Citations

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 Objectives: To investigate the antitumor potential of the widely used anticholesterol drug Atorvastatin (ATV) alone, in combination with Carboplatin (CBPT) and with the glycolytic inhibitor PFK158 (PFKi) in ovarian cancer (OC). Methods: MTT assay and the Chou-Talalay methodology were used to test anticancer activity in vitro; half maximal inhibitory concentration (IC50) and combination index (CI) were calculated. Cellular changes were studied with transmission electron microscopy (TEM). ATV was combined with PFKi as we previously showed that PFKi, in addition to glycolysis, inhibits lipid metabolism by targeting PLA2G3. PLA2G3 expression was studied by western blot given that downregulation in OVCAR8 using two shRNAs (sh33, sh35) induced autophagy, a prodeath condition in OC, and was associated with chemosensitization compared to nontargeted controls (NTC) (unpublished data). A random sample of 10 patient-derived OC xenografts (PDX) was studied by TEM. Results: OVCAR8 exhibited a dose dependent proliferation inhibition when treated with ATV (IC50 8μM). PFKi and CBPT IC50 were 4μM and 78μM. PFKi treatment combined with 4μM and 8μM of ATV resulted in ATV sensitizing cells to PFKi by shifting PFKi IC50 down to 2.7μM and 0.4μM, respectively. When ATV was combined in constant ratio with CBPT, CIs were >1.1 indicating antagonism. Combination of ATV 4μM with PFKi 2μM resulted in greater decrease in PLA2G3 and p62 and greater increase in cleaved PARP compared to PFKi alone suggesting higher levels of autophagy and apoptosis. ATV and combination treatment resulted in increased caveolin-1 levels, previously shown to be associated with apoptotic cell death. TEM analysis of ATV and PFKi treated cells showed greater number of lipid rich multilamellar bodies (MLB) compared to controls. PLA2G3 knockdowns exhibited higher MBL formation, lower p62, and when treated with statin and with PFKi, cleaved PARP was significantly higher compared to NTCs. TEM showed that PDXs clustered in low and high MLB groups suggesting a distinct novel phenotype. Conclusions: ATV could enhance PFKi antitumor activity by jointly targeting PLA2G3 leading to metabolic reprogramming of OC. Importantly, ATV antagonized CBPT. Additional studies are in progress to explore the mechanistic pathway of ATV and characterize the significance of MLB in OC as a prodeath phenotype and biomarker of response. Citation Format: Eleftheria Kalogera, Debarshi Roy, Jamie N. Bakkum-Gamez, William A. Cliby, Sean C. Dowdy, Viji Shridhar. Atorvastatin antagonizes carboplatin, synergizes with the glycolytic inhibitor PFK-158, and induces lipid laden multilamellar bodies in ovarian 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 5821.

Abstract Background: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries and the incidence and mortality of EC continue to rise in the US. When detected early, EC is highly curable, suggesting that early detection strategies could reduce EC mortality. Women who develop EC often have a prolonged history of abnormal bleeding, offering a window for identifying many at-risk women prior to the development of advanced cancer. To evaluate risk prediction, novel sampling and early detection strategies in women at increased risk of EC, we established a prospective cohort of women with abnormal bleeding that is followed for endometrial hyperplasia and cancer endpoints. Methods: We consecutively enrolled women ≥45 years old presenting to the Mayo Clinic for evaluation of abnormal uterine bleeding (AUB), postmenopausal bleeding (PMB), thickened endometrial stripe (ES) on imaging, or Lynch Syndrome (LS). From all women, an intravaginal tampon and an endometrial brushing via Tao brush were collected before endometrial biopsy. Epidemiological EC risk factor data, clinical data, and endometrial biopsy histology results were abstracted from medical records. Absolute risk of endometrial hyperplasia and EC were calculated overall and in strata based on clinical symptoms and risk factors. Results: Among the first 1,000 women enrolled into the study, 712 (71%) were overweight or obese, 534 (53%) were postmenopausal, and 214 (22%) were current hormone replacement therapy (HRT) users. Endometrial biopsy and, if indicated, subsequent hysterectomy, detected 39 ECs, 16 atypical hyperplasias, and 28 hyperplasias without atypia at baseline evaluation. Among 534 postmenopausal women, 453 (85%) reported any type of bleeding, with spotting (39%) and light bleeding (27%) being more common than heavy bleeding (14%). Among perimenopausal women with AUB (n=452), the absolute risk of EC at baseline was 0.9% and among women with PMB, the absolute risk of EC at baseline was 7.5%. Among women with PMB, EC risk was modified by HRT use (risk of 2.6% in women on HRT and 8.2% in women not on HRT, respectively), obesity (risk of 5.3%, 8.1% and 9.5% for women with normal, overweight, and obese BMI, respectively), and type of bleeding (risk of 9.7%, 4.9%, and 8.2% in women with spotting, light or heavy bleeding, respectively). Discussion: While risk of endometrial cancer in perimenopausal women with AUB is low, approximately 8% of women presenting for clinical work up of PMB have underlying EC. Clinical presentation and risk factors modify the absolute risk of EC and may inform clinical management. Additional recruitment and prospective follow-up is underway to improve estimates of short- and long-term EC risk in women with PMB. With its collection of tampon and Tao brush samples, the study will provide a unique resource to evaluate molecular markers of EC and EC risk in elevated-risk women. Citation Format: Nicolas A. Wentzensen, Megan Clarke, Viji Shridhar, Maureen Lemens, Matthew Hopkins, Lisa Ahlberg, Shannon Laughlin-Tommaso, Karl Podratz, Mark Sherman, Jamie Bakkum-Gamez. A prospective study of endometrial cancer detection in women presenting for evaluation of abnormal peri- and postmenopausal bleeding [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 2203.

