Refractory Population Research Articles

A Systematic Review of Pediatric Phase I Trials in Oncology: Toxicity and Outcomes in the Era of Targeted Therapies.

Pediatric phase I oncology trials have historically focused on safety and toxicity, with objective response rates (ORRs) <10%. Recently, with an emphasis on targeted approaches, response rates may have changed. We analyzed outcomes of recent phase I pediatric oncology trials. This was a systematic review of phase I pediatric oncology trials published in 2012-2017, identified through PubMed and EMBASE searches conducted on March 14, 2018. Selection criteria included full-text articles with a pediatric population, cancer diagnosis, and a dose escalation schema. Each publication was evaluated for patient characteristics, therapy type, trial design, toxicity, and response. Of 3,431 citations, 109 studies (2,713 patients) met eligibility criteria. Of these, 78 (72%) trials incorporated targeted therapies. Median age at enrollment/trial was 11 years (range 3-21 years). There were 2,471 patients (91%) evaluable for toxicity, of whom 300 (12.1%) experienced dose-limiting toxicity (DLT). Of 2,143 patients evaluable for response, 327 (15.3%) demonstrated an objective response. Forty-three (39%) trials had no objective responses. Nineteen trials (17%) had an ORR >25%, of which 11 were targeted trials and 8 were combination cytotoxic trials. Targeted trials demonstrated a lower DLT rate compared with cytotoxic trials (10.6% vs. 14.7%; p = .003) with similar ORRs (15.0% vs. 15.9%; p = .58). Pediatric oncology phase I trials in the current treatment era have an acceptable DLT rate and a pooled ORR of 15.3%. A subset of trials with target-specific enrollment or combination cytotoxic therapies showed high response rates, highlighting the importance of these strategies in early phase trials. Enrollment in phase I oncology trials is crucial for development of novel therapies. This systematic review of phase I pediatric oncology trials provides an assessment of outcomes of phase I trials in children, with a specific focus on the impact of targeted therapies. These data may aid in evaluating the landscape of current phase I options for patients and enable more informed communication regarding risk and benefit of phase I clinical trial participation. The results also suggest that, in the current treatment era, there is a rationale to increase earlier access to targeted therapy trials for this refractory patient population.

Selinexor: A First-in-Class Nuclear Export Inhibitor for Management of Multiply Relapsed Multiple Myeloma.

Objective: To review the pharmacology, pharmacokinetics, efficacy, and safety of selinexor for management of relapsed multiple myeloma (MM). Data Sources: A literature search was performed of PubMed and MEDLINE databases (January 1, 2000, to November 14, 2019), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from US National Institutes of Health ClinicalTrials.gov. Queries were performed using key words selinexor, SINE, XPO1, and Xpovio.Study Selection/Data Extraction: Human and animal studies related to the pharmacology, pharmacokinetics, efficacy, and safety of selinexor were identified. Data Synthesis: Although numerous advances have been made in MM management, there remains an unmet need for treatment of heavily relapsed/refractory disease. Selinexor is a first-in-class selective inhibitor of nuclear export, which, through inhibition of exportin-1, causes accumulation of tumor suppressor proteins, reduction in oncoproteins, and apoptosis of plasma cells. Selinexor exhibited an overall response in 26% of patients with multiply relapsed MM. Median progression-free survival was 3.7 months, and overall survival was 8.6 months. Common adverse effects include thrombocytopenia, neutropenia, fatigue, and nausea. Ongoing studies are investigating combination therapies utilizing selinexor. Relevance to Patient Care and Clinical Practice: This review describes the efficacy, safety, and clinical applicability of selinexor, a novel agent with potential to meet an unmet need in refractory MM. Conclusion: Selinexor has demonstrated activity in a heavily refractory patient population. Given the adverse effect profile and associated costs, additional studies are needed to further elucidate the appropriate clinical scenario and combinations for selinexor use.

Abstract 10: Early Neuroprognostication After Refractory VF/VT Cardiac Arrest Requiring ECPR

Background: Extracorporeal cardiopulmonary resuscitation (ECPR) can improve survival for refractory ventricular fibrillation (VF) cardiac arrest. Early prognostication will be critical to focus this resource-intensive care to patients likely to benefit. Objectives: The aim of this study is to examine the efficacy of current neuroprognostication tools early in the setting of ECPR for refractory VF. Methods: Consecutive patients transported for the University of Minnesota ECPR program and surviving to hospital admission between December 2015 and May 2019 were assessed. All patients received neurologic assessment with head CT, continuous EEG, cerebral near-infrared spectroscopy (NIRS), biomarkers including S100B and neuron specific enolase (NSE), and neurologic exam. All patients were considered viable unless they developed refractory shock, devastating brain injury, or family requested cessation of efforts. For this analysis, patients were divided into two groups: 1) neurologically favorable survival (CPC 1-2) and 2) those who died or had CPC 3-4. Data from the first 24 hours of hospital admission were used. Results: Of 168 patients, 130 patients survived to hospital admission. Of these, 42% (54/130) survived neurologically favorable. Abnormalities on admission head CT were predictive of poor outcomes; cerebral edema was 100% specific and 30% sensitive for poor outcomes while anoxic injury provided 98% specificity and 39% sensitivity. Admission NSE levels greater than three times the upper limit of normal were predictive with 98% specificity and 26% sensitivity for poor outcome. Admission S100B was highly variable failing to discriminate patient outcome. Absence of brainstem reflexes at 24 hours had 100% specificity and 32% sensitivity. An isoelectric EEG at 24 hours had 100% specificity and 20% sensitivity. NIRS did not predict poor outcomes. When combined, ≥ 1 of the following: anoxic injury on CT, edema on CT, NSE, absence of brainstem reflexes, isoelectric EEG have a specificity of 96% and sensitivity of 67% for poor outcome. Conclusions: Neuroprognostication after 24 hours of hospital admission may be possible in the refractory VF population requiring ECPR. High specificity is possible but sensitivity is limited. Further study is needed.

