bluuebunny/crossref_metadata_2025 huggingface dataset:
Tissue immune response in epithelial ovarian carcinoma.
Authors: Henriksen Jon , Donskov Frede , Waldstrøm Marianne , Hjortkjær Mette , Petersen Christina Braad , Thomsen Caroline Brenner , Jakobsen Anders Kristian Moeller , Steffensen Karina Dahl
Published: May 2019

2625

Background: Epithelial ovarian cancer (EOC) is a highly malignant disease with a fatal outcome for most patients. During recent years immunological mechanisms have proven important in relation to the treatment and prognosis of cancer, but within EOC the knowledge is still sparse. Understanding the importance of immune markers to the prognosis of ovarian cancer is essential for the future treatment of EOC. The aim of the present study was to investigate the prognostic impact of intratumoral PDL-1 expression, T cells, neutrophil granulocytes (NG) and Natural Killer (NK) cells in a population based cohort. Methods: All patients diagnosed with ovarian cancer in Denmark in 2005 were included in the study. Immunohistochemical staining was performed on tumor tissue from 412 patients. Antibodies for PD-L1, T cells (CD8), NG (CD66b), and NK cells (CD57) were used. Cell densities were analyzed using a digital image analysis method. The primary endpoint was overall survival (OS). Results: In high grade serous carcinoma (HGSC) the median OS in patients with a high level of tumor infiltrating T cells was 37 vs 25 months in patients with a low level(p = 0.0008). Multivariate analysis showed a hazard ratio (HR) of 0.72 (p = 0.020). The median OS in patients with a high level of tumor infiltrating NK cells was 45 vs 29 months in patients with a low level (p = 0.0310). Multivariate analysis showed a HR of 0.67 (p = 0.041). PD-L1 and NG had no statistically significant impact on OS. Only T cells showed prognostic significance across histological subtypes with a HR of 0.72 (p = 0.007) in favor of a high density of T cells. Conclusions: The present population based study demonstrated prognostic importance of tumor infiltrating T cells and NK cells in HGSC. Neither PD-L1 nor NG held prognostic significance.
The consensus Immunoscore adapted to biopsies in patients with locally advanced rectal cancer: Potential clinical significance for a “Watch and Wait” strategy.
Authors: El Sissy Carine , Kirilovsky Amos , Van Den Eynde Marc , Romero Alfredo , Marliot Florence , Lagorce Christine , Bibeau Frédéric , Iseas Ilma Soledad , Roca Enrique Luis , Vaccaro Carlos Alberto , Tougeron David , Carvalho Carlos Torres , Figueiredo Nuno , Perez Rodrigo O , Habr Gama Angelita , Scripcariu Viorel , Gerard Jean-Pierre , Galon Jerome , Zeitoun Guy , Pages Franck
Published: May 2019

2628

Background: We investigated whether an adaptation to rectal biopsies of the recently validated consensus Immunoscore, could predict the response to neoadjuvant treatment and delineate clinical responders that could benefit from a “Watch and Wait” (W&W) strategy with acceptable outcomes. Methods: Initial biopsies from 273 patients with locally advanced rectal cancer (LARC) treated by neoadjuvant chemoradiotherapy (nCRT) followed by Total Mesorectal Excision (TME), were immunostained for CD3+ and cytotoxic CD8+ T cells and quantified by digital pathology to determine the Immunoscore within pre-treatment Biopsy (ISB). Expression level of 44 immune related genes post-neoadjuvant treatment was investigated by Nanostring technology (n = 64 patients). Results were correlated with response to neoadjuvant treatment, disease free survival (DFS) and time to recurrence (TTR). Prognostic performance of ISB was finally assessed in 73 LARC treated by W&W strategy. Results: ISB Low, Intermediate and High were respectively observed in 23.3, 50.4 and 26.3 % of the cohort. ISB was positively and significantly correlated with the response to nCRT, as evaluated by Dworak classification (P = .0034), ypTNM (P = .0003), down-staging (P = .0014), and neoadjuvant rectal (NAR) score, (P < .0001). ISB status was also positively associated with the degree of local immune activation post-neoadjuvant treatment. ISB High patients were at low risk of relapse, with 5-year DFS rates of 81.1 % (CI, 71.3-92.1 %) as compared to 57.8 % (CI, 45.9-72.9 %) in ISB low patients. In multivariate analysis, ISB was the only significant parameter at presentation associated with DFS (High vs Low: P = .001). Among W&W patients, significant difference was observed for TTR according to ISB status (High vs Low: P = .025). Conclusions: ISB could provide a reliable estimate of the response to nCRT and risk of recurrence in LARC patients' treated by TME or W&W strategy.
A multiplex immunofluorescence assay to assess immune checkpoint inhibitor-targeted CD8 activation and tumor colocalization in FFPE tissues.
Authors: Navas Tony , Fino Kristin , Fung King Leung , Cutuli Facundo , Kinders Robert J. , Sharma Aditi , O'Sullivan-Coyne Geraldine , Chen Alice P. , Hecht Toby Tucker , Doroshow James H. , Parchment Ralph E.
Published: May 2019

