Dueck, Amylou C.

Background There is currently a lack of consensus on how health-related quality of life and other patient-reported outcome measures in cancer randomized clinical trials are analyzed and interpreted. This makes it difficult to compare results across randomized controlled trials (RCTs) synthesize scientific research, and use that evidence to inform product labeling, clinical guidelines, and health policy. The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data for Cancer Clinical Trials (SISAQOL) Consortium aims to develop guidelines and recommendations to standardize analyses of patient-reported outcome data in cancer RCTs. Methods and Results Members from the SISAQOL Consortium met in January 2017 to discuss relevant issues. Data from systematic reviews of the current state of published research in patient-reported outcomes in cancer RCTs indicated a lack of clear reporting of research hypothesis and analytic strategies, and inconsistency in definitions of terms, including “missing data,”“health-related quality of life,” and “patient-reported outcome.” Based on the meeting proceedings, the Consortium will focus on three key priorities in the coming year: developing a taxonomy of research objectives, identifying appropriate statistical methods to analyze patient-reported outcome data, and determining best practices to evaluate and deal with missing data. Conclusion The quality of the Consortium guidelines and recommendations are informed and enhanced by the broad Consortium membership which includes regulators, patients, clinicians, and academics.

Abstract Introduction. VSV-IFNβ-NIS is an oncolytic vesicular stomatitis virus (VSV; Rhabdovirus family) with rapid replication kinetics and potent antitumor activity. VSV-IFNβ-NIS encodes the human interferon beta (IFNβ) gene as a STING agonist and the human sodium iodide symporter (NIS) as a reporter gene for tracking the pharmacokinetics (PK) of virus replication in infected tumors. VSV replicates selectively in cancer cells and has promising preclinical antitumor activity across a broad spectrum of cancer types. We report here the safety and correlative data from an FIH trial of intravenous (IV) administration of VSV-IFNβ-NIS in patients with stage IV or recurrent endometrial cancer (EC). Methods. There are two ongoing IV FIH trials using VSV-IFN-NIS, in patients with EC (NCT03120624) and one in patients with hematological malignancies (NCT03017820). In EC, it is a classical 3+3 phase I trial, starting at 5x109 TCID50 through 5x1011 TCID50, given as a single IV dose. The primary objective is safety and tolerability; secondary objectives include monitoring the PK of viral replication through SPECT/CT imaging with NIS gene, viremia, virus shedding, preliminary efficacy, changes in the immune profile of peripheral blood leukocytes, and immunohistochemistry for immune cell infiltrates in tumors. Results. Nine patients have received IV VSV-IFNβ-NIS to date; three with EC and six with hematologic malignancies. The highest dose administered to date is 1.7x1010 TCID50 and dose escalation is ongoing. No DLTs have been observed. Patients experienced the expected infusion related AEs including rigors, chills, nausea, fever, hypotension, and hot flashes. Multiple cytokines increased at 4h post infusion of virus, but most returned to baseline levels by 24h. Viremia was detectable in all patients at the end of infusion, and to varying levels at 30 mins, 1, 2, 4, 24, 48h or 72 hours post virus infusion. No persistent viremia was observed. No infectious virus was recovered in buccal swabs or urine and neutralizing anti-VSV antibodies were present by day 29. Extensive immune phenotyping for T cells, NK, MSDC, myeloid cells performed on peripheral blood cells collected at baseline and at day 3, 8, 15 and 29 post virus infusion showed a trend towards increased PD-1 expression on CD8+ cells. Early IHC data suggests an increase in CD3+ and CD8+ cells in tumor biopsies at day 29 and 3 months in patients with EC treated at the first dose level. Elispot assays for shared EC antigens are pending. Conclusions. IV administration of VSV-IFNβ-NIS up to doses of 1.7x1010 is safe and well tolerated. There is evidence of T cell activation with increased PD-1 expression in CD8+ T cells in the peripheral blood and increased in CD3+ and CD8+ cells in tumor biopsies. Updated results for the EC study will be reported. Citation Format: Jamie Bakkum-Gamez, Matthew S. Block, Nanda Packiriswamy, Bethany A. Brunton, Upreti Deepak, Jonathan M. Mitchell, Lukkana Suksanpaisan, Pamela Atherton, Amylou Dueck, Stephen J. Russell, Martha Q. Lacy, Kah-Whye Peng. First in human (FIH) dose escalation studies of intravenous administration of VSV-IFNβ-NIS (Voyager-V1™) in Stage IV or recurrent endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT072.