Polatuzumab Vedotin Plus Obinutuzumab and Lenalidomide in Patients With Relapsed/Refractory Follicular Lymphoma: Primary Analysis of the Full Efficacy Population in a Phase Ib/II Trial

Polatuzumab Vedotin Plus Obinutuzumab and Lenalidomide in Patients With Relapsed/Refractory Follicular Lymphoma: Primary Analysis of the Full Efficacy Population in a Phase Ib/II Trial

Trends in the Multiple Myeloma Treatment Landscape: A United States Analysis of Oscer Electronic Health Record Data 2011-2019

Introduction The treatment (tmt) for multiple myeloma (MM) is evolving with the introduction of novel immunomodulatory drugs (IMiD), monoclonal antibodies (MoAB), and proteasome inhibitors (PI). As new efficacious therapies are approved, the prevalence of MM continues to increase and remains an incurable disease. There is limited real-world evidence describing these temporal changes (Song 2016, Curr Med Res Opin; Fonseca 2017, Leukemia). This study characterizes trends in MM tmts and patient (pt) survival from 2011-19 in the US-based Flatiron electronic health records (EHR) database. Methods Data analyzed were from an enhanced database of oncology EHR contained in the Oncology Services Comprehensive Electronic Records (OSCER), generated by Flatiron Health that includes additional unstructured data processing (New York, NY, March 31, 2019). OSCER represents a longitudinal, demographically and geographically diverse database with data from over 265 cancer clinics representing over 2 million active pts treated at primarily community-based hematology/oncology practices in the US. Inclusion criteria included adult pts ≥18 years (yrs) with a diagnosis of MM (ICD9: 203.x; ICD-10: C90.x) and at least two clinic visits after 2011. Pt and disease characteristics were characterized; line of therapy (LOT) (1-5), year of therapy initiation, and all tmt regimens received. Follow-up time was measured from tmt index until death or last follow-up. Kaplan-Meier overall survival (OS) proportions were estimated from LOT tmt index. Results A total of 9289 pts were identified. At diagnosis the median age was 69 yrs, with 54% of pts male and 68% white. The majority of pts were treated in the community setting (89%) and 11.5% presented with high risk cytogenetics (del17p, t(4;14), t(14;16)). International Staging System (ISS) data was available in 49.2% of subjects, with 16.6%, 16.1% and 16.3% stage 1, 2, and 3 respectively. Among the 91% of pts who received tmt for newly diagnosed MM, median time to tmt was 30 days. In 2017-18, triplet combination (comb) PI-IMiD-dexamethasone (dex) was the most common front (48%) and second line regimen (27%); and the use of this comb increased in both first and second lines over the study period. In contrast, the use of IMiD or PI -dex doublet regimens decreased. In third line setting, PI-IMiD-dex remained the most common comb in 2017-18 (21%) but gradually decreased over the study period with a dip in 2013-14 while MoAB-IMiD-dex combs increased from 3% to 12% (2015/16-2017/18). In second, third, and fourth line MoAB-IMiD-dex comb increased to 8%, 12%, and 14% respectively beginning in 2015 (Table 1). MM tmt regimens changed over the study period, most notably in the first and second LOTs. By 2017-18, triplets replaced doublets as the most common front line (58%) and second line (45%) therapies over the study period. Across all LOTs, triplets were the most prescribed comb in 2017-18 with 42%, 42% and 30% in third, fourth, and fifth lines. Over the study period, monotherapies decreased to 12% in frontline, but their use has remained constant in later lines (Table 2). Overall, 26% of pts received a transplant during follow-up. Approximately 34% of pts survived until the end of follow-up. With each LOT, OS deceased. Median OS of pts treated in first line was 57 months and decreased to 44 months, 32 months, and 25 months in second, third, and fourth lines respectively (Figure 1). OS of MM pts who received first line tmt appears to increase the more recently they were diagnosed. Median OS of MM pts diagnosed in 2013-14 was slightly longer compared to pts diagnosed in earlier yrs (2011-12); 60 months compared to 56 months. Median OS was not reached in 2015-16 (Figure 2). Conclusion Triplet therapies have replaced doublet therapies over time as more options became available to MM pts, especially in frontline setting; frontline monotherapies have nearly halved since the beginning of the study period. In 2015, tmt patterns begin to shift as MoAB based triplets were approved and comprised a higher proportion of the regimens in the relapsed and refractory population. Yet, the majority of pts are still receiving PI-IMiD-dex triplets. OS estimates suggest survival in front line treated pts is slowly increasing in recent yrs. These data illustrate the current tmt landscape of MM and the changes that have occurred since the introduction of novel therapies over the past 8 yrs. MM disease management continues to evolve. Disclosures Braunlin: Amgen, Inc.: Employment. Belani:Amgen, Inc: Employment, Equity Ownership. Buchanan:Amgen Inc.: Employment, Other: Owns Amgen stock, Research Funding. Kim:Amgen, Inc.: Employment, Equity Ownership.

