Citations

Study Design: Retrospective, single institution, multisurgeon case control series. Objective: To determine whether there are differences in reoperation rates or outcomes for patients undergoing 2-level posterolateral fusion (PLF) augmented by a transforaminal lumbar interbody fusion (TLIF) at only one of the levels or at both. Methods: A total of 416 patients were identified who underwent 2-level PLF with a TLIF at either one of those levels (n = 183) or at both (n = 233) with greater than 1-year follow-up. Demographic, surgical, radiographic, and clinical data was reviewed for each patient. These included age, sex, race, body mass index, smoking status, Charleston Comorbidity Index, operative time, estimated blood loss, length of stay, and patient-reported outcome measures. Results: Each cohort underwent 24 reoperations. Although the number of overall reoperations was not significantly different ( P > .05), among the reoperation types, there were significantly more reoperations for adjacent segment disease in the 2-level group compared to the 1-level group (19 vs 12, P = .04). There was no difference in reoperation for pseudarthrosis between the groups ( P > .05). Although both groups experienced significant improvements in Oswestry Disability Index ( P < .001) and Short Form–12 health questionnaire ( P < .001), there were no differences between improvements for 1- versus 2-level cohorts. Conclusions: For patients undergoing 2-level PLF in the setting of a TLIF, using a TLIF at one versus both levels does not seem to influence reoperation rates or outcomes. However, reoperation rates for adjacent segment disease are increased in the setting of a 2-level PLF augmented by a 2-level TLIF.

Abstract Background Crohn’s rectovaginal fistulizing disease remains notoriously difficult to treat. A phase I clinical trial to evaluate the safety and feasibility of a novel protocol using a mesenchymal stem cell (MSC)–coated Gore Bio-A fistula plug for the treatment of medically and surgically refractory Crohn’s rectovaginal fistulas was conducted. Methods Five patients underwent an autologous subcutaneous adipose tissue harvest via a 2-cm abdominal wall incision at time of exam under anesthesia (EUA) with seton placement. MSCs were isolated, expanded, and impregnated on the plug. After 6 weeks, patients returned to the operating room for placement of the MSC-coated plug. The primary end points were safety and feasibility; the secondary end point was clinical and radiographic healing at 6 months. Results Five female patients (median age [range], 49 [38–53] years) with a median disease duration (range) of 23 (7–34) years who were on biologic (n = 5) or combination therapy (n = 3) had successful harvest and expansion of MSCs and delivery of the Gore Bio-A plug. There were no serious adverse events or adverse events related to the MSCs or plug during the 6-month follow-up. At 6 months, 3 patients had complete cessation of drainage, and 2 had &gt;50% reduction in drainage; all had a persistent fistula tract identified on magnetic resonance imaging and EUA at 6 months. Conclusions Surgical placement of an autologous adipose-derived MSC-coated fistula plug in diverted patients with Crohn’s rectovaginal fistulas was safe and feasible. All patients had a reduction in the size of their fistula tract, and 3 of 5 had cessation of drainage, but none achieved complete healing. This was a phase I clinical trial of autologous mesenchymal stem cells on a plug for rectovaginal Crohn’s fistulas.

