Citations

Abstract Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR translocations and activating mutations is implicated in many cancers, including CCA. FGFR2 translocations are the most common FGFR alterations, which occur in ~13% of pts with intrahepatic CCA and involve a variety of fusion partners/breakpoints. INCB054828 is a novel, orally available, selective inhibitor of FGFR1, FGFR2, and FGFR3 tyrosine kinase activities (AACR 2015; Abstract 771). Methods: This phase 2, open-label trial will evaluate INCB054828 monotherapy in pts with advanced/metastatic or surgically unresectable CCA (Table; NCT02924376). Pts will be prescreened centrally for FGF/FGFR status and enrolled in the following cohorts prior to start of treatment: FGFR2 translocations (Cohort A); other FGF/FGFR alterations (Cohort B); no FGF/FGFR alterations (Cohort C; negative control for effects of FGF/FGFR alterations on objective response rate [ORR]). Pts must be aged ≥18 years, with Eastern Cooperative Oncology Group performance status ≤2, disease progression after ≥1 prior systemic therapy, and no prior use of selective FGFR inhibitors. Pts will self-administer INCB054828 orally at a starting dose of 13.5 mg once-daily on a 21-day cycle (2 weeks on; 1 week off); treatment will continue until disease progression or unacceptable toxicity. The primary endpoint will be ORR (complete or partial response per independent radiologic review committee using Response Evaluation Criteria in Solid Tumors v1.1) in pts with FGFR2 translocations (Cohort A). Secondary endpoints will include ORR in pts positive or negative for any FGF/FGFR alterations and duration of response, progression-free survival, overall survival, and safety (all cohorts). The study is currently open for enrollment (estimated primary completion date, April, 2018). Study DesignPrescreen for FGF/FGFR Status• Adults with metastatic/surgically unresectable cholangiocarcinoma with disease progression after ≥1 previous systemic treatment- FGFR2 translocations → cohort A (n~60)- Other FGF/FGFR alterations → cohort B (n~20)- No FGF/FGFR alterations → cohort C (n~20)Screen for eligibility criteria and patient characteristics• Eastern Cooperative Oncology Group performance status ≤2• Adequate hepatic function (total bilirubin ≤1.5 × upper limit of normal [ULN; ≤2.5 × ULN for Gilbert syndrome or disease involving liver]; aminotransferases <2.5 × ULN [<5 × ULN with liver metastases])• Adequate renal function (creatinine clearance ≥30 mL/min; serum phosphate >institutional ULN; serum calcium >institutional normal range; potassium >institutional lower limit of normal)• Life expectancy ≥12 weeksEnroll and initiate INCB054828 treatment• Oral once daily dosing: 21-day (2-weeks-on/1-week-off) cycleStart response assessment after cycle 2• Stable disease/partial or complete response → continue treatment with restaging after cycle 4; imaging assessments increase to every 3 cycles after cycle 4• Disease progression → discontinue treatment; safety and survival follow-up Citation Format: Mitesh J. Borad, S. Lindsey Davis, Maeve A. Lowery, Ekaterine Asatiani, Christine F. Lihou, Huiling Zhen, Ghassan K. Abou-Alfa. Phase 2, open-label, multicenter study of the efficacy and safety of INCB054828 in patients (pts) with advanced, metastatic, or surgically unresectable cholangiocarcinoma (CCA) with inadequate response to prior therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT063. doi:10.1158/1538-7445.AM2017-CT063

AbstractBackgroundColonic pseudo‐obstruction (CPO) is characterized by colonic distention in the absence of mechanical obstruction or toxic megacolon. Concomitant secretory diarrhea (SD) with hypokalemia (SD‐CPO) due to gastrointestinal (GI) loss requires further characterization.AimTo perform a systematic review of SD‐CPO, report a case study, and compare SD‐CPO with classical CPO (C‐CPO).MethodsWe performed a search of MEDLINE, EMBASE, Cochrane, and Scopus for reports based on a priori criteria for CPO, SD and GI loss of potassium. An additional case at Mayo Clinic was included.ResultsNine publications met inclusion criteria, with a total of 14 cases. Six studies had high, three moderate, and our case high methodological quality. Median age was 74 years (66‐97), with 2:1 male/female ratio. Kidney disease was present in 6/14 patients. Diarrhea was described as profuse, watery, or viscous in 10 patients. Median serum, stool, and urine potassium concentrations (mmol/L) were 2.4 (range: 1.9‐3.1), 137 (100‐180), and 17 (8‐40), respectively. Maximal diameter of colon and cecum (median) were 10.2 cm and 10.5 cm, respectively. Conservative therapy alone was effective in five out of 14 patients. Median potassium supplementation was 124 mEq/d (40‐300). Colonic decompression was effective in three out of six patients; one had a total colectomy; three out of 14 had died. The main differences between SD‐CPO and C‐CPO were lower responses to treatments: conservative measures (35.7% vs 73.6%, P=.01), neostigmine (17% vs 89.2%, P<.001), and colonic decompression (50% vs 82.4%, P=.02).ConclusionSD‐CPO is a rare phenotype associated with increased fecal potassium and is more difficult to treat than C‐CPO.

