Assessment Of Clinical Activity Research Articles

Ultrasonographic Evaluation of the Ankle Joint in Relation to Rheumatoid Factor Status and Disease Activity in Patients with Rheumatoid Arthritis

Abstract Background: Rheumatoid arthritis (RA) is a form of inflammatory disease whose clinical pattern is largely dependent on the presence of both anti-citrullinated protein antibodies and rheumatoid factor (RF). Although this is still debatable, seronegative RA seems to be a somewhat less serious condition. The present study aimed to evaluate ankle joint ultrasound in relation to RF status and disease activity in RA patients. Methods: A cross-sectional study involving RA patients from a single center was conducted. Laboratory test evaluations and clinical activity assessments were carried out. The ankle joint was examined using musculoskeletal ultrasound (US). Results: The study included 100 patients with established RA in total. Eighty-two patients tested positive for RF with a mean age of 42.3, whereas only 18 tested negative with a mean age of 39.6. Patients who tested positive for RF had a longer duration of illness (9.39 ± 5.39 vs. 4.56 ± 3.24). There were no differences in clinical activity scores between the seropositive and seronegative groups. The pathological US findings of any ankle joint showed no differences between the seropositive and seronegative groups. Patients with US findings of tibialis posterior tenosynovitis in the left ankle and synovitis and erosion in the right ankle, particularly in the tibiotalar and talonavicular joints, had significantly high Disease Activity Score 28-Erythrocyte sedimentation rate-scores. The increased disease activity was accompanied by significant erosions on both ankles. Conclusion: In terms of disease activity, there is no clinically significant difference between seropositive and seronegative RA patients. Sonographic ankle joint abnormalities do not appear to be associated with the patients’ RF status. High RA disease activity, on the other hand, is associated with synovitis and erosions, particularly in the talonavicular and tibiotalar joints, as well as tibialis posterior tenosynovitis.

Abstract B041: A phase 1 study of DS-8201a in combination with olaparib in HER2-expressing malignancies (CTEP #10355): Results of module 1 dose escalation

Abstract Background: DS-8201a is a HER2-targeting antibody drug conjugate with a topoisomerase 1 (top1) inhibitor payload. Preclinical evidence suggests that inhibiting PARP can potentiate top1 inhibitor-induced DNA damage and cytotoxicity. However, the clinical activity of combined top1-inhibiting chemotherapy and PARP inhibition has been limited by toxicity. We hypothesized that targeted delivery of a top1 inhibitor via DS-8201a may reduce systemic toxicity while maintaining synergistic cytotoxic activity in combination with olaparib. This combination is being investigated in the ongoing phase 1 trial CTEP #10355 (NCT04585958) in patients (pts) with advanced solid tumors expressing HER2. We present the safety analysis of pts enrolled to Module 1 (Mod 1) of dose escalation (continuous olaparib). Preliminary efficacy results are explored. Methods: Accrual was limited to pts ≥18 years old with advanced or recurrent solid tumors expressing HER2, defined as HER2 IHC ≥1+ (local testing allowed) or amplification of ERBB2 by NGS or ISH. In Mod 1, pts received DS-8201a IV once every 3 weeks and olaparib twice daily (BID) continuously in a 3+3 dose escalation design. Dose Level 1 (DL1) of Mod 1 evaluated DS-8201a dosed at 4.4mg/kg with olaparib 100mg BID Days 1-21. Dose Level 2 (DL2) of Mod 1 evaluated DS-8201a dosed at 5.4mg/kg with olaparib 100mg BID Days 1-21. The primary objective was to evaluate the safety and tolerability of combined DS-8201a + olaparib as graded by CTCAE v5. Secondary objectives include assessment of clinical activity as measured by objective response rate (ORR), clinical benefit rate (CBR; partial response [PR] + complete response [CR] + stable disease [SD] ≥6 months [mo]), median progression-free survival (PFS), and duration of response (DOR). Results: As of 30-Nov-2022, 10 pts were treated in Mod 1, with median age of 62.5 years. 10% were Asian, 10% were African American, and 80% were white. 40% had endometrial cancer and 60% had ovarian cancer. 6 of 7 pts treated on DL1 were DLT-evaluable, of which 1 patient experienced a DLT of Grade (G) 4 neutropenia. All 3 pts in DL2 were DLT-evaluable, and each experienced a DLT (2 pts with G4 febrile neutropenia, 1 pt with G4 neutropenia). Most common TRAEs in Mod 1 included: ANC decrease (60% G4, 20% G3, 20% G1/2), platelet count decrease (20% G4, 20% G3, 40% G1/2), and anemia (70% G3, 20% G1/2). All Mod 1 pts required dose holds, dose reductions, and/or discontinuation of olaparib. Of the 10 pts in Mod 1, 40% achieved a RECIST response (1 CR, 3 PR). 40% had SD lasting ≥6 mo, for a CBR of 80%. Median PFS is estimated at 7.4 mo (95% CI 4.7mo-not reached), with 7 patients alive and progression-free at 6 mo. Conclusion: Continuous dosing of olaparib in combination with DS-8201a yielded an unacceptable safety profile and dose escalation in Mod 1 was not continued. An alternative dosing schedule was initiated in Module 2 (Mod 2) evaluating DS-8201a IV every 3 weeks and olaparib BID Days 8-14; accrual to Mod 2 is ongoing. There is preliminary evidence of clinical activity of this combination. Citation Format: Elizabeth K. Lee, Andrea E. Wahner Hendrickson, Gerardo Colon-Otero, Cheryl A. Pickett, Niya Xiong, Su-Chun Cheng, Madeline Polak, Hannah Sawyer, Martin Hayes, Ursula A. Matulonis, Geoffrey I. Shapiro, Panagiotis A. Konstantinopoulos. A phase 1 study of DS-8201a in combination with olaparib in HER2-expressing malignancies (CTEP #10355): Results of module 1 dose escalation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B041.