2629

Background: Immune checkpoint inhibitors promote antitumor immune responses by enhancing T-cell activity. Measuring the pharmacodynamic effects of these drugs is challenging, as it requires assessing both immune cell and cancer cell populations. To evaluate T cell activation in tumor tissue from patient biopsies, we developed a robust multiplexed immunofluorescence assay. Methods: Our assay uses novel oligo-conjugated antibodies (Ultivue) for simultaneous quantitation of TCR activation (phospho-CD3zeta), immune checkpoint signaling via PD-1 (p-SHP1/p-SHP2), and the net stimulation/inhibition resulting from the integration of these two pathways in CD8 cells (p-ZAP70), while also providing the proximity of CD8 cells to tumor tissues, identified by β-catenin. The method was clinically validated using custom tissue microarrays (TMA) containing tumor biopsies of 3 different histologies (CRC, NSCLC, and breast). Results: From a total of 192 tumor core biopsies, 20/64 NSCLC, 9/64 CRC, and 3/65 breast TMA cores were found to have a significant number of CD8+ tumor infiltrating lymphocytes (TILs) at baseline ( > 50 cells in the examined section). In 18 of the 20 NSCLC cores, ≥50% of CD8 cells both inside and outside of the tumor were activated (CD3z-pY142+). In 6/9 CRC cores, ≥50% of CD8+ cells inside tumor tissues were activated, and in 4/9 CRC cores, ≥50% of CD8+ cells in stroma were activated. In 2/3 breast tumor cores, 90% of CD8+ cells inside tumor tissues were activated; in the remaining core, 90% of CD8+ cells in stroma were activated. Interestingly, all 192 cores had minimal to no expression of activated Zap70 (pY493) in CD8+ cells. Conclusions: Depending on tumor histology, baseline biopsy samples may contain variable numbers of activated CD8+ TILs (CD3z-pY142+), which may reside inside or outside of tumor regions and express very low levels of Zap70-pY493. Anti-PD-1 therapy is predicted to enhance T-cell cytotoxic activity, as demonstrated by an increased number of TILs and elevated Zap70-pY493 expression. This assay is being used for pharmacodynamic evaluations in ongoing immunotherapy clinical trials. Funded by NCI Contract No HHSN261200800001E.
Tumor mutational burden (TMB) and PD-L1 expression as predictors of response to immunotherapy (IO) in NSCLC.
Authors: Castellanos Emily , Snider Jeremy , Ali Siraj Mahamed , Backenroth Daniel , Albacker Lee A. , Murugesan Karthikeyan , Li Gerald , Frampton Garrett M. , Alexander Brian Michael , Carson Kenneth Robert
Published: May 2019

