinib activity. Results: Overall, 42 (23 pre-colectomy; 19 post-colectomy) patients with FAP were enrolled, with a median age of 33 (range, 19-61) years. No clear effect on polyp burden was observed at Week 24. Gut mucosal and polyp concentrations of lorpucitinib were much higher than plasma concentrations, indicating an enteric-selective distribution. Mean sigmoid colon, rectum, and polyp concentrations of lorpucitinib at Week 8 were 112-, 473-, and 108-fold higher, respectively, than the observed maximum plasma concentration at Week 8 (1 hour). At Week 8, lorpucitinib achieved JAK tyrosine kinase inhibition in mucosal biopsies as evidenced by a median 37% reduction in normalized pSTAT-3 levels. Lorpucitinib reduced serum-based inflammatory biomarkers such as C-reactive protein and serum amyloid A by Week 16 of therapy. Some patients reported an improvement of clinical symptoms such as less frequent bowel movements and less blood in the stool. The most common adverse events (AEs) were abdominal pain (16%), bilirubin increased (13%), headache (13%), lipase increased (13%), and diarrhea (13%). There were no treatment-related serious AEs, grade 3 treatment-emergent AEs, serious infections, or venous thromboembolisms. Conclusions: These results show that lorpucitinib had no clear effect on polyp burden. The study found that lorpucitinib is safe and exhibits an enteric-selective distribution in FAP patients. Inhibition of JAK tyrosine kinase signaling was associated with reduced STAT-3 phosphorylation in mucosal biopsies from FAP patients. While reductions observed in polyp burden were not clinically significant, lorpucitinib treatment lowered levels of several serum inflammatory biomarkers. Treatment with lorpucitinib was safe and well tolerated, and may improve clinical symptoms associated with FAP. Clinical trial information: NCT05014360 .
Stromal contamination is one of the major confounding factors in the analysis of solid tumor samples by single nucleotide polymorphism (SNP) arrays. As we propose to use genome-wide SNP microarray ...analysis as a diagnostic platform for neuroblastoma, the sensitivity, specificity, and accuracy of these studies must be optimized. To investigate the effects of stromal contamination, we derived early-passage cell lines from nine primary tumors and compared their genomic signature with that of the primary tumors using 100K SNP arrays. The average concordance between tumor and cell line for raw loss of heterozygosity (LOH) calls was 96% (range, 91-99%) and for raw copy number alterations, 71% (range, 43-87%). In general, there were a larger number of LOH events identified in the cell lines compared with the matched tumor samples (mean increase, 3.2% +/- 1.9%). We have developed an algorithm that shows that the presence of stroma contributes to under-reporting of LOH and copy number loss. Notable findings in this sample set were uniparental disomy of chromosome arms 11p, 1q, 14q, and 15q and a novel area of amplification on chromosome band 11p15. Our analysis shows that LOH was identified significantly more often in derived cell lines compared with the original tumor samples. Although these may in part be due to clonal selection during adaptation to tissue culture, our study indicates that stromal contamination may be a major contributing factor in underestimation of LOH and copy number loss events.
Copy number alterations (CNAs) are a hallmark of pediatric cancer genomes. An increasing number of research groups use multiple platforms and software packages to detect and analyze CNAs. However, ...different platforms have experimental and analysis-specific biases that may yield different results. We sought to estimate the concordance of CNAs in children with de novo acute myeloid leukemia between two experimental platforms: Affymetrix SNP 6.0 array and Illumina OmniQuad 2.5 BeadChip. Forty-five paired tumor-remission samples were genotyped on both platforms, and CNAs were estimated from total signal intensity and allelic contrast values using the allele-specific copy number analysis of tumors (ASCAT) algorithm. The two platforms were comparable in detection of CNAs, each missing only two segments from a total of 42 CNAs (4.6%). Overall, there was an interplatform agreement of 96% for allele-specific tumor profiles. However, poor quality samples with low signal/noise ratios showed a high rate of false-positive segments independent of the genotyping platform. These results demonstrate that a common analytic pipeline can be utilized for SNP array data from these two platforms. The customized programming template for the preprocessing, data integration, and analysis is publicly available at https://github.com/AplenCHOP/affyLumCNA.
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Background: JNJ-63723283 (JNJ-283), an anti-programmed cell death protein-1 antibody, enhances T cell-mediated cytokine induction and reduces tumor volume in preclinical models. A ...phase 1/2 study is ongoing to evaluate the safety and efficacy of JNJ-283 in patients (pts) with advanced cancers. Methods: Eligible pts have advanced or refractory solid tumor malignancies. Phase 1 dose escalation starting from 80 mg Q2W was supported by a modified continual reassessment method to identify the recommended phase 2 dose(s) (RP2D). Safety and efficacy of the RP2D(s) will be evaluated in phase 2. Pharmacokinetics (PK), receptor occupancy (RO) and other pharmacodynamic parameters were assessed. Results: As of data cut-off, 32 pts were treated with JNJ-283 80 mg (n = 4), 240 mg (n = 16) or 460 mg (n = 4) Q2W, or 480 mg (n = 8) Q4W; 16 pts remain on study drug. Median duration of treatment was 58 days (range 16 – 240). Median age was 56 years (range 27 - 80) and median prior lines of therapy was 3 (range 1 - 12). One dose-limiting toxicity of grade 3 pleural effusion was reported at 240 mg Q2W. An RP2D of 240 mg Q2W is being evaluated in phase 2. Most common adverse events (AEs) were anemia (28.1%), hypertension (28.1%), diarrhea (21.9%) and hyponatremia (21.9%). Observed serious AEs were pleural effusion, pneumonia and chest pain (6.3% each). Infusion-related AEs of nausea and rash occurred in 6.3% of pts each. Immune-related AEs (irAEs) were reported in 21.8% of pts and were mostly grade 1-2; grade 3 irAEs included pleural effusion, pneumonitis, AST increased and ALT increased. One pt discontinued treatment due to a treatment-related AE. Three pts achieved a partial response at 240 mg Q2W; 18 pts achieved stable disease or better. Preliminary serum JNJ-283 concentrations demonstrated linear PK with dose-proportional increases and interpatient variability generally consistent with monoclonal antibody therapeutics. Preliminary circulating T cell RO demonstrated dose-independent saturation. Conclusions: JNJ-283 displayed a well-tolerated safety profile with preliminary antitumor activity in pts with advanced cancers. The trial is ongoing to further characterize the safety, PK and clinical activity of JNJ-283. Clinical trial information: 2016-002017-22.