Clinical Significance of Serum Cholinesterase in the Diagnosis and Assessment of Clinical Activity in Patients with IBD

Abstract Background Inflammatory bowel diseases (IBD), including Crohn’s disease and Ulcerative colitis, witnessed dramatic rise in incidence in the past few decades. Fecal calprotectin has been widely established as laboratory marker in assessment, diagnosis and severity of IBD. It showed low specificity and high number of false positive results. Cholinesterase (ChE) enzymatic glycoprotein used in hydrolosis of acetylcholine, showed significant correlation with IBD activity, it showed also potential role in diagnosis and assessing clinical severity in IBD patients. We will evaluate the role of serum cholinesterase in diagnosis and assessment of severity in IBD patients. Aim of the Work The aim of this study is to evaluate the role of serum cholinesterase (ChE) in diagnosis and assessment of activity in IBD patients Patients and Methods A Case control study in outpatients and inpatients in departments of Internal Medicine, Ain Shams University Hospital for Six months since beginning of data collection (till fulfilling the sample size) on 70 subjects divided into 3 groups: Group A: 25 patients with Crohn’s disease evidenced by colonoscopy and tissue biopsy, group B: 25 patients with Ulcerative Colitis disease evidenced by colonoscopy and tissue biopsy, group C: 20 age-matched, sex-matched healthy controls Results Our results confirmed that, compared with healthy controls, serum ChE levels were decreased in patients with IBD, and the decline in serum ChE levels was more pronounced as clinical activity in IBD increased. We also found that the serum ChE levels of patients with CD and those with UC were significantly different. It needs to be further clarified the relationship between serum ChE and endoscopic activity in the future. Conclusion Serum ChE levels can be used as a simple, economical method to help diagnose and distinguish the different stages of IBD. With the increasing biomedical research on the cholinergic anti-inflammatory pathway and ChE, serum ChE is expected to become a new immunotherapy target for IBD.

C-reactive protein/albumin ratio and IL-6 are associated with disease activity in patients with ulcerative colitis.

Cytokines are key mediators of the inflammation in ulcerative colitis (UC); there are inconsistent data on cytokines profile in patients with UC. C-reactive protein/albumin ratio (CRP/ALB) has also been found as an inflammatory indicator. However, the role of CRP/ALB in UC remains unclear. We aimed to evaluate the CRP/ALB ratio and cytokines profile in patients with UC. We further explore the association between CRP/ALB and inflammatory markers, such as erythrocyte sedimentation rate (ESR), fecal calprotectin (FC) and cytokines. One hundred thirty UC patients and 65 controls were included in the study. Clinical and laboratory findings were retrospectively reviewed; differences in variables between two groups were examined using the Mann-Whitney U-test. The association between CRP/ALB, cytokines, and clinical parameters was determined by Spearman's correlation test. CRP/ALB levels were significantly elevated in active UC patients. The optimal cutoff level of the CRP/ALB was 0.083. The patients with active UC had a median interleukin-6 (IL-6) level of 7.715 pg/ml (interquartile ranges, IQR 3.475-14.63), which was significantly higher than those in remission (2.95 pg/ml, IQR 2.17-5.44) (p< 0.001). Positive correlations between CRP/ALB and inflammatory markers were also observed. Our results suggest that CRP/ALB and IL-6 could be potential biomarkers for assessment of clinical activity in Chinese patients with UC.

Model-based meta-analysis of non-small cell lung cancer with standard of care PD-1 inhibitors and chemotherapy for early development decision making.