2630

Background: PD-L1 expression and TMB, as a proxy for neoantigen burden, have been correlated with response to IO in advanced NSCLC (aNSCLC) clinical trials, but their combined utility is unclear. We assessed TMB and PD-L1 as predictors of response in aNSCLC patients (pts) after IO monotherapy in a real-world setting. Methods: Pts had a diagnosis of aNSCLC, comprehensive genomic profiling of 186-315 genes/1.1 megabase (Mb), PD-L1 testing of pre-IO specimens, and were treated in the Flatiron Health network (1/2011 - 6/2018). Clinical characteristics and real-world tumor response (rwTR) were obtained via technology-enabled abstraction of clinician notes and radiology/pathology reports, and linked to genomic data in the Flatiron Health-Foundation Medicine Clinico-Genomic Database. A general additive model examined the predictive value of TMB (as continuous measure) and PD-L1 level on rwTR. A reduced PD-L1-only model was compared to the full model using Akaike Information Criterion (AIC). rwTR predictions at representative TMB and PD-L1 levels were calculated. Results: Of 426 pts, PD-L1 expression was high (≥50%) in 140, low (1-49%) in 123, and negative (<1%) in 163. Median TMB was 9.6 mut/Mb (IQR 4.4 - 14.8) overall, 11.3 in responders and 8.7 in non-responders. TMB did not correlate with PD-L1 level (Kruskal-Wallis p=0.29). The TMB + PD-L1 model had superior prediction of rwTR than the PD-L1 model, as assessed by lower AIC score. In the combined model, higher TMB and PD-L1 levels were each associated with higher rwTR likelihood (Table). Predicted rwTR probability, % (95% CI), by TMB and PD-L1 in line 1. Conclusions: TMB and PD-L1 expression are independent markers that, when combined, have increased predictive power for response to IO. High TMB + low/neg PD-L1 behaved similarly to low TMB + high PD-L1, and high TMB + high PD-L1 predicted the highest rwTR. Investigation of these biomarkers as complementary predictors of progression and overall survival is ongoing.[Table: see text]
Survival by stage and tumor measurability in metastatic melanoma patients treated with autologous dendritic cell tumor cell vaccines.
Authors: Dillman Robert O. , Cornforth Andrew N , McClay Edward Francis , DePriest Carol
Published: May 2019

2637

Background: Survival of cancer patients is greatly affected by stage and tumor burden. The purpose of this study was to determine survival for melanoma patients who were treated with patient specific vaccines in the context of prospective clinical trials, by cohorts defined by stage and tumor measurability. Methods: Metastatic melanoma patients were treated with autologous dendritic cells loaded with antigens from irradiated cells from short-term autologous tumor cell lines (DCV). All patients had a metastatic melanoma lesion surgically resected, from which a tumor cell line was established. Irradiated tumor cells (ITC) were incubated with autologous dendritic cells (DC) to produce the DCV, which were injected s.c. in 500 micrograms GM-CSF weekly x 3 weeks, then monthly for 5 months. Data was pooled for DCV-treated patients enrolled in either of two phase II trials: one single-arm (NCT00948480), one randomized (NCT00436930). Patients were assigned to one of three cohorts based on their most advanced stage of disease prior to treatment, and whether they had measurable disease at the time of treatment. Survival was determined per Kaplan and Meier. Results: The final therapeutic products consisted of autologous DC with non-phagocytosed ITC making up 0% to 20% of cells in the final product. There were 45 men and 27 women. Median age was 52 years (range 17 to 83). Tumor sources were 37-lymph node, 20-viscera, and 15-soft tissue. No patients were lost to follow up; all surviving patients were followed 5 years. Toxicity was minimal. Median overall survival (OS) for all 72 patients was 49.4 mos; 5-year OS 46%. There was no correlation between survival and the number of DC or ITC in the first three injections. Patients with recurrent stage 3 disease that had not recurred (n=18) had a 72% 5-year OS; patients with non-measurable stage 4 (n=30) had a 53% 5-year OS. Patients with measurable stage 4 (n=18) had received an average of four prior therapies. They had a median OS of 18.5 months, and 2-year OS of 46%. Conclusions: This patient-specific DCV was associated with encouraging survival in all three clinical subsets. Because of its mechanism of action and absence of toxicity, it should be evaluated further. Clinical trial information: NCT00948480, NCT00436930.
Preliminary results of a phase I clinical trial using an autologous dendritic cell cancer vaccine targeting HER2 in patients with metastatic cancer or operated high-risk bladder cancer (NCT01730118).
Authors: Maeng Hoyoung M. , Wood Lauren Virginia , Moore Brittni , Bagheri Mohammadhadi H. , Webb Santhana , England Lee , Martinez Giselle , Steinberg Seth M. , Pack Svetlana , Stroncek David , Morris John Charles , Terabe Masaki , Berzofsky Jay A.
Published: May 2019