Abstract Purpose: p95HER2 is a truncated form of HER2 that confers resistance to trastuzumab in vitro, but clinical results have been conflicting to date. Given that p95HER2 levels correlate with total HER2 expression levels, which confer better outcomes, we sought to evaluate the p95HER2/HER2 ratio in the North Central Cancer Treatment Group N0337 and N98-32-52 trials. Experimental Design: The HERmark assay and VeraTag technology (Monogram Biosciences) were used to measure total HER2 and p95HER2 expression levels in 91 patient samples. Results: In the multivariate model, increasing total HER2 level was significantly associated with longer (OS; HR, 0.33; P = 0.002) and decreasing p95HER2 level was significantly associated with longer OS (HR, 4.2; P = 0.01). Total HER2 expression level was significantly associated with longer progression-free survival (PFS) (HR, 0.57; P = 0.04), whereas p95HER2 level was not (HR, 1.7; P = 0.25). However, there was a positive association between p95HER2 and total HER2 expression levels (R2 = 0.48; P < 0.001). Consistent with our hypothesis, the ratio of p95HER2/HER2 was significantly associated with worsening PFS (HR, 1.7; P = 0.04) and OS (HR, 2.8; P = 0.002). Patients with the highest tertile of p95HER2/HER2 values had significantly less favorable PFS (HR, 1.8; P = 0.06) and OS (HR, 2.3; P = 0.02). Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 24(13); 3053–8. ©2018 AACR.

Background/Objectives Behavioral problems in individuals with Alzheimer's disease ( AD ) impose major management challenges. Current prevention strategies are anchored to cognitive outcomes, but behavioral outcomes may provide another, clinically relevant opportunity for preemptive therapy. We sought to determine whether personality changes that predispose to behavioral disorders arise during the transition from preclinical AD to mild cognitive impairment ( MCI ). Design Longitudinal observational cohort study. Setting Academic medical center. Participants Members of an apolipoprotein E ( APOE ) ɛ4 genetically enriched cohort of Maricopa County residents who were neuropsychiatrically healthy at entry (N = 277). Over a mean interval of 7 years, 25 who developed MCI and had the Neuroticism, Extraversion, and Openness Personality Inventory—Revised ( NEO ‐ PI ‐R) before and during the MCI transition epoch were compared with 252 nontransitioners also with serial NEO ‐ PI ‐R administrations. Intervention Longitudinal administration of the NEO ‐ PI ‐R and neuropsychological test battery. Measurements Change in NEO ‐ PI ‐R factor scores (neuroticism, extraversion, openness, agreeableness, conscientiousness) from entry to the epoch of MCI diagnosis or an equivalent follow‐up duration in nontransitioners. Results NEO ‐ PI ‐R neuroticism T‐scores increased significantly more in MCI transitioners than in nontransitioners (mean 2.9, 95% confidence interval ( CI ) = 0.9–4.9 vs 0, 95% CI = −0.7–0.7, P = .02), and openness decreased more in MCI transitioners than in nontransitioners (−4.8, 95% CI = −7.3 to −2.4 vs −1.0, 95% CI = −1.6 to −0.4, P < .001). Concurrent subclinical but statistically significant changes in behavioral scores worsened more in MCI transitioners than nontransitioners for measures of depression, somatization, irritability, anxiety, and aggressive attitude. Conclusion Personality and subclinical behavioral changes begin during the transition from preclinical AD to incident MCI and qualitatively resemble the clinically manifest behavioral disorders that subsequently arise in individuals with frank dementia.