Single-arm cohorts/trials are often used in early phase oncology programs to support preliminary clinical activity assessments for investigational products, administered alone or in combination with standard of care (SOC) agents. Benchmarking clinical activity of those combinations against other treatments, including SOC, requires indirect comparisons against external trials, which presents challenges including cross-study differences in trial populations/other factors. To facilitate such nonrandomized comparisons, we developed a comprehensive model-based meta-analysis (MBMA) framework to quantitatively adjust for factors related to efficacy in metastatic non-small cell lung cancer (mNSCLC). Data were derived from 15 published studies assessing key programmed cell death protein-1 (PD-1) inhibitors pembrolizumab (n=8) and nivolumab (n=7), representing current SOC in mNSCLC. In the first stage, a mixed-effects logistic regression model for overall response rate (ORR) was developed accounting for effects of various population covariates on ORR. The ORR model results indicated an odds ratio (OR) of 1.02 for squamous versus non-squamous histology and OR of 1.20 for PD-ligand 1 tumor proportion score (TPS) per every 10% increase of TPS level. Next, a nonparametric mixed-effects model for overall survival (OS) was developed with ORR/other clinical covariates as input. Subsequently, MBMA simulations of relevant hypothetical scenarios involving single-arm trial design predicted OS hazard ratios as a function of ORR with matched patient characteristics. Findings from this MBMA and derived parameter estimates can be generally applied by the reader as a framework for interpreting efficacy data from early phase trials to support ORR-based go/no-go decisions and futility rules, illustrated through examples in this report.

Objective Disease Monitoring Strategies from a Tertiary Inflammatory Bowel Disease Center in Hungary.

Emerging data suggest that a treat-to-target approach and early therapeutic intervention using regular objective disease assessment leads to improved outcomes. Our aim was to evaluate the value of objective disease monitoring during regular follow-up in a single tertiary inflammatory bowel disease center. Consecutive inflammatory bowel disease patients (n = 161, Crohn's disease: 118/ulcerative colitis: 43; biological therapy: 70%) were included and followed up for 1 year between January and December 2018. Data on clinical disease activity, biomarkers, endoscopy, imaging, outpatient visits, treatment optimization, hospitalization, and surgery were collected. We compared the monitoring strategy according to the clinical activity (remission/flare/post-flare/continuous activity) every 3 months (assessment period). In total, n = 644 assessment periods were evaluated. Biomarkers were evaluated in 82.9%-83.9% of patients in each assess ment period regardless of clinical activity. Colonoscopy was more frequently performed in active disease (flare/continuous disease activ ity: 21.1%/18.9% vs. clinical remission: 10.1% per assessment period). Magnetic resonance imaging was performed in 7.7%-16.7%/ period in Crohn's disease patients, while the use of computed tomography was low (2.4%/period) and mainly performed in active dis ease. Treatment optimization was more frequent in patients with active disease (biological start/dose optimization: 31.1%/33.8%/ period, steroid start: 13.2%/period). Patients with continuous activity (2.62), flare (2.45), and post-flare (2.05) had higher mean patient visit counts compared to remission (1.68/period). Objective monitoring strategy was applied with routine assessment of clinical activity and biomarkers. Fast-track colo noscopic evaluations were adapted to the clinical stage of the disease while screening colonoscopies and magnetic resonance imaging were frequently used. Objective monitoring resulted in the early optimization of medical therapy and frequent specialist follow-up visits.

Adherence to Objective Therapeutic Monitoring and Outcomes in Patients with Inflammatory Bowel Disease with Adalimumab Treatment. A Real-world Prospective Study

Objective monitoring and effective early treatment using a treat-to-target approach are key to improving therapeutic outcomes in IBD patients. This study aimed to assess adherence to objective monitoring (clinical, biomarkers, and endoscopy) and its impact on clinical outcomes. A prospective, multicenter study included consecutive IBD patients starting on adalimumab therapy between January 2019 and December 2020. Disease activity, assessed by the Harvey-Bradshaw index (HBI), partial Mayo, C-reactive protein (CRP), fecal calprotectin (FCAL), and endoscopy were evaluated at adalimumab initiation and 3, 6, 9 and 12 months. Therapeutic drug monitoring, changes in treatment, drug sustainability, and clinical outcomes were assessed. 104 IBD patients were enrolled (78.8% CD, median age 34.3 years, disease duration 9 years). During the 12 months follow-up, high adherence to clinical activity assessment was observed in both CD (81.3%- 87.7%) and UC patients (76.5-90.9%). CRP measurement decreased over time in both CD (37.3%-54.9%) and UC (29.4%-50.0%). The adherence to serial FCAL monitoring was low in CD (22.7-31.3%) and UC patients (17.6-56.0%). UC patients had higher adherence to early endoscopic assessment (<6 months) compared to CD patients (40.9% vs. 21.5%). Adherence to early combined clinical and biomarkers resulted in earlier dose optimization in CD and UC (log-rank<0.001), but drug sustainability was not different. The patients with early combined adherence had a significantly higher clinical remission rate at 1 year compared to non-adherence (70.2% vs. 29.8%, p=0.007) but no significant difference in UC patients. The adherence to early objective monitoring with combined clinical and biomarkers assessment in IBD patients starting adalimumab therapy led to dose optimization and improved 1-year clinical remission in CD but did not change drug sustainability and clinical remission in UC.