2639

Background: We developed a HER2 targeting autologous dendritic cell (DC) vaccine transduced with an adenovirus expressing the extracellular and transmembrane domains of HER2 (AdHER2). In mice, the homologous vaccine cured virtually all mice with established or metastatic tumors. Protection was dependent on antibodies against HER2 that inhibited phosphorylation, but was ADCC independent. We translated these findings into a clinical trial. Methods: This is an open-label, phase I study in patients with 1) metastatic cancer that progressed after ≥ 1 standard therapies, or 2) history of high risk bladder cancer with definitive treatment, whose tumor is HER2 immunohistochemistry (IHC) score ≥ 1+ or FISH HER2/CEP17 ratio ≥ 1.8. Part 1 of the study enrolled patients naïve to HER2-directed therapies and Part 2 enrolled patients who progressed with ≥ 1 anti-HER2 therapy. Results: In Part 1, the lowest dose level (5E+6 viable DCs, N=7, 2 inevaluable) showed no benefit. At the second and third dose level (10E+6 and 20E+6; N=7 and N=4; 0 and 1 inevaluable in each), 1 CR (ovarian), 1 PR (stomach), and 3 SD (1 ovarian carcinosarcoma and 2 colon) were observed. Two bladder cancer patients who received vaccine as an adjuvant did not recur for +24 and +36 month each. In Part 2 (N=6, 2 inevaluable), 1 male breast cancer patient showed SD. Response assessed by Modified Immune Related Response Criteria is summarized in the Table. Injection-site reactions occurred in all patients and were self-limited. Echo, EKG and troponin follow up to 2 years showed no cardiac toxicity. Dose-expansion cohort (40E+6) is enrolling. Conclusions: We have translated a cancer vaccine from mice to a clinical trial. Preliminary results of a phase I trial of an autologous AdHER2 DC vaccine show potential clinical benefit in select patients with HER2 expressing tumors with no cardiac toxicity. Clinical trial information: NCT01730118. [Table: see text]
A phase I study (E011-MEL) of a TriMix-based mRNA immunotherapy (ECI-006) in resected melanoma patients: Analysis of safety and immunogenicity.
Authors: Arance Fernandez ANA Maria , Baurain Jean-Francois , Vulsteke Christof , Rutten Annemie , Soria Ainara , Carrasco Javier , Neyns Bart , De Keersmaecker Brenda , Van Assche Tim , Lindmark Bertil
Published: May 2019