Abstract Background: Combination studies with histone deacetylase (HDAC) inhibitors plus hypomethylating agents (HMA) have suggested beneficial clinical activity in higher risk MDS and AML, though exceptions have also been reported. Pracinostat is a potent oral HDAC inhibitor selective for class I, II and IV isoforms. A pilot phase Ib study of pracinostat in combination with azacitidine (AZA) in higher risk MDS demonstrated a complete response (CR)/CR with incomplete blood count recovery (CRi) rate of 89% (Proc ASH:3821, 2012). Preliminary data on 33 patients from a multi-center, open-label, single-arm Phase II study of Pracinostat in combination with AZA in elderly AML also reported a high CR/CRi rate (ASH 2014). Herein we report the latest survival and response results for this study. Methods: Eligibility includes previously untreated AML (≥20% bone marrow blasts), age ≥65 years, unsuitable for intensive therapy due to co-morbidities and/or AML related features, and intermediate or high-risk cytogenetics. Study therapy includes pracinostat, 60 mg p.o. 3 alternate days/week for 3 weeks plus AZA, 75 mg/m2) days 1-7 or days 1-5 and 8-9 either s.c. or i.v. with cycles repeated every 28 days until progressive disease, lack of response or intolerance. The primary endpoint is CR+CRi+ morphologic leukemia free state (MLFS) per IWG criteria. Response assessments occur at the end of cycle 1 or 2 then every other cycle or when clinically indicated. A Simon 2-stage statistical design is utilized with the following assumptions: null=0.10, alternate=0.25, a=0.10, power=0.90. Stage 1 n=27 and total stage 2 n=40. Secondary endpoints include overall response rate (ORR; CR+CRi+MLFS+partial response [PR]+PRi), duration of response and overall survival. Results: Between Dec 2013 and Dec 2014, 50 patients from 15 study sites were enrolled. At this time, 50 are evaluable for efficacy. Baseline disease characteristics for all patients include: median age 75 (range 66-84); 32 de novo AML, 13 evolved from AHD, 5 were treatment-related; 28 intermediate-risk and 20 high-risk cytogenetics and 2 unknown; baseline bone marrow blast counts ranged from 20% to 89% with a median of 40%. Thirty-one patients (62%) continue to be followed for survival (range: 8.5 to 18.5 months). Median overall survival has not been reached in the overall study population and neither in patients with high-risk cytogenics or those with AML secondary to MDS or prior anti-cancer therapy. The 1-year overall survival estimate is 60%. The primary endpoint of CR +CRi +MLFS has been observed in 27/50 evaluable patients (54%) to date, including 21/50 (42%) CR. The 60-day all-cause mortality rate is 10% (5/50). Treatment emergent adverse events (TEAEs) Grade ≥3 seen in >5% of patients: febrile neutropenia 30%; thrombocytopenia 22%; neutropenia 10%; cellulitis 10%; anemia 8%; fatigue 8%; sepsis 6%, and pancytopenia 6%. TEAE's leading to study therapy discontinuation: peripheral motor neuropathy (1), parainfluenza (1), atrial fibrillation/prolonged QTc (1), subdural hematoma after a fall (1), and sepsis (3). Conclusions: Pracinostat plus AZA produces a high rate of durable responses in this AML population. Median overall survival has not been reached; 1-year overall survival is estimated at 60%. Final response data and overall survival estimates will be presented at the meeting. Disclosures Off Label Use: Azacitidine is not approved for use in acute myelogenous leukemia.. Khaled:Sequenom: Research Funding. Arellano:Cephalon Oncology: Research Funding. Butler:MEI Pharma, Inc.: Employment. Ashby:MEI Pharma, Inc.: Employment. Medeiros:Celgene: Honoraria, Research Funding; Agios Pharmaceuticals: Honoraria.

Abstract Purpose: The surface receptor MET is highly expressed on primary uveal melanoma; MET inhibitors demonstrated early clinical signals of efficacy in slowing uveal melanoma growth. The primary objective of our study was to compare the progression-free survival rate at 4 months (PFS4) of patients with uveal melanoma treated with cabozantinib or chemotherapy. Patients and Methods: Patients with metastatic uveal melanoma and RECIST measurable disease were randomized 2:1 to receive either cabozantinib (arm 1) versus temozolomide or dacarbazine (arm 2) with restaging imaging every two cycles. Cross-over from arm 2 to cabozantinib after progression was allowed (arm 2X). Available tumor specimens were analyzed by whole-exome sequencing (WES) and results were correlated with outcome. Results: Forty-six eligible patients were accrued with 31, 15, and 9 in arms 1, 2, and 2X, respectively. Median lines of prior therapy, including hepatic embolization, were two. Rates of PFS4 in arm 1 and arm 2 were 32.3% and 26.7% (P = 0.35), respectively, with median PFS time of 60 and 59 days (P = 0.964; HR = 0.99). Median overall survival (OS) was 6.4 months and 7.3 months (P = 0.580; HR = 1.21), respectively. Grade 3–4 Common Terminology Criteria for Adverse Events were present in 61.3%, 46.7%, and 37.5% in arms 1, 2, and 2X, respectively. WES demonstrated a mean tumor mutational burden of 1.53 mutations/Mb and did not separate OS ≤ or &gt;1 year (P = 0.14). Known mutations were identified by WES and novel mutations were nominated. Conclusions: MET/VEGFR blockade with cabozantinib demonstrated no improvement in PFS but an increase in toxicity relative to temozolomide/dacarbazine in metastatic uveal melanoma.