Ivo-Nivo: A Phase II Study of the IDH1 Inhibitor Ivosidenib (AG-120) in Combination with the Checkpoint Blockade Inhibitor Nivolumab for Patients with IDH1 Mutated Relapsed/Refractory AML and High Risk MDS

Background: The normal function of isocitrate dehydrogenase 1 (IDH1) is to catalyze the conversion of cytoplasmic isocitrate to α-ketoglutarate (aKG) in the Krebs cycle. In hematologic malignancies a hotspot mutation at arginine 132 within the conserved active site of IDH1 leads to loss of the expected Krebs Cycle reaction as well as production of the oncometabolite 2- hydroxyglutarate (2-HG). In acute myeloid leukemia (AML) increased cellular 2-HG levels has been shown to impact the tumor microenvironment and promotes tumorigenesis via paracrine stimulation as well repression of the tumor associated immune system. Ivosidenib (AG-120) is a small molecule inhibitor of mIDH1 and is FDA approved for the treatment of patients (pts) with relapsed refractory IDH1 mutant AML. Ivosidenib is known to lower 2-HG levels, independent of response. By reducing 2-HG levels that promote immune escape of IDH-mutant tumors with ivosidenib, we hope to harness the known programmed death receptor pathway dysregulation in AML and high risk myelodysplastic syndrome (MDS). Study Design and Methods: IVO-NIVO is a single arm, multi-institutional phase II investigator initiated clinical trial with a safety cohort to confirm safety and tolerability of combination AG-120 and nivolumab. To be included pts must have MDS or AML with a documented IDH1 mutation in blood or bone marrow within 30 days of inclusion based on mutational testing by PCR or sequencing in a CLIA certified laboratory and be willing to undergo a bone marrow biopsy. Pts will initially start therapy with AG-120, 500mg by mouth daily for 1 cycle. A cycle is defined as 28 days of therapy. On cycle 2 day 1 enrolled pts will receive nivolumab 480 mg that will subsequently be infused every four weeks. Disease response to treatment will be serially assessed through the evaluation of blood (at least monthly) and bone marrow biopsies and aspirates. A complete response assessment will be performed after 6 cycles of therapy. Transplant eligible pts may proceed to allogeneic stem cell transplant (ASCT) if complete response (CR) or morphologic complete remission with incomplete count recovery (CRi) is achieved. Pts that are not eligible for ASCT will continue to receive AG-120- nivolumab combination therapy until documented progression or unacceptable toxicity (figure 1). Safety Cohort: We will have an interim safety analysis after the first 6 pts finishing the first cycle of combination therapy to ensure dosing is safe and tolerable. Pts will undergo clinical assessment with each cycle of therapy, with particular attention to known toxicities like differentiation syndrome that may be life threatening. If 0 to 1 of the first 6 subjects experienced unacceptable toxicities the study will continue as planned. If 2 pts experienced unacceptable toxicities, accrual will be temporarily suspended in order to conduct a review of safety data. If after review, a safety issue is identified and can be corrected, the protocol will be amended accordingly, and enrollment will restart. If an additional 2 pts (4 of 12) or more experience an unacceptable toxicity the patient will be taken off trial and the trial will be terminated. Statistical plan: It is estimated that 45 pts will be enrolled on trial. Using optimal Simon Stage 2 minimax design, if less than 7 of the first 16 pts respond the treatment will be study will be stopped for futility (type 1 error 0.05, type 2 error 0.2). Primary endpoint: We aim to improve the cumulative response rate after 6 cycles of therapy from 40% to 60% (Two-sided alpha risk of 0.05, 1-Beta of 0.8 = 38 pts + 7 additional pts for potential drop-off observed in prior studies) in pts with mIDH1 relapsed/ refractory AML and MDS. Based on published data, it is known that overall response rate is approximately 40% to single agent AG-120 in the relapsed/ refractory IDH1 mutant AML population. Therefore, we expect a 20% ORR improvement compared to historical control after 6 cycles of treatment, based on MDS International Working Group 2006 criteria and AML MDS International Working group MDS/AML criteria. Secondary endpoints: Progression-free survival (the interval between the time of initiation of olaparib to the time of documentation of olaparib failure or last follow-up), overall survival (the interval between the time of initiation of olaparib to the time of death or last follow-up) and percentage of pts that can be bridged to ASCT. Disclosures Prebet: novartis: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; pfizer: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Genentech: Consultancy; novartis: Honoraria; pfizer: Honoraria; novartis: Honoraria; Boehringer Ingelheim: Research Funding; novartis: Honoraria; pfizer: Honoraria; pfizer: Honoraria; Tetraphase: Consultancy; Agios: Consultancy, Research Funding; pfizer: Honoraria; novartis: Honoraria; Boehringer Ingelheim: Research Funding. OffLabel Disclosure: We will use Ivosidenib and nivolumab in combination as a part of a clinical trial to improve care of patients with relapsed/ refractory AML and MDS