2641

Background: ECI-006 is a combination of TriMix (mRNAs encoding for dendritic cell [DC] activating molecules [CD40L, CD70 and caTLR4]), and mRNAs encoding for melanoma-specific tumor-associated antigens (TAAs): tyrosinase, gp100, MAGE-A3, MAGE-C2, and PRAME. DCs transfected ex vivo with TriMix and TAAs mRNAs showed significant clinical activity in combination with ipilimumab in metastatic melanoma without increasing toxicity. This study aims to assess the safety and immunogenicity of ECI-006 vaccine administered intranodally (i.n.) in an adjuvant setting for patients with resected melanoma. Methods: Twenty patients who underwent resection of stage IIc/III/IV cutaneous melanoma received 5 administrations of ECI-006 (either 600 µg or 1800 µg [n = 10, each]) injected i.n. on Day 1 and after 2, 4, 6 and 14 weeks. Treatment-emergent adverse events (TEAEs) were graded using CTCAE version 4.0.3. Blood samples for immune monitoring (ELISPOT and intracellular cytokine staining [ICS]) were collected pre-dose and at weeks 4, 7, 14 and 15. Results: Nineteen patients completed the treatment. One patient in the low dose group discontinued the study after 4 doses due to disease relapse. Administration of ECI-006 was well tolerated. No serious adverse events or TEAEs Grade 3 or higher were reported. Of all TEAEs, myalgia and fatigue were the most reported in 3 (15%) and 5 (25%) patients, respectively. ELISPOT and ICS were performed on T cells pre-stimulated in vitro for 10-12 days, using a previously in-house validated protocol. Vaccine-induced immune responses according to predefined criteria were detected in 4/10 and 3/9 patients treated with the low and high dose, respectively. Samples from these patients are currently being subjected to T-cell receptor repertoire analysis. Conclusions: Among patients undergoing resection of stage IIc/III/IV melanoma, i.n. administration of ECI-006 at 600 or 1800 µg was generally well tolerated. ECI-006 demonstrated to be immunogenic in a proportion of patients. These results warrant further development of ECI-006 in combination with anti-PD-1 therapy in melanoma patients. Clinical trial information: NCT03394937.
A phase I study of mirvetuximab soravtansine (IMGN853) and gemcitabine (G) in patients with FOLR1-positive recurrent epithelial ovarian (EOC), endometrial cancer (EC), or triple-negative breast cancer (TNBC).
Authors: Cristea Mihaela C. , Frankel Paul Henry , Synold Timothy W. , Mortimer Joanne E. , Stewart Daphne B. , Wang Edward Wenge , Jung Alex , Wilczynski Sharon P. , Konecny Gottfried E. , Parungao Dia , Eng Melissa , Kilpatrick Lindsay , Chen Yi-Jen , Glaser Scott , Han Ernest Soyoung , Dellinger Thanh Hue , Hakim Amy , Lee Stephen , Morgan Robert , Wakabayashi Mark Tsuneo
Published: May 2019

3009

Background: IMGN853 is an antibody-drug conjugate targeting the folate receptor alpha (FOLR1), linked to maytansinoid, DM4. IMGN853 has promising single agent activity in FOLR1+ EOC. The recommended phase 2 dose (RP2D) is 6 mg/kg, based on adjusted ideal body weight (AIBW) IV every 3 wks. This study evaluates IMGN853 and G. Methods: Patients (pts) with FOLR1+ tumors including: platinum resistant EOC with ≤4 prior chemotherapy (CT) regimens, EC with ≤2 CT and TNBC ≤4 CT are eligible. FOLR1 + is defined as ≥25% of tumor staining (all tumors) ≥2+ intensity (EOC, EC) and ≥1+ (TNBC). A standard 3+3 design combines IMGN853 and G. EOC pts undergo one research biopsy to assess intratumoral vs. circulating DM4 level and biopsy vs. archival tissue FOLR1 expression. Dose-limiting toxicity (DLT) is assessed during cycle 1. Responses as per RECIST 1.1 are assessed at 12 wks. and adverse events (AEs) are evaluated by CTCAE v4.0. Results: From 10/2017 to 1/2019 a total of 15 pts. were treated (3 additional pts have consented on dose level [DL] 4):10 EOC, 3 EC and 2 TNBC. One pt. on DL1 had grade (G) 4 thrombocytopenia (PLT) DLT. Three pts were inevaluable for DLT and were replaced: 1 pt. at DL1 with G4 neutropenia without fever of unknown duration due to delayed follow up blood work, 1 pt. at DL2 and 1 pt. at DL3 due to incomplete cycle 1. No DLTs were observed on DL2-3. Day 8 cycle 1 dose modifications were required in 3 of 4 patients on DL3 (for mucositis [1 pt.], and PLT [2 pts]). We are now enrolling at the RP2D for both agents, and MTD will be determined prior to May 2019. Conclusions: IMGN853 in combination with G is achievable at clinically relevant doses and the recommended Phase 2 dose and MTD will be reported. Support: NCCN grant; with support from ImmunoGen Corp and Cancer Center Support Grant P30CA033572. Clinical trial information: NCT02996825. [Table: see text]
Phase 1 dose escalation study of XMT-1536, a novel NaPi2b-targeting antibody-drug conjugate (ADC), in patients (pts) with solid tumors likely to express NaPi2b.
Authors: Tolcher Anthony W. , Ulahannan Susanna Varkey , Papadopoulos Kyriakos P. , Edenfield William Jeffery , Matulonis Ursula A. , Burns Timothy F. , Mosher Rebecca , Fielman Barbara , Hailman Eric , Burris Howard A. , Moore Kathleen N. , Hamilton Erika Paige
Published: May 2019