BACKGROUND: Medication Therapy Management (MTM) is a strategy for developing a variety of non-dispensing clinical pharmacy services to patients which aim to optimize therapeutic outcomes by identifying and resolving drug therapy problems. We conducted a pilot study to see if MTM could serve as a measurable value-add as demonstrated by improved outcomes for IBD injectable biologic patients and reduced disease management burden for clinicians and office staff. METHODS: Adult patients with either UC or CD prescribed new self-injectable biologic agents (adalimumab [ADA], certolizumab pegol [CTZ], golimumab [GOL], or ustekinumab [USTE]) were recruited from outpatient clinics at Mayo Clinic Rochester, Arizona, Florida or Health System. Exclusion criteria included prescriptions that were refills, patients with need for urgent hospitalization, pregnant patients, those without a reliable and confirmed shipping address or reliable telephone access, or patients residing outside of the United States. Patients were randomized to receive standard care or be enrolled in a collaborative, high-touch MTM program administered by Curant Health PharmD's. Patients randomized to MTM were further stratified to either having medications filled by Curant Health or specialty pharmacy as dictated by insurance plan. Patients receiving standard care were managed as per discretion of the treating physician. Patients receiving MTM arms were contacted per a defined protocol with calls at specified time points. The primary outcome of interest was number of unsolicited calls/messages from patients to practice sites during the study time period along with total time spent on the managing of those messages either electronically or via telephone. Secondary outcomes of interest included medication adherence as defined by percent of patients with a score of >6 at week 24 (MMAS-8) and disease activity as measured by relevant disease indices. RESULTS: 20 patients were randomized to MTM and 19 to standard care. There was no difference in median age or sex distribution among groups. The majority of patients were started on ADA, 1 CTZ and 1 USTE. One patient was enrolled twice with different medications to the standard group. Nine MTM patients required additional support to optimize therapy with 1 patient requiring 6 additional calls. The majority of calls involved injection administration, how to treat injection site reaction, pain and misfiring. The number of unsolicited calls overall in the MTM arm were significantly higher than standard care: 3 vs 1 ( P < 0.05). The overall adherence to medication at week 24 was significantly higher with MTM; scores ranged from 7.5–8 vs 5.5–6 in the standard care group ( P < 0.05). The median disease score of the MTM group also improved significantly for both diseases by >50% at week 24 for 13/20 patients compared with 10/19 for standard group. CONCLUSION(S): Patients in the high-touch, collaborative MTM arm received additional engagement as evidenced by the significant increase in unsolicited patient calls. MTM patients also showed improved adherence and improved disease outcomes to injectable therapy. This suggests that MTM services are an effective mechanism to relieve burden of office staff while improving patient care.

9506 Background: Survival is poor in mUM and treatment options are limited. MET kinase is over-expressed on UM and the MET inhibitor cabo showed activity in an early trial. Methods: A091201 was a 2:1 randomized phase II study testing progression-free survival (PFS) of cabo (60 mg daily) vs chemo (DTIC/TMZ). We studied baseline metastatic tumor samples (n = 19; 1 lung, 18 liver) by whole exome sequencing (WES) and RNAseq. We correlated data with OS and made comparisons for mUM vs. primary tumors from TCGA (n = 80). Results: 46 patients were accrued with 96% and 63% with liver metastases and elevated LDH, respectively. Toxicities were similar to prior reports of cabo and chemo. The trial stopped at interim analysis due to no difference in PFS (p = 0.964; HR = 0.99) or OS (p = 0.580; HR = 1.21). WES showed tumor mutational burden of 46±4 (mean±SEM) and did not separate OS at 1 year (p = 0.14, two-sided Wilcoxon rank sum test) in A091201. Recurrent known mutations included GNAQ/11, SF3B1, BAP1; novel mutations included GOLGA6L10, PKD1L3, and FAM228B. Gene expression signatures differed significantly between A091201 and TCGA cohorts including MET signaling (p = 7.87e-22), T cell-inflamed (p = 0.004), homologous recombination deficiency (p = 0.004), proliferation (p = 0.009) and hypoxia (p = 5.2e-10) (two-sided Student’s t-test). Tumor immune cell enrichment analysis revealed significant differences with lower M1:M2 macrophage (p = 1.2e-10) and higher Tregs (p = 6.0E-21) in mUM relative to TCGA (two-sided Wilcoxon rank sum test). Epithelial-mesenchymal transition gene expression signature was significantly associated with worse OS in A091201 (p = 0.02) with angiogenesis signature trending toward significance (p = 0.21) (log-rank test). OS separated by differentially expressed genes with OS ≤ 1 year associating with increased expression of the angiogenesis/immune-associated molecule neuropilin 1. Conclusions: These results provide insights between primary and mUM indicating potential novel therapeutic approaches. Support: U10CA180821, U10CA180882, T32GM007019, Exelixis. https://acknowledgments.alliancefound.org ; Clinical trial information: NCT01835145.