Initial efficacy and biomarker analysis of a phase 1b study targeting IL-1β and PD-1 with chemotherapy in metastatic pancreatic cancer (PanCAN-SR1).

e16287 Background: Pancreatic ductal adenocarcinoma (PDA) has been refractory to therapeutic targeting of the immune microenvironment. In preclinical work, IL-1β was upregulated in PDA tumors, and in mouse models, IL-1β expression led to activation of pancreatic stellate cells and immunosuppression. We hypothesize that blockade of IL-1β and PD-1 will result in significant alterations in immune and fibroblast subsets within the PDA microenvironment. Methods: We conducted an open-label multicenter Phase Ib study evaluating gemcitabine and nab-paclitaxel with canakinumab (ACZ885), a high-affinity human anti-interleukin-1β (IL-1β) mAb, and spartalizumab (PDR001), a mAb directed against human PD-1. 10 subjects with untreated metastatic PDA and RECIST measurable disease were enrolled. The primary objective was to identify a recommended phase II/III dose by evaluating the incidence of DLTs in the first 56 days. All subjects underwent baseline and on-study tissue and blood collection for extensive exploratory correlative studies. Secondary objectives including safety and tolerability and preliminary assessment of clinical activity. Results: 10 subjects were enrolled between November 2020 and March 2021. 6 out of 10 were evaluable for the dose confirmation. In the dose confirmation analysis there were no dose limiting toxicities (DLTs) and the recommended Phase II/III dose was established as; gemcitabine (1000 mg/m2 IV) and nab-paclitaxel (125 mg/m2 IV) on day 1,8,15; canakinumab (250 mg via subcutaneous injection) and spartalizumab (400 mg IV) on day 1; of each 28 day cycle. Adverse events were consistent with those seen with chemotherapy and were predominately hematologic. A preliminary efficacy analysis confirms 1 PR and 7 pts with SD. Two of the 7 pts have been treated for 11 and 12 cycles, respectively, without progression. Activation of CD8 T cells in peripheral blood and increased serum levels of IFN-induced chemokines CXCL9/10 were observed in patient samples. Using an in vitro suppression assay, we showed that baseline serum, from patients deriving clinical benefit, could induce myeloid derived suppressor cells, but that this effect was abrogated with treatment. Single cell transcriptional profiling also revealed treatment-dependent shifts in T cell activation state and myeloid cells in the tumors of patients experiencing clinical benefit. Conclusions: In this Phase Ib study, we established the Phase II/III dose of canakinumab and spartalizumab with chemotherapy in first line metastatic PDA. Translational studies suggest putative biomarkers that may help identify responding pts. This novel combination is being evaluated in a randomized Phase II/III study through the Precision Promise clinical trial network. Clinical trial information: NCT04581343.

A phase 1b study evaluating IL-1β and PD-1 targeting with chemotherapy in metastatic pancreatic cancer (PanCAN-SR1).

557 Background: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy that is refractory to therapeutic targeting of the immune microenvironment. In preclinical work, IL-1β was shown to be upregulated in pancreatic cancer tumors, and in mouse models, IL-1β expression led to activation of pancreatic stellate cells and immunosuppression (Das et al 2020). We hypothesize that blockade of IL-1β and PD-1 will result in alterations in myeloid, lymphoid, and fibroblast subsets within the pancreatic cancer microenvironment and add therapeutic benefit in combination with chemotherapy in PDA. Methods: We are conducting an open-label multicenter Phase Ib study evaluating a 4 drug regimen including gemcitabine and nab-paclitaxel with the addition of canakinumab (ACZ885), a high-affinity human anti-interleukin-1β (IL-1β) monoclonal antibody (mAb), and spartalizumab (PDR001), a mAb directed against human Programmed Death-1 (PD-1). Eligible subjects have metastatic PDA without prior anti-cancer therapy for metastatic disease and RECIST measurable disease. The primary objective was to identify a recommended phase II/III dose of combination therapy by evaluating the incidence of dose limiting toxicities in the first 56 days (8 weeks) of dosing in at least 6 evaluable subjects utilizing a Bayesian logistic regression model. All subjects underwent baseline and on-study tissue and blood collection for extensive exploratory correlative studies. Secondary objectives including safety and tolerability of quadruple therapy and preliminary assessment of clinical activity. Results: 10 subjects were enrolled between November 2020 and March 2021, and the first 6 subjects to complete 8 weeks of therapy were included in the dose confirmation analysis. There were no dose limiting toxicities and the recommended Phase II/III dose was established as; gemcitabine (1000 mg/m2 IV) on day 1,8,15; nab-paclitaxel (125 mg/m2 IV) on day 1,8,15, canakinumab (250 mg via subcutaneous injection) on day 1, spartalizumab (400 mg IV) on day 1; of each 28 day cycle. Adverse events were consistent with those seen with chemotherapy and were predominately hematologic. The majority of subjects completed the on-treatment blood and tissue collection for correlative analysis. The study is ongoing with subjects remaining on therapy and all subjects will be evaluated for efficacy. Conclusions: In this Phase Ib study, we demonstrated the feasibility and safety of adding canakinumab and spartalizumab to standard of care chemotherapy in first line metastatic PDA and established the recommended Phase II/III dose. This novel 4 drug combination will be tested in a randomized Phase II/III study through the Precision Promise clinical trial network. Preliminary correlative and efficacy data will be reported. Clinical trial information: NCT04581343.