Abstract
Background: Familial adenomatous polyposis (FAP) is the most common hereditary polyposis syndrome. It is an autosomal dominant inherited disorder characterized by the early onset of hundreds ...to thousands of adenomatous polyps throughout the colon. If left untreated, nearly all individuals with this syndrome develop colorectal cancer (CRC) by the third decade of life. Prophylactic colectomy is the standard of care, but individuals remain at risk for malignant transformation of duodenal polyps, rectal polyps for those who have undergone rectal-sparing surgeries, and ileal pouch polyps for those with ileal pouch-anal anastomoses. Multiple studies with both nonselective and selective cyclooxygenase inhibitors (such as sulindac or celecoxib) have shown that anti-inflammatory agents may prevent the formation and inhibit the growth of colorectal adenomatous polyps. However, toxicities associated with these agents and their limited efficacy have prevented their further development. Therefore, there is a high unmet need for novel treatment options to reduce polyp burden, delay or eliminate the need for colectomy and recurrent rectal surgery, and intercept the development of adenocarcinomas in individuals with FAP. Polyps from individuals with FAP display inflammatory features associated with the activation of the IL-23/IL-17/JAK/STAT3 pathway. This inflammation is thought to contribute to further carcinogenesis, culminating in tumor development. Specifically, IL-23 is linked to tumor growth and progression in CRC, and adenomas with high-grade dysplasia showed elevated levels of IL-17A and pSTAT3. Guselkumab, a human monoclonal antibody directed against the p19 subunit of IL-23, specifically targets IL-23 and inhibits its interaction with the IL-23 receptor. Pre-clinical models suggest that inhibition of IL-23 signaling will result in less inflammation and reduce tumor development. Methods: This randomized, blind, placebo-controlled study will evaluate the safety and efficacy of guselkumab in adults with FAP (genetic or clinical diagnosis) who have already undergone colectomy. Polyps with a sum of diameters ≥10 mm in the rectum or pouch are required. Subjects will be randomized equally to one of three study arms: 100 mg, 300 mg, or placebo given subcutaneously every 4 weeks for 6 doses. The primary efficacy endpoint is percentage change from baseline in rectal/pouch polyp burden after 24 weeks. Secondary efficacy endpoints include duodenal polyp burden change and changes in InSiGHT and Spigelman staging. Exploratory translational research objectives will explore changes in RNA expression profiles, epigenomic profiles, cytokine levels, and the microbiome. Exclusion criteria include prior IL-23 targeted therapies and any polyps >1 cm that cannot be removed. While participating, subjects are required to stop any other FAP-directed drug therapy except for aspirin. As of January 2019, 18% of the planned 72 subjects have been enrolled. ClinicalTrials.gov Identifier: NCT03649971.
Citation Format: Eduardo Vilar-Sanchez, Carol Burke, Marcia R. Cruz Correa, Evelien Dekker, William M. Grady, Philippe Grandval, Bryson W. Katona, Xavier Llor, Douglas L. Riegert-Johnson, Jean-Christophe Saurin, Peter Stanich, Daniel A. Sussman, David Weinberg, Edward F. Attiyeh, Devanand Joseph, Kelly Raybold, Gary V. Borzillo, Thomas J. Prior, Michael Smith, Hong Xie, Kurtis E. Bachman, Jeffrey R. Infante, Niloy Jewel Samadder. A phase 1b, multicenter, randomized, blinded, placebo-controlled study to evaluate the efficacy of guselkumab in subjects with familial adenomatous polyposis abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT236.
As a transcription factor, localization to the nucleus and the recruitment of co-factors to regulate gene transcription is essential. Nuclear localization and nucleosome remodeling and histone ...deacetylase (NuRD) complex binding are required for the zinc finger transcription factor CASZ1 to function as neuroblastoma (NB) tumor suppressor. However, the critical amino acids (AAs) that are required for CASZ1 interaction with NuRD complex and the regulation of CASZ1 subcellular localization have not been characterized. Through alanine scanning, immunofluorescence cell staining and co-immunoprecipitation we define a critical region at the CASZ1 N-terminus (AA23-40) that mediates the CASZ1b nuclear localization and NuRD interaction. Furthermore, we identify a nuclear export signal (NES) at the N-terminus (AA176-192) that contributes to CASZ1 nuclear-cytoplasmic shuttling in a chromosomal maintenance 1 (CRM1)-dependent manner. An analysis of CASZ1 protein expression in a primary neuroblastoma tissue microarray shows that high nuclear CASZ1 staining is detected in tumors from NB patients with good prognoses. In contrast, cytoplasmic-restricted CASZ1 staining or low nuclear CASZ1 staining is found in tumors from patients with poor prognoses. These findings provide insight into mechanisms by which CASZ1 regulates transcription, and suggests that regulation of CASZ1 subcellular localization may impact its function in normal development and pathologic conditions such as neuroblastoma tumorigenesis.
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