PurposeDespite the intra- and intertumoral heterogeneity seen in glioblastoma multiforme (GBM), there is little definitive data on the underlying cause of the differences in patient survivals. Serial imaging assessment of tumor growth allows quantification of tumor growth kinetics (TGK) measured in terms of changes in the velocity of radial expansion seen on imaging. Because a systematic study of this entire TGK phenotype—growth before treatment and during each treatment to recurrence —has never been coordinately studied in GBMs, we sought to identify whether patients cluster into discrete groups on the basis of their TGK.Patients and MethodsFrom our multi-institutional database, we identified 48 patients who underwent maximally safe resection followed by radiotherapy with imaging follow-up through the time of recurrence. The patients were then clustered into two groups through a k-means algorithm taking as input only the TGK before and during treatment.ResultsThere was a significant survival difference between the clusters ( P = .003). Paradoxically, patients among the long-lived cluster had significantly larger tumors at diagnosis ( P = .027) and faster growth before treatment ( P = .003) but demonstrated a better response to adjuvant chemotherapy ( P = .048). A predictive model was built to identify which cluster patients would likely fall into on the basis of information that would be available to clinicians immediately after radiotherapy (accuracy, 90.3%).ConclusionDichotomizing the heterogeneity of GBMs into two populations—one faster growing yet more responsive with increased survival and one slower growing yet less responsive with shorter survival—suggests that many patients who receive standard-of-care treatments may get better benefit from select alternative treatments.