3010

Background: XMT-1536 is a Dolaflexin ADC targeting the sodium-phosphate cotransporter NaPi2b, expressed in ovarian, non-squamous lung, papillary thyroid, endometrial, papillary renal and salivary duct cancers. Methods: In this ongoing Phase 1 study, pts with solid tumors likely to express NaPi2b, who progressed on standard therapy, are treated with intravenous XMT-1536 using a 3+3 design with a modified Fibonacci escalation. NaPi2b expression by IHC is being examined retrospectively in archived tumors. Primary objectives in dose escalation are safety and tolerability and determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). (ClinicalTrials.gov NCT03319628). Results: As of Jan. 28, 2019, 36 pts (22 ovarian, 7 endometrial, 4 NSCLC, 3 other) have received treatment with XMT-1536. Treatment was initially given every 3 weeks (q3w); 20 pts were treated in dose cohorts from 3 to 40 mg/m2. There was one DLT of reversible AST elevation at 40 mg/m2. The dosing interval was then changed to every 4 weeks (q4w), and dose escalation was restarted at 20 mg/m2. There was one DLT of reversible AST elevation at 30 mg/m2 on the q4w schedule. Further followup and dose escalation are ongoing. The most common (≥10% of patients) treatment-related adverse events (TRAEs) have been nausea, fatigue, headache, increased AST, anorexia, increased alkaline phosphatase, fever, increased GGT, myalgia, and vomiting. Grade 3 TRAEs were reversible AST increases in 3 patients and increased GGT, decreased lymphocytes, and systolic congestive heart failure in 1 patient each. Treatment-related serious AEs of fever and systolic congestive heart failure occurred in 1 patient each. Among patients dosed at 20 mg/m2 or higher who had restaging scans (n=20), there were 2 PR, in ovarian cancer pts at 30 mg/m2 q3w and 20 mg/m2 q4w, and 11 SD, with disease control maintained for up to 24 weeks. Patient-level results for NaPi2b expression will be presented. The systemic exposure of total payload showed approximately dose-proportional increase. Plasma concentration of free drug payload and its active metabolite were low. Conclusions: XMT-1536 has been well-tolerated up to the 30 mg/m2 dose level with early signs of anti-tumor activity. Dose escalation continues in pts with advanced solid tumors likely to express NaPi2b. Clinical trial information: NCT03319628.
Phase 1, first-in-human study of TRAIL receptor agonist fusion protein ABBV-621.
Authors: Ratain Mark J. , Doi Toshihiko , De Jonge Maja J. , LoRusso Patricia , Dunbar Martin , Chiney Manoj , Motwani Monica , Glasgow Jaimee , Petrich Adam Matthew , Rasco Drew W. , Calvo Emiliano
Published: May 2019