The Addition of Ibritumomab Tiuxetan (IT) to the ATG/TLI Preparative Regimen Is Safe and May Enhance Post-Transplant Response and Outcomes for Patients with Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

The Addition of Ibritumomab Tiuxetan (IT) to the ATG/TLI Preparative Regimen Is Safe and May Enhance Post-Transplant Response and Outcomes for Patients with Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

Real-world evidence of tofacitinib effectiveness and safety in patients with refractory ulcerative colitis

BackgroundPhase III trials demonstrated effectiveness of tofacitinib, an oral Janus kinase inhibitor, to induce and maintain remission in patients with moderate-to-severe active ulcerative colitis (UC). AimsWe report the real-world effectiveness and safety of tofacitinib in patients with UC in France. MethodsFrom February 2017 to December 2018, we performed a national French cohort study, which included all consecutive patients with an active UC refractory to anti-TNF and vedolizumab, who received tofacitinib. Outcomes were survival without colectomy, survival without tofacitinib discontinuation and steroid-free clinical remission at weeks 14, 24 and 48. ResultsThirty-eight patients were included, with a median follow-up of 41.5 (18.5–56.8) weeks. Survival without colectomy was 77% [95% confidence interval (95%CI): 59.3–87.9] at week 24 and 70% (95%CI: 50.9–82.8) at week 48. Survival without treatment discontinuation was 70% (95%CI: 52.6–82.3) at week 24. Steroid-free clinical remission was observed in 13 (34%) patients at week 48. Adverse events occurred in 14 (37%) patients, including 6 severe adverse events and three herpes zoster infections. ConclusionIn a highly refractory UC population, one third of patients treated with tofacitinib achieved steroid-free clinical remission at week 14 and 70% of patients avoided colectomy at one year, with an acceptable safety profile. These data confirm tofacitinib effectiveness in UC, especially after multiple biologic failures.

Blinatumomab in Combination with Tyrosine Kinase Inhibitors Safely and Effectively Induces Rapid, Deep, and Durable Molecular Responses in Relapsed and Refractory Philadelphia Positive Acute Leukemias

Background The addition of tyrosine kinase inhibitors (TKIs) to chemotherapy improves the prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Single agent blinatumomab, a bi-specific T-cell engaging CD3-CD19 antibody construct, is more effective than multi-agent chemotherapy in relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and successfully achieves minimal residual disease (MRD) negativity in MRD positive patients. Limited data is available on the safety and efficacy of these agents in combination and uncertainties remain regarding the optimal use of blinatumomab +TKIs. Dual therapy with blinatumomab and TKIs may offer a safe and effective treatment option for relapsed and refractory patients without the incorporation of chemotherapy. Patients and Methods We report our retrospective experience in 18 patients who received blinatumomab +TKI for relapsed/refractory (R/R) Ph+ ALL (n=14), MRD+ Ph+ ALL (n=2) and chronic myeloid leukemia in lymphoid blast crisis (CML-LBC) (n=2). Ten patients received ponatinib; 8 patients received second generation TKIs (dasatinib, n=5; nilotinib, n=2; bosutinib, n=1). Blinatumomab was administered according to the package insert and TKI was initiated on day 1. Median follow up was 15 months and median number of blinatumomab +TKI cycles was 2 (range, 1-5). The median age was 47 years (range, 22-77). The median number of prior therapies was 2 (range, 1-8) and the median number of prior TKIs was 2 (range 1-4). Preexisting T315I mutations were present in one third of patients and 5 patients had relapsed following allogeneic stem cell transplant (alloHSCT). Results Transient grade 2-3 transaminase elevation was observed in 3 patients (ponatinib=2, dasatinib=1). Cytokine Release syndrome was observed in 2 patients. Transient neurotoxicity was observed in 3 patients (1patient with grade 3). All grade 2 and 3 toxicities were observed during the first cycle and all patients were successfully able to complete induction with blinatumomab +TKI. One patient on dasatinib experienced a PICC-associated DVT. There were no other vascular events observed. For patients with r/r disease the CR rate was 88% (14/16) with most of these remissions being MRD negative by flow and PCR (12/14). Both of the patients treated for MRD positivity achieved an MRD negative response. Among T315I mutated patients, 5/6 achieved a CR and 4/5 were MRD negative. The median time to remission was 35 days. The 1 year survival was 80% and the median overall survival following blinatumomab therapy was 45 months. Among 16 pts who achieved an initial response to blinatumomab +TKI, six have expired at the time of this analysis. At the time of relapse on combination therapy, 3/8 pts exhibited new T315I mutations. Of note, all of these were treated with blinatumomab in combination with a second generation TKI. All patients maintained their CD19 positivity at the time of relapse. Both pts with CML-LBC were able to move to a transplant following therapy with blinatumomab +TKI and both attained MRD negative status as measured by Bcr/Abl PCR values. In total, 10 patients treated with blinatumomab +TKI proceeded to alloHSCT, 7 of these are still alive. Median duration of response (DOR) was 5.1 months with maximum DOR of 23.3 months. Discussion While limited due to its retrospective nature and relatively small sample size, this data set begins to answer important regarding the safety and efficacy of blinatumomab +TKI. Combination therapy was effective at achieving rapid and deep responses in this refractory patient population. The toxicities observed with blinatumomab +TKI were in keeping with those seen with blinatumomab alone. However, care should be taken in regard to potential overlapping toxicities of TKIs and blinatumomab, such as hepatotoxicity. The study also suggests a role for blinatumomab treatment in patients with CML-LBC, a rare and difficult disease state to treat. The identification of T315I mutation at relapse in 40% of patients on blinatumomab +second generation TKIs supports further prospective studies with ponatinib and blinatumomab in combination. Finally, loss of C19, which has relevance with regards to the potential benefit of subsequent CD19-directed therapies such as chimeric antigen receptor T-cell therapy was not seen in patients treated with blinatumomab +TKI. Disclosures McCloskey: Jazz: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. Gagnon:Amgen: Speakers Bureau. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; Bristol-Myers Squibb: Consultancy; COTA: Equity Ownership. Koprivnikar:Amgen: Speakers Bureau; Pfizer: Honoraria; Novartis: Speakers Bureau; Abbvie: Speakers Bureau.