A Phase 1 First-in-Human Study of Tnb-383B, a BCMA x CD3 Bispecific T-Cell Redirecting Antibody, in Patients with Relapsed/Refractory Multiple Myeloma

A Phase 1 First-in-Human Study of Tnb-383B, a BCMA x CD3 Bispecific T-Cell Redirecting Antibody, in Patients with Relapsed/Refractory Multiple Myeloma

The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy

Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease (GD). Choice of treatment should be based on the assessment of clinical activity and severity of GO. Early referral to specialized centers is fundamental for most patients with GO. Risk factors include smoking, thyroid dysfunction, high serum level of thyrotropin receptor antibodies, radioactive iodine (RAI) treatment, and hypercholesterolemia. In mild and active GO, control of risk factors, local treatments, and selenium (selenium-deficient areas) are usually sufficient; if RAI treatment is selected to manage GD, low-dose oral prednisone prophylaxis is needed, especially if risk factors coexist. For both active moderate-to-severe and sight-threatening GO, antithyroid drugs are preferred when managing Graves' hyperthyroidism. In moderate-to-severe and active GO i.v. glucocorticoids are more effective and better tolerated than oral glucocorticoids. Based on current evidence and efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness, and patient choice after extensive counseling, a combination of i.v. methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 g of i.v. methylprednisolone in 12 weekly infusions is the optimal regimen. Alternatively, higher cumulative doses not exceeding 8 g can be used as monotherapy in most severe cases and constant/inconstant diplopia. Second-line treatments for moderate-to-severe and active GO include (a) the second course of i.v. methylprednisolone (7.5 g) subsequent to careful ophthalmic and biochemical evaluation, (b) oral prednisone/prednisolone combined with either cyclosporine or azathioprine; (c) orbital radiotherapy combined with oral or i.v. glucocorticoids, (d) teprotumumab; (e) rituximab and (f) tocilizumab. Sight-threatening GO is treated with several high single doses of i.v. methylprednisolone per week and, if unresponsive, with urgent orbital decompression. Rehabilitative surgery (orbital decompression, squint, and eyelid surgery) is indicated for inactive residual GO manifestations.

Color Doppler Ultrasound Assessment of Clinical Activity in Inflammatory Bowel Disease

Background: Ulcerative colitis (UC) and Crohn's disease (CD) are two varieties of inflammatory bowel disease (IBD). Clinicians need a monitoring technique in the IBD. The disease activity can be assessed with endoscopy, activity indexes, and imaging techniques. Color Doppler US (CDUS) is also a non-invasive, radiation, and contrast material free examination which shows the intramural blood flow. Objective: To evaluate the usefulness of B-mode, CDUS, and a newly developed software Color Quantification (CQ) to determine the activity of the IBD. Methods: The disease activity was assessed by clinical activity indexes. Caecum, terminal ileum, ascending colon, transverse colon, and descending colon were evaluated by B-mode, CDUS, and the CQ. Bowel wall thickness (BWT), loss of bowel stratification, loss of haustration, and the presence of enlarged lymph nodes, mesenteric masses, abscesses, fistula, visual vascular signal patterns of the bowel as “hypo and hyper-flow” and the CQ values were investigated. BWT compared with laboratory results and clinical activities. Vascular signal patterns and the CQ values compared with BWT and clinical activity. The diagnostic performances of the CQ were investigated. Results: Fifty-two patients with IBD were evaluated. Patients with increased BWT at the transverse colon had increased frequency of “hyper-flow” pattern. Clinically active patients had increased incidence of “hyper-flow” pattern at the terminal ileum, ascending colon, and whole segments. They had increased CQ values at the terminal ileum, ascending colon, and descending colon, and whole segments. A cut-off value for the CQ (24.7%) was obtained at the terminal ileum. In the diagnostic performances of CQ, we observed utilities significantly at the ascending colon, descending colon, terminal ileum, and whole segments. There was a positive correlation between the CQ values and BWT at the caecum, ascending colon, transverse colon, and descending colon. Conclusion: Increased visual vascular signal scores and CQ values might be useful for monitoring the disease activity in patients with IBD.