3013

Background: ABBV-621 is a potent tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist fusion protein that induces apoptotic cell death, particularly in DR4/5 expressing tumor models. Methods: Patients (pts) with previously treated solid tumors and ECOG 0–2 were administered ABBV-621 (2.5–15 mg/kg IV) on day (D) 1 (dose level [DL] 1) or D1D8 (DL2 and beyond) of each 21-day cycle. Dose escalation (DE) was guided by a Bayesian continual reassessment method. In addition to PK studies, blood-based PD markers of apoptosis (M30, M65) and drug binding were assessed. Results: As of 14 December 2018, 57 pts were enrolled in the DE portion, of which 30% had pancreatic, 23% colorectal cancer, and 47% other tumor types; 13 were KRAS mutant. Median age was 61 yrs. 60% were male; pts had a median of 4 prior regimens (range 1–10). Pts per DL: 2.5 (5 on D1, 16 on D1D8), 3.75 (12), 5 (6), 6.5 (6), 8.5 (4), 11 (4), and 15 mg/kg (4). Median duration of ABBV-621 exposure was 2 cycles (range 1–11). Seven pts had dose-limiting toxicities: respiratory failure (5 mg/kg; Grade 5, the only treatment-related death), blood bilirubin increased (3.75, 6.5 mg/kg), nausea (3.75 mg/kg), fatigue (3.75 mg/kg), increased ALT (2.5, 3.75, 6.5, 15 mg/kg), and increased AST (6.5 mg/kg). Summary of AEs is shown in Table. Clinical trial information: NCT03082209. A partial response (duration 20 weeks) was observed in a pt with pancreatic cancer (2.5 mg/kg D1D8). 27 pts had stable disease (6 pts for > 12 weeks). ABBV-621 PK was linear (mean ± SD clearance was 1.79 mL/h/kg ± 0.44) with a terminal half-life of 36.7 ± 5.55 h (n = 49). ABBV-621 bound to decoy receptors on neutrophils for up to 168 h; the duration of binding was dose-dependent. M30 and M65 increased at 8, 24, and 48 h following ABBV-621, but effect was independent of dose. Conclusions: ABBV-621 shows evidence of antitumor activity and effect on blood-based markers of apoptosis, with acceptable toxicity (MTD not reached). NCT03082209.[Table: see text]
Phase I trial of IACS-010759 (IACS), a potent, selective inhibitor of complex I of the mitochondrial electron transport chain, in patients (pts) with advanced solid tumors.
Authors: Yap Timothy A , Rodon Ahnert Jordi , Piha-Paul Sarina Anne , Fu Siqing , Janku Filip , Karp Daniel D. , Naing Aung , Ileana Dumbrava Ecaterina Elena , Pant Shubham , Subbiah Vivek , Tsimberidou Apostolia Maria , Hong David S. , Rose Kelsey Meagan , Xu Quanyun , Vellano Christopher P. , Mahendra Mikhila , Jones Philip , Di Francesco Maria Emilia , Marszalek Joseph R. , Meric-Bernstam Funda
Published: May 2019

3014

Background: A subset of tumors possess genetic or microenvironmental alterations that render cells dependent on mitochondria oxidative phosphorylation (OXPHOS) for survival. IACS, a potent oral selective inhibitor of mitochondrial complex I, showed robust responses in multiple preclinical tumor models, providing strong rationale for clinical testing. Methods: Pts with advanced cancers received IACS in increasing dose levels (DL) using 3+3 dose escalation. 7-day QD induction of IACS was followed by maintenance weekly (QW) or twice weekly (BIW) dosing. Phamacokinetics (PK), lactate and pH were assessed serially. Paired tumor biopsies were assessed for pharmacodynamic and predictive biomarkers. Results: 18 pts were treated; M/F 16/2; ECOG PS 0/1: 3/15. Mean age 49 (23-69) yrs. Tumors comprised advanced colorectal (n = 4), castration resistant prostate cancer (CRPC) (n = 3), pancreatic (n = 2), other cancers (n = 9). DL1: 2mg QD 7 days induction/0.5mg QW maintenance (n = 3); DL2: 2.5mg QD 7 days/1mg QW (n = 3); DL3: 3mg QD 7 days/3mg QW (n = 3); DL4: 2.5mg QD 7 days/2.5mg BIW (n = 4); DL5: 2mg QD 7 days/2mg BIW (n = 5). IACS was well tolerated with 12 (67%) pts reporting G1-2 IACS related toxicities, such as raised lactate (n = 10), nausea (n = 8), fatigue (n = 7), vomiting (n = 5), myalgia (n = 4) and peripheral neuropathy (n = 4). 1 pt in DL3 and 2 pts in DL4 had ≥G3 IACS related toxicities, such as nausea (n = 2), vomiting (n = 1), raised lactate (n = 1), dehydration (n = 1), visual changes (n = 1), and peripheral neuropathy (n = 1). Raised lactate was not associated with acidosis. DL5 is now being expanded to assess the maximum tolerated dose (MTD). PK showed good oral bioavailability, with long T1/2 and low intrapatient variability. Cmax = 14nM on Day 7 at the end of DL5 induction phase, confirming biologically active doses. 7 pts had best response of RECIST stable disease. A pt with heavily pretreated CRPC achieved RECIST partial response with resolution of CRPC related pain. Conclusions: IACS is well tolerated with preliminary evidence of antitumor activity. MTD expansions include CRPC, TNBC, pancreatic cancer and molecularly selected (ENO1 loss; SMARCA4 mutation) tumor cohorts. Clinical trial information: NCT03291938.
Circulating androgen receptor (AR) gene amplification and resistance to 177Lu-PSMA-617 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of a phase II clinical trial.
Authors: De Giorgi Ugo , Severi Stefano , Sarnelli Anna , Sansovini Maddalena , Monti Manuela , Gurioli Giorgia , Nicolini Silvia , Scarpi Emanuela , Casadei Chiara , Conteduca Vincenza , Matteucci Federica , Di Iorio Valentina , Amadori Dino , Paganelli Giovanni
Published: May 2019