Donor-Derived CD19 CAR Cytokine Induced Killer (CIK) Cells Engineered with Sleeping Beauty Transposon for Relapsed B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Donor-Derived CD19 CAR Cytokine Induced Killer (CIK) Cells Engineered with Sleeping Beauty Transposon for Relapsed B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Brivaracetam: First Canadian Experience in an Intractable Epilepsy Population.

To evaluate the effectiveness and tolerability of brivaracetam (BRV) in a refractory epilepsy population in an outpatient clinical setting. Retrospective medical information system review and self-report questionnaire for all patients treated with BRV until the end of 2017. Thirty-eight patients were included, 73.7% female and mean age 36.2. The mean number of antiepileptic drugs (AEDs) for previous use was 8.9, and for current use was 2.5. Mean seizure frequency in the last 3 months was 12 per month. At 3, 6, 12, and 15 months, the 50% responder rates were 36.1%, 32%, 41.2%, and 45.5%, respectively. Patients took BRV for a median duration of 8.25 months, ranging from 7 days to 60 months. Retention rate was 75.0%, 72.0%, 59.2%, and 47.9% at 3, 6, 12, and 15 months, respectively. Overall, the main reasons for discontinuation were adverse events (AEs) (52.3%), lack of efficacy (35.3%), or both (11.8%). The rate of total AEs was 60.5% according to medical records and 85.7% according to questionnaire, including mostly tiredness, psychiatric, and memory complaints. Psychiatric side effects occurred in 31.6% according to medical records and 47.4% according to questionnaire results, which is higher than previously reported and persisted throughout the study period. BRV appears to be a useful and safe add-on treatment, even in a very refractory group of patients. In this real-life clinical setting, psychiatric AEs were found at a higher rate than previously published.

678 Efficacy of Upadacitinib as an Induction Therapy in Severe and Refractory Ulcerative Colitis: Sub-Group Analysis of the Phase 2b Study U-ACHIEVE

INTRODUCTION: An unmet need exists to find effective therapy in more severe ulcerative colitis (UC) patients, especially those who have failed multiple therapies. The efficacy and safety of upadacitinib, a selective Janus Kinase 1 inhibitor, has been assessed in an 8-week double-blind, placebo-controlled, dose-ranging, phase 2b induction study in adult patients with moderately-to-severely active UC (U-ACHIEVE).1,2 METHODS: In U-ACHIEVE, adult patients with moderately-to-severely active UC as determined by the Adapted Mayo Score (5-9 points and centrally-read endoscopy subscore 2-3) were randomized to receive extended-release upadacitinib 7.5, 15, 30, 45 mg once daily (QD) or placebo for 8 weeks. In the current sub-analysis, the efficacy of upadacitinib in more severe and/or more refractory patient populations was assessed. Patients who at baseline had failed ≥2 prior biologic agents, had pancolitis, and/or an Adapted Mayo score &gt;7, were included. Pairwise comparisons between upadacitinib doses and placebo for the primary endpoint, clinical remission per Adapted Mayo Score at Week 8 (defined as stool frequency subscore ≤1, rectal bleeding subscore = 0, and endoscopic subscore ≤1) and secondary endpoints were conducted using the Fisher's Exact test and no multiplicity adjustments were applied. Non-responder imputation was utilized for missing values. RESULTS: At baseline, 142 (56.8% of the total study population) patients had failed ≥2 prior biologics, 135 (54.0%) patients had pancolitis, and 90 (36.0%) patients had an Adapted Mayo score &gt;7. The proportions of patients achieving endoscopic improvement, clinical response per Adapted Mayo score, and clinical response per Partial Mayo score were significantly higher (nominal P-value &lt; 0.05) with upadacitinib doses ≥30 mg QD versus the placebo group in patients who failed ≥2 biologics or had pancolitis at baseline (Table 1). Trends of higher proportions of patients achieving clinical remission per Adapted Mayo score, endoscopic improvement, clinical response per Adapted Mayo score, and clinical response per Partial Mayo score were observed with all upadacitinib groups versus placebo in all the sub-analyses. CONCLUSION: In this dose-ranging induction study, upadacitinib demonstrated greater efficacy compared to placebo with dose response in the more severe and refractory population; significantly greater efficacy was demonstrated with upadacitinib at doses ≥30 mg QD for most of the endpoints evaluated.