Level of Evidence for FDA Drug Approvals in Pivotal Clinical Trials of Hematological Malignancies

BACKGROUND Clinical trials are integral to improve treatment outcomes for patients with hematological malignancies. Although early phase (I/II) clinical trials may provide evidence of clinical efficacy, the main goal for early phase trials is to assess safety signal. Results of phase III clinical trials provide the strongest evidence to support the use of new cancer medications. The Food and Drug Administration (FDA) is responsible to ensure appropriate control and supervision of pharmaceutical drugs. METHODS On the basis of publicly available study protocols and FDA reviews, the authors reviewed the level of evidence in 52 clinical trials supporting 49 drug approvals from 2016 to 2020. Data cut point was May 2020. These trials resulted in approval of medications to treat leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, myeloproliferative neoplasms and multiple myeloma. RESULTS A total of 52 clinical trials were assessed in the 5 years period. Phase III trials supported 61.5% while earlier phase trials supported 36.5% of subsequent FDA hematological malignancies approvals. The level of evidence to support FDA approvals improved with time with 50% of approvals in 2016 and 2017 supported by phase III clinical trials compared to 69% in 2019. Approvals were based on early phase trials in mantle cell lymphoma (100%), chronic myeloid leukemia (100%), diffuse large B cell lymphoma (100%), classic Hodgkin's lymphoma (67%) and acute myeloid leukemia (56%). Phase III trials enrolled 87% of the patients (14238 from16429 patients). Eighteen drug approvals (37% of all approvals) were based on 13% of the total number of patients in the studied period. CONCLUSIONS Level of evidence to support drug approvals in hematological malignancies was based on early phase trials in more than a third of the times. Although early phase studies are appropriate for safety signals, further clinical activity assessment should be done to support the use of new drugs to treat hematological malignancies. Previous successful early phase studies failed to show clinical activity in phase III studies. Despite the fact that use of new approved drugs based on early phase studies evidence may be needed, patients and healthcare providers should be aware of such possibility when using newly approved medications. Figure Disclosures Ramos: Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Kuur Therapeutics: Research Funding.

Clinical features and clinical course of thyroid-associated ophthalmopathy: a case series of 3620 Chinese cases.

To determine the clinical features and course of thyroid-associated ophthalmopathy (TAO) in a large sample of Chinese patients. We retrospectively identified a cohort of consecutive patients diagnosed with TAO at the West China Hospital from October 1, 2009 to October 1, 2019. We analysed clinical data from 3620 patients, including demographic data, clinical manifestations, ophthalmology examinations, and prognosis. TAO most frequently occurred with hyperthyroidism, with most patients developing TAO after thyroid disease (TD). The TAO phenotype was asymmetric in 375 (50.7%) euthyroid patients, 25 (27.8%) hypothyroid patients, and 314 (12.1%) hyperthyroid patients (p < 0.0001). The most frequent symptom was lid lag and the most commonly involved extraocular muscle was the inferior rectus. Severity assessment (NOSPECS score) and clinical activity assessment (Clinical Activity Scores, CAS) differed significantly between male and female patients (P < 0.000). The majority (88.8%) of patients had clinically inactive TAO, and only 3.2% of cases were sight-threatening. Regarding the clinical process, 75.5% of patients had an active phase time less than 12 months and 2.1% showed complete remission. TAO most commonly develops in females and is closely related to hyperthyroidism. Euthyroid TAO often has an asymmetric clinical phenotype. CAS combined with magnetic resonance imaging can improve the detection of TAO. NOSPECS scores should be slightly refined regarding the criteria for corneal involvement. Clinical management of TAO should be individualized according to CAS or NOSPECS assessments and a multidisciplinary approach is paramount. A minority of patients showed complete remission.

Serum Cholinesterases, a Novel Marker of Clinical Activity in Inflammatory Bowel Disease: A Retrospective Case-Control Study.

Background The aim of our study was to investigate whether serum cholinesterase (ChE) levels were associated with inflammatory bowel disease (IBD). Materials and Methods We conducted a retrospective case-control study to clarify the relationship between serum ChE levels and IBD that included 142 patients with ulcerative colitis (UC), 60 patients with Crohn's disease (CD), and 264 healthy controls (HCs). We used ROC curves to evaluate the diagnostic value of serum ChE levels for IBD. Results Substantially lower serum ChE levels were detected in patients with UC than in HCs (6376 U/L versus 8418 U/L, P < 0.001) and in patients with CD than in HCs (5181 U/L versus 8418 U/L, P < 0.001). Additionally, patients with CD displayed significantly lower serum ChE levels than patients with UC (5181 U/L versus 6376 U/L, P < 0.01). We also found that there was a negative association between serum ChE levels and the Crohn's Disease Activity Index (CDAI) score of patients with CD (P = 0.011) and the Simple Clinical Colitis Activity Index (SCCAI) score of patients with UC (P = 0.018). The area under the curve (AUC) for serum ChE for the diagnosis of IBD was 0.826, and the AUCs of serum ChE for the diagnosis of CD and UC were 0.890 and 0.800, respectively. Conclusions Serum ChE levels have important clinical significance in the diagnosis and assessment of clinical activity in patients with IBD, and the cholinergic anti-inflammatory pathway may provide new ideas for targeted treatment of IBD.