432 Background: In clinical trials and clinical practice, tumor response assessment with computed tomography (CT) defines critical end points in patients with metastatic disease treated with systemic agents. Methods to reduce errors and improve efficiency in tumor response assessment could improve patient care. Methods: Eleven readers from 10 different institutions independently categorized tumor response according to three different therapeutic response criteria using paired baseline and initial post-therapy CT studies from 20 randomly selected patients with metastatic renal cell carcinoma treated with sunitinib as part of a completed phase III multi-institutional study. Images were evaluated with a manual tumor response evaluation method (standard-of-care) and with computer-assisted response evaluation (CARE) that included stepwise guidance, interactive error-identification and correction methods, automated tumor metric extraction, calculations, response categorization, and data/image archival. A cross-over design, patient randomization, and two-week washout period were used to reduce recall bias. Comparative effectiveness metrics included error rate and mean patient evaluation time. Results: The standard-of-care method was on average associated with one or more errors in 30.5% (6.1/20) of patients while CARE had a 0.0% (0.0/20) error rate (p<0.001). The most common errors were related to data transfer and arithmetic calculation. In patients with errors, the median number of error types was 1 (range 1-3). Mean patient evaluation time with CARE was twice as fast as the standard-of-care method (6.4 vs. 13.1 minutes, p<0.001). Conclusions: Computer-assisted tumor response evaluation reduced errors and time of evaluation, indicating better overall effectiveness than manual tumor response evaluation methods that are the current standard-of-care.

AbstractObjectivesWe performed a systematic review and meta‐regression analysis of randomized control trials to investigate the association between response to initial treatment and survival outcomes in patients with newly diagnosed multiple myeloma (MM).MethodsResponse outcomes included complete response (CR) and the combined outcome of CR or very good partial response (VGPR), while survival outcomes were overall survival (OS) and progression‐free survival (PFS). We used random‐effect meta‐regression models and conducted sensitivity analyses based on definition of CR and study quality.ResultsSeventy‐two trials were included in the systematic review, 63 of which contributed data in meta‐regression analyses. There was no association between OS and CR in patients without autologous stem cell transplant (ASCT) (regression coefficient: .02, 95% confidence interval [CI] −0.06, 0.10), in patients undergoing ASCT (−.11, 95% CI −0.44, 0.22) and in trials comparing ASCT with non‐ASCT patients (.04, 95% CI −0.29, 0.38). Similarly, OS did not correlate with the combined metric of CR or VGPR, and no association was evident between response outcomes and PFS. Sensitivity analyses yielded similar results.ConclusionsThis meta‐regression analysis suggests that there is no association between conventional response outcomes and survival in patients with newly diagnosed MM.

Abstract Renal fibrosis is the common pathological hallmark of progressive chronic kidney disease ( CKD ) with diverse aetiologies. Recent researches have highlighted the critical role of hypoxia during the development of renal fibrosis as a final common pathway in end‐stage kidney disease ( ESKD ), which joints the scientist's attention recently to exploit the molecular mechanism underlying hypoxia‐induced renal fibrogenesis. The scaring formation is a multilayered cellular response and involves the regulation of multiple hypoxia‐inducible signalling pathways and complex interactive networks. Therefore, this review will focus on the signalling pathways involved in hypoxia‐induced pathogenesis of interstitial fibrosis, including pathways mediated by HIF , TGF ‐β, Notch, PKC / ERK , PI 3K/Akt, NF ‐κB, Ang II / ROS and micro RNA s. Roles of molecules such as IL ‐6, IL ‐18, KIM ‐1 and ADO are also reviewed. A comprehensive understanding of the roles that these hypoxia‐responsive signalling pathways and molecules play in the context of renal fibrosis will provide a foundation towards revealing the underlying mechanisms of progression of CKD and identifying novel therapeutic targets. In the future, promising new effective therapy against hypoxic effects may be successfully translated into the clinic to alleviate renal fibrosis and inhibit the progression of CKD .