6531 Background: This survey of Targeted Agent and Profiling Utilization Registry (TAPUR) Study physicians examined use, attitudes, and perception of tumor genomic testing (TGT), defined as any DNA test performed on tumor specimen/plasma. TAPUR is a multibasket study of marketed agents targeting tumor genomics. Methods: 333 physicians at 54 TAPUR sites were surveyed (2016-2017). Survey domains included use of TGT, barriers to ordering TGT, and genomic confidence. Surveys included 3 scenarios for TGT ordering 1) pretreated advanced cancer patients (pts) without options, 2) newly diagnosed, untreated, metastatic pts and 3) early stage/potentially curable pts with standard options. Data were analyzed with descriptive statistics. Results: 112 physicians responded (33%). The table displays demographics and genomic confidence. Respondents reported a median of 25% of their pts had TGT in past 12 months for trials/routine care (range 0-85%). Barriers to testing included access to tumor specimen (86%), insurance coverage (67%), concerns that results will not be actionable (55%), and test issues (wait time, unsure which test/lab to use, test accuracy) (54%). TGT was ordered most often for scenario 1 (96%) and 2 pts (70%). Few respondents (32%) would order testing in scenario 3. Of those who reported testing for scenarios 1 & 2, most told pts that results could inform treatment/prognosis/trials (97%) or may be uninformative (84%). In all scenarios, pt expectations of TGT results were discussed prior to testing. A minority reported frequently telling pts in advance that results could inform heritable cancer susceptibility (37%). Conclusions: Confidence in using TGT was high. TGT was performed most for pts with advanced cancer and few options. Availability of specimens was largest barrier reported, indicating the importance of blood-based tests. Few respondents discussed implications of germline findings in advance, despite growing evidence of germline findings in somatic testing. [Table: see text]

5510 Background: Single agent aromatase inhibitor (AI) therapy is associated with limited clinical activity in ovarian cancer (OC) and endometrial cancers (EC). AI therapy was associated with a progression free survival (PFS) at 12 weeks of only 20% in relapsed OC (Bowman et al, 2002) and a median PFS of 1 month in relapsed EC (Rose et al, 2000). In Estrogen Receptor (ER) positive metastatic breast cancer, clinical studies had shown a significant prolongation of PFS with the addition of the cyclin kinase 4/6 inhibitor ribociclib to AI (Hortobagyi et al, 2016). Here, we report the results of a phase 2 clinical trial of the combination of ribociclib and letrozole in patients with relapsed ER positive OC or EC. Objectives: Primary endpoint was the proportion of patients with relapsed ER positive OC or EC alive and progression-free after 12 weeks of therapy (PFS12) with the combination of ribociclib given at a dose of 400 mg orally daily and letrozole 2.5 mg orally daily. A PFS of 45% was considered a favorable result based on the data referenced above from Bowman et al. Methods: Eligibility criteria included patients with relapsed ER positive OC or EC, with measurable disease, not previously treated with ribociclib or AIs. Xenografts were created from CT guided tumor biopsies at baseline to assess feasibility. Results: A total of 40 patients were enrolled (20 with OC and 20 with EC) ) with a median age of 61 years (range: 30-82) and 64.5 (range: 52-75) in the OC and EC groups respectively. Among the OC patients, 17 had high grade serous carcinomas and 3 had low grade serous carcinomas. 11 EC patients had endometrioid cancers (3 with grade 1 tumors) and 9 had high grade serous tumors. Ten out of 20 OC patients and 11/20 EC patients were alive and progression-free at 12 weeks (PFS12 of 50 and 55%, respectively). The most common grade 3 or higher adverse events (occurring in at least 5 pts) were leukopenia (18%), lymphopenia (18%), neutropenia (13%), and fatigue (13%). 34 tumor biopsies were suitable for injection into mice and 44% engrafted. ER expression persisted through multiple passages in mice. Two of three EC PDX models exhibited improved PFS with letrozole/ribociclib compared to letrozole alone. Conclusions: The combination of ribociclib and letrozole is associated with a promising 50% and 55% PFS12 in patients with ER positive relapsed OC or EC respectively. Creation of xenograft tumor models from CT guided biopsies of OC and EC tumors was feasible. Clinical trial information: NCT02657928.