612P - SPICE, a phase I study of enadenotucirev in combination with nivolumab in tumours of epithelial origin: Analysis of the metastatic colorectal cancer patients in the dose escalation phase

BackgroundEnadenotucirev (EnAd) is a tumor-selective chimeric Ad11/Ad3 group B oncolytic adenovirus. Following IV dosing of EnAd, viral delivery has been shown in various carcinomas together with CD8+ T-cells. These data provide a rationale for combination of EnAd with nivolumab (anti-PD-1). MethodsEnAd was escalated in patients with metastatic epithelial tumors in a 3 + 3 design. Subjects received increasing dose levels and/or cycles of EnAd followed by up to 8 cycles of nivolumab. The primary objective of the dose escalation phase was to evaluate safety and recommend a dose for expansion. Secondary endpoints include ORR and OS. Results31 patients with metastatic colorectal cancer (mCRC), with median 4 prior lines of therapy, were treated. Of these, 22 are confirmed MSS. EnAd dosing ranged between 1x1012 and 3x1012 virus particles infused IV 3 times weekly for one or two weeks, followed by nivolumab. Flu-like symptoms were reported in the majority of patients following EnAd administration. Adverse events of infusion reaction and hypoxia meeting DLT criteria were reported on C2D1 administration of EnAd requiring increased prophylaxis. Grade 4 acute renal injury was reported in one subject, with renal biopsy showing membranoproliferative glomerulonephritis (GN) indicative of immune complex deposition. Additional monitoring revealed changes suggestive of post-infectious GN in ∼25% of patients after 3-4 weeks of EnAd dosing. These were asymptomatic and resolved without treatment. Kinetics, cytokines and anti-drug antibody responses were consistent with known profiles for both agents. As of 03May2019, median OS is reported as 12.6mo and median PFS is 2.8mo. There were no objective responses, but PD markers in 6/8 matched biopsy samples show evidence of increased CD8 T cell infiltration and upregulation of markers of T cell activation. Stable disease exceeding 4mo was seen in 6/31 (4/22 MSS). ConclusionsThe combination of EnAd and nivolumab has a manageable toxicity profile supporting further investigation in study expansion. Favourable OS outcome in a highly refractory CRC population was noted and may suggest delayed immune antitumor activity in this population. Clinical trial identification2017-001231-39. Legal entity responsible for the studyPsiOxus Therapeutics Ltd. FundingPsiOxus Therapeutics Ltd; Bristol-Myers Squibb. DisclosureP. Basciano: Full / Part-time employment: Bristol-Myers Squibb. R. Brown: Shareholder / Stockholder / Stock options, Full / Part-time employment: PsiOxus Therapeutics Ltds. O. Arogundade: Full / Part-time employment: PsiOxus Therapeutics Ltds. C. Cox: Full / Part-time employment: PsiOxus Therapeutics Ltds. G. Di Genova: Full / Part-time employment: PsiOxus Therapeutics Ltds. D. Krige: Full / Part-time employment: PsiOxus Therapeutics Ltds. H. McElwaine-Johnn: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: PsiOxus Therapeutics Ltds. All other authors have declared no conflicts of interest.

834 Early Symptom Improvement With Risankizumab Treatment in Patients With Moderately to Severely Active Crohn’s Disease: Analysis From a Phase 2 Study

INTRODUCTION: Risankizumab (RZB), an IL-23 p19 inhibitor, has shown safety and efficacy in inducing clinical remission in patients with Crohn’s disease (CD) in a Phase 2 study.1 Here we assessed early symptom improvement during the randomized, double-blind, placebo-controlled induction phase of the trial. METHODS: This Phase 2 study enrolled adult patients with moderate-to-severe CD with a Crohn’s Disease Activity Index (CDAI) of 220–450, ulcers in the ileum and/or colon, and a Crohn’s Disease Endoscopic Index of Severity (CDEIS) ≥7 (≥4 for patients with isolated ileitis) assessed by ileocolonoscopy confirmed by a blinded central reader. Patients were randomized 1:1:1 to receive intravenous RZB (200 mg or 600 mg) or placebo at Weeks 0, 4, and 8. Endpoints examined in this post hoc analysis included changes from baseline at Weeks 2, 4, 8, and 12 in CDAI, average daily stool frequency (SF) and average daily abdominal pain score (AP) for all patients with available data, and newly defined clinical remission at Week 12, based on symptom improvement, defined as SF ≤ 2.8 and AP ≤1, both not worse than baseline, in patients with baseline SF ≥ 4 or AP ≥2. Continuous endpoints were analyzed using observed case; non-responder imputation was used for missing data of binary endpoints. Statistical comparisons of median change were based on Wilcoxon rank sum test. RESULTS: 121 patients were randomized in the induction phase. Baseline characteristics were similar among treatment arms.1 Mean (SD) disease duration at baseline was 13.4 (9.4) years; 94.2% of patients received previous anti-TNF therapy. Significant improvements in CDAI and AP were observed with RZB (600 mg) versus placebo as early as Week 2 and in SF at Week 8 (Table 1). The proportion of patients with clinical remission based on symptom improvement was significantly higher in the 600 mg RZB group versus placebo at Week 12 (23.7% versus 6.1%; P &lt; 0.05), supporting the previously reported superiority of RZB versus placebo for inducing CDAI remission at Week 12 (36.6% of 600 mg RZB versus 15% of placebo; P &lt; 0.05). CONCLUSION: RZB induction treatment was associated with significant early improvements in clinical symptoms and disease activity in a highly refractory patient population with moderately to severely active CD.