Assessment of clinical activity and severity using serum ANCA and ASCA antibodies in patients with ulcerative colitis

BackgroundUlcerative colitis (UC) is a chronic, non-specific inflammatory bowel disease (IBD) with unknown etiology. The lack of specific clinical manifestations, standard diagnostic criteria, objective and accurate indicators to the severity of the disease and the efficacy of the treatment, often results in difficulties in diagnosis and timely treatment of UC. Therefore, there is a need to develop a clinically suitable serum biomarker assay with high specificity and sensitivity.Objective and methodsTo explore the significance of anti-neutrophil cytoplasmic antibodies (ANCA) and anti-saccharomyces cerevisiae antibodies (ASCA) in the diagnosis, differential diagnosis and treatment assessment in patients with ulcerative colitis (UC). Serum levels of ANCA-IgG, ASCA-IgA and ASCA-IgG were measured by an enzyme-linked immunosorbent assay (ELISA) in 105 UC patients, 52 non-UC patients and 100 healthy controls.Results(1) Both the ANCA-IgG level and its positive rate in UC patients were significantly higher than those in non-UC controls and healthy controls (p < 0.01). However, the levels of ASCA-IgA, ASCA-IgG and the positive rates in UC patients had no statistical differences when compared with those in non-UC controls or healthy controls (p > 0.05). (2) The sensitivity of ANCA+ and ANCA+/ASCA− in detecting UC patients was 61.90% and 55.24%, respectively, whereas the specificity was 91.45% and 94.08%, respectively. The sensitivity of ASCA+ and ASCA+/ANCA− in non-UC disease controls was 5.33% and 3.85%, respectively, and specificity was 83.9% and 88.78%, respectively. (3) When UC patients were grouped into mild, moderate or severe subtypes, the ANCA-IgG levels were correlated with the severity of UC, and the differences of the ANCA-IgG levels were statistically different among the three subtypes (p < 0.05). There was no correlation between the levels of ANCA-IgG and the disease locations of UC.Conclusions(1) Serum levels of ANCA may be useful in the diagnosis of UC. (2) Dynamic quantitation of ANCA-IgG levels may be helpful in determining the severity of UC and therefore, may guide treatment of UC.

Assessment of Clinical Activity of PD-1 Checkpoint Inhibitor Combination Therapies Reported in Clinical Trials

Because cancer drugs given in combination have the potential for increased tumor-cell killing, finding the best combination partners for programmed cell death 1 (PD-1) checkpoint inhibitors could improve clinical outcomes for patients with cancer. To identify optimal strategies for combining PD-1 immune checkpoint inhibitors with other cancer therapies. This cross-sectional study compiled 319 results from 98 clinical trials testing PD-1 pathway inhibitors alone or in combination with other agents among 24 915 patients with metastatic cancer. All clinical trials had a primary completion date before September 16, 2018. Data analysis was conducted from November 2018 to August 2019. Patients with metastatic cancer were treated with PD-1 immune checkpoint inhibitors alone or with other cancer therapies. Clinical activity was measured as objective response rates (ORRs). Combination measures included fold change from monotherapy to combination ORR, comparison of observed combination ORRs with estimated combination ORRs based on independent additivity, and a computational model to assess clinical synergy. To assess whether the ORRs of various combinations may be greater than the independent contribution of each agent, a Bliss independent activity model was used to analyze observed combination ORRs, and a Z score, measuring the difference between observed and calculated ORRs, was generated. In 319 results from 98 clinical trials among 24 915 patients, ORRs for monotherapy were compared with combination data by indication and line of therapy, demonstrating an increased ORR in 105 of 127 results (82.7%) where ORRs were available for both PD-1 pathway inhibitor monotherapy and combination therapy. A few combinations showed increases above the Bliss-estimated activity, possibly identifying limited clinical synergy. The mean (SD) Z score for all trials was 0.0430 (0.0243). The mean (SD) Z score was 0.0923 (0.0628) for platinum chemotherapy regimen combinations, 0.0547 (0.0821) for vascular endothelial growth factor or vascular endothelial growth factor receptor tyrosine kinase inhibitor combinations, 0.0893 (0.086) for indoleamine 2,3-dioxygenase inhibitor combinations, and 0.0558 (0.0849) for cytotoxic T-lymphocyte-associated protein 4 inhibitor combinations. In this cross-sectional study, most combination trials showed the expected benefit of combining 2 active anticancer agents, but few combination trials showed clinical synergy according to the Bliss independent activity model.