Abstract Background: Pathological complete response (pCR) is accepted by FDA as a surrogate endpoint for accelerated approval of targeted agents in combination with chemotherapy based on better long-term outcomes compared to residual disease (Cortazar 2014). Methods: The multi-center, adaptively-randomized I-SPY2 platform trial uses pCR as the primary endpoint to identify investigational agents that will improve outcomes in women with stage 2/3 breast cancer with high risk of early recurrence, across all signatures, based on hormone receptor (HR), HER2, and 70-gene (MammaPrint) status. For patients with HR+ HER2- tumors, only 70-gene (Mammaprint) high-risk patients are enrolled. To date, 1200+ patients have been randomized to one of 14 arms: control (paclitaxel followed by AC); veliparib/carboplatin; neratinib; MK2206; trebananib; trastuzumab/pertuzumab; ado-trastuzumab emtansine/pertuzumab; pembrolizumabx4; ganitumab/metformin; ganetespib; PLX-3397. 7 agents graduated in at least one signature (> 85% probability of success in a 300-patient phase III confirmatory trial); 2 did not graduate; 1 stopped for toxicity, and 3 are enrolling (patritumab/trastuzumab, talazoparib/irinotecan, pembrolizumabx8). Local pathologists were centrally trained using the Residual Cancer Burden (RCB) assessment to ensure uniform evaluation and response classification; RCB 0 = pCR. Results: We evaluated the relationship between pCR and event free (EFS) and distant disease free survival (DDFS) in the first 522 pts (median follow-up:2.5 years). 180 pts achieved pCR (36%) while 338 did not (RCB=1-3). There were 82 EFS and 65 DRFS events. Over the entire group (including all arms), pCR was highly associated with 3-year EFS (p<0.001 for both). Pts achieving pCR had a 3% recurrence risk (RR) at 3 years; those with non-pCR had 24% RR over this time period. For distant recurrence, the 3-year RR with pCR was 2%, compared to 20% in pts with non-pCR. As expected, pCR rates varied by breast cancer subtype (HR+/HER2: 18% (35/196), HR+/HER2+: 40% (33/82), HR-/HER2+:68% (34/50), HR-/HER2-:41% (76/188)). The relationship between pCR and EFS was significant and clinically impactful within each subtype. 3-year survival (pCR group)Hazard Ratio OverallOverallHR+/HER2-HER2+TNBCEFS97%0.08 (0.03-0.23)0.14 (0.02-1.04)0 (NA)0.11 (0.03-0.37)DDFS98%0.08 (0.03-0.26)0.17 (0.01-1.23)0 (NA)0.09 (0.02-0.40) Conclusions: The first long-term efficacy results from the I-SPY2 TRIAL demonstrate that achieving pCR is a very strong surrogate endpoint for improved EFS and DDFS in a high-risk population, across all treatment arms, regardless of subtype. I-SPY2 shows substantially lower estimated EFS hazards for patients achieving pCR, compared to the 5 yr EFS hazard ratio for pCR vs not in Cortazar (hazard ratio 0.49), demonstrating important differences between a metaanalysis compared to a platform trial with uniform high-risk eligibility, standardized pathology assessment, and multiple targeted therapies. Our data support the use of pCR as a primary endpoint for accelerated approval of new drugs if EFS is evaluated in the same population. Based on these findings, the I-SPY2 TRIAL will test whether therapy can be deescalated or escalated for individual patients with the goal of achieving pCR for all. Citation Format: Yee D, DeMichele A, Isaacs C, Symmans F, Yau C, Albain KS, Hylton NM, Forero-Torres A, van't Veer LJ, Perlmutter J, Rugo HS, Melisko M, Chen Y-Y, Balassanian R, Krings G, Datnow B, Hasteh F, Tipps A, Weidner N, Zhang H, Tickman R, Thornton S, Ritter J, Amin K, Klein M, Chen B, Keeney G, Ocal T, Feldman M, Klipfel N, Sattar H, Mueller J, Gwin K, Baker G, Kallakury B, Zeck J, Duan X, Ersahin C, Gamez R, Troxell M, Mansoor A, Grasso LeBeau L, Sams S, Wisell J, Wei S, Harada S, Vinh T, Stamatakos MD, Tawfik O, Fan F, Adams A, Rendi M, Minton S, Magliocco A, Sahoo S, Fang Y, Hirst G, Singhrao R, Asare SM, Wallace AM, Chien AJ, Ellis ED, Han HS, Clark AS, Boughey JC, Elias AD, Nanda R, Korde L, Murthy R, Lang J, Northfelt D, Khan Q, Edmiston KK, Viscusi R, Haley B, Kemmer K, Zelnak A, Berry DA, Esserman LJ. Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-08.

Objective We describe a novel way to calculate estimated blood loss (EBL) using an intraoperative pictographic tool in gynecologic surgery. Methods A pictographic tool to estimate sponge saturation was developed to calculate EBL during surgery. A prospective cohort of women 18 years or older undergoing benign vaginal hysterectomy with planned adnexal surgery at Mayo Clinic were consented for use of the pictographic tool. Demographic, preoperative, intraoperative, and postoperative data were abstracted. Estimated blood loss was compared among surgeons, anesthesia providers, and the pictographic tool and then correlated with change in hemoglobin. Results Eighty-one patients met inclusion with mean age of 45.3 ± 8.7 years. Successful vaginal hysterectomy was achieved in all patients with successful completion of planned adnexectomy in 69 (85.2%). Mean EBL among surgeons, anesthesia providers, and pictographic estimates, respectively, was as follows: 199.4 ± 81.9 mL, 195.5 ± 152.2 mL, and 288.5 ± 186.6 mL, with concordance correlation coefficients for surgeons and anesthesia providers versus pictographic tool of 0.40 (95% confidence interval, 0.29–0.51) and 0.68 (95% confidence interval, 0.57–0.79), respectively. The mean postoperative change in hemoglobin was −1.8 g/dL; there were no postoperative transfusions. Change in hemoglobin was more correlated with blood loss estimates from surgeons ( r = −0.31, P = 0.008) and anesthesia providers ( r = −0.37, P = 0.003) than the pictographic tool ( r = −0.19, P = 0.11). Conclusions Use of a pictographic tool to objectively estimate blood loss demonstrated significant overestimations compared with both anesthesia providers’ and surgeons’ estimates because the pictographic tool was less correlated with postoperative change in hemoglobin than anesthesia provider and surgeon estimates.