Prospective evaluation of oral cannabis extracts in children with epilepsy

PurposeInterest in the use of artisanal cannabinoids in pediatric epilepsy has increased but safety and utility data are lacking. Our aim was to prospectively characterize the use of oral cannabis extracts (OCE) in a refractory pediatric epilepsy population. MethodsFamilies considering the use of an OCE were enrolled in a prospective observational study. Baseline seizure frequency was assessed over a period of 4 weeks. Seizure frequency, CBD and THC-COOH levels were assessed every 4 weeks during a 12-week treatment period. Response was defined as at least a 50% reduction in seizure frequency over the final 8 weeks of the study relative to baseline. ResultsConsent was obtained in 32 children; 11 were excluded from analysis (3 failed to complete baseline data, 3 started OCE before completing baseline period and 5 did not start OCE) leaving 21 to be included in subsequent analyses. Median age was 10.3 years (IQR 6.8–12.6), 13 (62%) were male and median seizure frequency was 2.7 seizures/day during the baseline period. The median of the high dose of CBD that was administered during the observation period was of 0.9 (0.6–2.2) mg/kg/day. Of the 21 subjects who were included in the analysis, 5 (24%) were responders. OCE was stopped early in 3 subjects (14%) due to a perceived increase in seizures. THC-COOH and CBD blood levels did not have a significant association with response status (p = 0.95 CBD, p = 0.53 THC-COOH, N = 14). ConclusionThe observed response rate in this study is similar to placebo rates in prospective randomized trials of pharmaceutical grade products and the withdrawal rate is greater than rates obtained with retrospective methods. Doses of OCE administered were lower than doses used in randomized trials.

Abstract 2173: Developing a high-throughput, high content screening technology to identify new anticancer drug treatments

Abstract The high attrition rate of new chemotherapeutic drugs represents the single most important challenge in anticancer drug development. With only one drug out of 10, 000 test compounds gaining FDA-approval, attrition is often attributed to failure of in vitro drug efficacy to translate to clinical success. The overall drug discovery and development pipeline can be dramatically improved with new, innovative assays of high pharmacological relevance that can shorten the discovery/preclinical phase and ensure rapid translation to clinic. We report the development of a three-dimensional phenotypic drug screening platform based on spheroidsMARY-X. The tight, compact spheroidsMARY-X form spontaneously due to innate molecular determinants with proliferative cells on the outer periphery and a dormant tumor cell core. These features mimic the intratumoral biological complexities of tumor tissue and thus provide a relevant in vitro model for drug discovery with a high degree of predictive value. Significantly, this model allows analysis of drug targeting of dormant tumor cells, the difficult to treat resistant or highly refractory cell population. Drug response can be reliably assessed using brightfield microscopy and can be quantified by measuring spheroid circularity (i.e., dissolution index). Evaluation of soluble factor concentration is performed using molecular rotors through restricted intramolecular rotation upon protein binding with a subsequent quantum yield. Overall, we present a 3-dimensional anticancer assay that provides a rapid, efficient, relevant platform for the evaluation of drug response and allows identification of small molecule hits in both proliferative and more importantly, dormant tumor cells, the major cause of relapse and recurrent metastatic disease. Citation Format: Andrew T. Milcarek, Kevin Daus, Mary L. Alpaugh. Developing a high-throughput, high content screening technology to identify new anticancer drug treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2173.

Acute Severe Ulcerative Colitis: The Oxford Criteria No Longer Predict In-Hospital Colectomy Rates.