P127 Lemann Index for Assessment of Crohn’s disease association with the quality of life, endoscopic disease activity and magnetic resonance indices of activity

Abstract Background Crohn’s disease (CD) is one of the subtypes of idiopathic inflammatory bowel disease and is characterised by continuing inflammation and progressive gut damage. Despite many scoring indices of CD, there is a lack of more global assessment tools for the evaluation of the total disease impact on the gut. Methods One hundred adult patients with proven CD underwent magnetic resonance enterocolonography (MR-EC), colonoscopy and clinical activity assessment. Patients’ quality of life was assessed by IBDQ. MR-EC was used to evaluate the Magnetic Resonance Index of Activity (MaRIA- global (G)), modified (m)MaRIA-G, Clermont-G and the Lemann Index (LI). The CD Endoscopic Index of Severity (CDEIS) was used to score the endoscopic activity of the disease. Results LI and IBDQ (r = −0.813, p &amp;lt; 0.01) showed a strong negative correlation. IBDQ also demonstrated a strong negative correlation with other MR-EC indices: MaRIA-G, mMaRIA-G and Clermont-G (r = −0.731, r = −0.749, r = −0.726, p = 0.01) respectively. Moreover, there was a moderate correlation between MaRIA-G and CDEIS, also MaRIA-G and LI, respectively (r = 0.698 and r = 0.658, p = 0.01). As well as MaRIA-G and LI, other MR-EC indices mMaRIA-G and Clermont-G showed good correlation with CDEIS (r = 0.580 and r = 0.585, p = 0.01). Conclusion A strong negative correlation between LI and the quality-of-life measured by IBDQ was determined. This correlation was less pronounced when using the MaRIA-G index; therefore, the LI could be more helpful in assessing more global characteristics of the disease, besides the inflammatory activity of the gut.

Potential Utility of Therapeutic Drug Monitoring of Adalimumab in Predicting Short-Term Mucosal Healing and Histologic Remission in Pediatric Crohn's Disease Patients.

BackgroundLimited data exist regarding mucosal healing (MH) and therapeutic drug monitoring (TDM) in pediatric Crohn's disease (CD) patients treated with adalimumab (ADL). We aimed to investigate the associations between ADL trough levels (TLs) and MH, and between ADL TLs and histologic remission (HR) at 16 weeks from ADL treatment in pediatric CD patients.MethodsThis was a prospective study on moderate-to-severe luminal pediatric CD patients receiving ADL. Ileocolonoscopies and biopsies, as well as clinical activity assessments, laboratory examinations, including tests for ADL TLs and antibody to ADL, were performed 16 weeks after ADL initiation. MH was defined as a Simple Endoscopic Score for CD of 0. HR was defined as the complete absence of microscopic inflammation.ResultsSeventeen subjects (13 males, 4 females) were included. At 16 weeks from ADL initiation, 14 (82.4%), 8 (47.1%), and 4 (23.5%) patients achieved clinical remission, MH, and HR, respectively. ADL TLs were significantly higher in patients who achieved MH compared to those who did not (13.0 ± 6.5 vs. 6.2 ± 2.6 μg/mL, respectively; P = 0.023) and also significantly higher in patients who achieved HR compared to those who did not (17.9 ± 5.3 vs. 6.8 ± 2.5 μg/mL, respectively; P = 0.02). The optimal TL for predicting MH was 8.76 μg/mL.ConclusionSerum ADL TLs at 16 weeks were significantly higher in pediatric patients with CD who achieved MH and HR, respectively. TDM may guide in optimizing treatment efficacy and better target MH in the era of treat-to-target.

Lemann Index for Assessment of Crohn's Disease: Correlation with the Quality of Life, Endoscopic Disease Activity, Magnetic Resonance Index of Activity and C- Reactive Protein.

AimCrohn’s disease (CD) is characterized by continuing inflammation and progressive gut damage. Despite many scoring indices of CD, there is a lack of more global assessment tools for the evaluation of the total disease impact on the gut.MethodsFift y-three adult patients with proven CD underwent magnetic resonance enterocolonography (MR-EC), colonoscopy, and clinical activity assessment, including CRP. Quality of life was assessed using IBDQ. MR-EC was used to evaluate the Magnetic Resonance Index of Activity (MaRIA- global (G)) and the Lemann Index (LI). The CD Endoscopic Index of Severity (CDEIS) was used to score the endoscopic activity of the disease.ResultsA signifi cant correlation between the LI and IBDQ was found (r=-0.812, P<0.01). LI and MaRIA-G correlated moderately, while the LI did not correlate significantly with CRP and CDEIS. For the detection of endoscopically active CD, MaRIA-G was more sensitive and specific (83.3%; 73.3%) compared to the LI (66.7%; 60.0%). There was a moderate correlation between CRP and MaRIA-G, as well as CRP and CDEIS (r=0.496; r=0.527,<0.01).ConclusionA signifi cant negative correlation between the LI and quality of life, measured by IBDQ, was found in our study, suggesting that the LI could resemble more global features of the disease, besides inflammatory activity of the gut.