Patients admitted to hospital with acute severe ulcerative colitis have a short-term in-hospital colectomy rate of 30%. The Oxford criteria state that if the CRP is greater than 45mg/l or there are more than eight bowel movements in 24h at day 3 of intravenous corticosteroids, there is an 85% risk of an in-hospital colectomy. The aim of this study was to determine whether this high rate of colectomy continues to be accurate in this medically refractory patient population. We performed a retrospective chart review of 80 patients admitted to a tertiary hospital between 2013 and 2017 with acute severe ulcerative colitis. Sixteen (20%) patients required an in-hospital colectomy. Of the 33 patients that fulfilled the Oxford criteria, 12 (36%) patients required a colectomy during admission. Only four (9.5%) patients who did not fulfill the Oxford criteria required a colectomy during admission. Twenty-two patients that had fulfilled the Oxford criteria received infliximab as second-line medical therapy. In a patient population that fulfilled the Oxford criteria, the in-hospital colectomy rate has reduced from 85% in 1996 to 36% in 2017. These results should be considered when discussing with patients the opportunity to commence infliximab or cyclosporine as second-line medical therapy.

Changes in Vedolizumab Utilization Across US Academic Centers and Community Practice Are Associated With Improved Effectiveness and Disease Outcomes.

BackgroundVedolizumab effectiveness estimates immediately after Food and Drug Administration (FDA) approval for ulcerative colitis (UC) and Crohn’s disease (CD) are limited by use in refractory populations. We aimed to compare treatment patterns and outcomes of vedolizumab in 2 time frames after FDA approval.MethodsWe used 2 data sets for time trend analysis, an academic multicenter vedolizumab consortium (VICTORY) and the Truven MarketScan database, and 2 time periods, May 2014–June 2015 (Era 1) and July 2015–June 2017 (Era 2). VICTORY cumulative 12-month clinical remission, corticosteroid-free remission, and mucosal healing rates, and Truven 12-month hospitalization and surgery rates, were compared between Eras 1 and 2 using time-to-event analyses.ResultsA total of 3661 vedolizumab-treated patients were included (n = 1087 VICTORY, n = 2574 Truven). In both cohorts, CD and UC patients treated during Era 2 were more likely to be biologic naïve. Compared with Era 1, Era 2 CD patients in the VICTORY consortium had higher rates of clinical remission (31% vs 40%, P = 0.03) and mucosal healing (42% vs 58%, P < 0.01). These trends were not observed for UC. In the Truven database, UC patients treated during Era 2 had lower rates of inflammatory bowel disease–related hospitalization (22.4% vs 9.6%, P < 0.001) and surgery (17.2% vs 9.4%, P = 0.008), which was not observed for CD.ConclusionSince FDA approval, remission and mucosal healing rates have increased for vedolizumab-treated CD patients, and vedolizumab-treated UC patients have had fewer hospitalizations and surgeries. This is likely due to differences between patient populations treated immediately after drug approval and those treated later.

087 Janus kinase inhibitors demonstrate effectiveness in a real-world multi-biologic DMARD refractory rheumatoid arthritis population

087 Janus kinase inhibitors demonstrate effectiveness in a real-world multi-biologic DMARD refractory rheumatoid arthritis population

Encapsulated human mesenchymal stem cells (eMSCs) as a novel anti-cancer agent targeting breast cancer stem cells: Development of 3D primed therapeutic MSCs.

Breast cancer is a leading cause of mortality in women across the globe. The major reason for its recurrence and high mortality is due to the presence of a drug refractory and self-renewing population of cells, the cancer stem cells (CSCs). Mesenchymal stem cells (MSCs) have recently emerged as a promising cell-based therapeutic agent for the treatment of different cancer types. However, the anti-tumor effect of MSCs has been indicated to be substantially reduced by their in vivo tumor-trophic migration property and direct cell-to-cell integration with tumor stromal elements. To address this drawback, the present study uses a biomaterial, sodium alginate, for the encapsulation of MSCs from the perinatal tissue, Wharton's jelly (WJMSCs) into microbeads, to study the effect of WJMSCs beads on breast CSCs derived from two breast cancer cell lines, MDA-MB-231 and MCF7. Encapsulation with sodium alginate facilitated the prevention of direct cell-to-cell interaction and these microbeads provided a three-dimensional (3D) microenvironment for the encapsulated WJMSCs (eWJMSCs). Compared to two dimensional (2D) culture, eWJMSC increased proliferation of WJMSCs with an increase in pluripotency genes, epithelial to mesenchymal transition (EMT), immune-modulation, and angiogenesis. Interestingly, the tumor invasion suppressor protein E-cadherin was highly expressed in eWJMSCs as shown by Western blot analysis. In addition, eWJMSCs had an increased secretion of anti-inflammatory cytokines VEGF, TGF-β, TNF-α, IFN-γ, IL-10 and -6, and IL-3β when compared to 2D culture. Treatment of CSCs with eWJMSCs reduced cell viability, inhibited migration, and exerted an anti-angiogenic effect. eWJMSCs treatment of CSCs increased caspase 3/7 activity, nitric oxide production, and reactive oxygen species production, suggesting its anti-tumorigenic activity. Gene expression analysis revealed that CSCs treated with eWJMSCs had a downregulation of pro-proliferation markers, drug transporters, epithelial-mesenchymal transition-associated markers, and angiogenesis related genes. The mode of anti-proliferative action of WJMSCs beads was possibly through inhibition of the Wnt/β-catenin signaling pathway as indicated by the upregulation of the Wnt antagonists sFRP4 and DKK1. These data suggest that alginate-encapsulated WJMSCs could be an efficient cell contact-free system for developing stem cell-based therapies for CSCs.