3020

Background: Plasma AR gain is associated with poor prognosis in mCRPC pts treated with abiraterone/enzalutamide, however these pts could benefit from docetaxel (Conteduca et al, Eur Urol 2019). In a phase 2 clinical trial with 177Lu-PSMA-617 in mCRPC pts who progressed after standard survival-prolonging treatments, we aimed to determine if plasma AR gene status enable early assessment of 177Lu-PSMA-617 activity for mCRPC. Methods: Between April 2017 and November 2018, 43 mCRPC pts were treated with 177Lu-PSMA-617 in a phase 2 study. Pts younger than 75 years and not heavily pretreated received 5.5 GBq of 177Lu-PSMA-617, while other pts received 4.2 GBq per cycle, for a total of 4-6 cycles, q8 weeks. We determined AR copy number by droplet digital polymerase chain reaction (ddPCR) on pretreatment plasma samples. We evaluated associations between plasma AR amplification and PSA response (≥50% PSA decline from baseline) and imaging response/progression (as measured by bone scan, CT, and PSMA PET/CT). Logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (95% CI) in order to evaluate the independent relevance of AR status and pts without PSA response and those with early progressive disease defined as treatment interruption occurring within 4 months of the start of 177Lu-PSMA-617. Results: Forty of 43 pts (median age: 72 years, range 54-86) were fully evaluable for this analysis. A PSA response was reported in 15 (37.5%) of the 40 pts, 3 of 15 (20%) with AR gene gain, and 12 of 25 (48%) with no gain (P = 0.080). Early progressive disease was observed in 17 (42.5%) of the 40 pts, 12 of 15 (80%) with AR gene gain and 5 of 25 (20%) with no gain (P = 0.0002). The OR for pts without PSA response (decline < 50%) having AR gain was 3.69, 95% CI 0.83-16.36, p = 0.085. The OR for pts with early PD having AR gain was 16.00, 95% CI 3.23-79.27, p = 0.0007. The evaluation of germline alterations in DNA damage repair (DDR) genes is ongoing (i.e., BRCA2, BRCA1, ATM). Conclusions: Plasma AR status assessment using ddPCR identifies mCRPC resistant to 177Lu-PSMA-617. These data suggest potential better activity of 177Lu-PSMA-617 in earlier phases of prostate cancer. Prospective evaluation of treatment decision making based on plasma AR status is warranted. Clinical trial information: NCT03454750.
Phase 1a study results investigating the safety and preliminary efficacy of ABL001 (NOV1501), a bispecific antibody targeting VEGF and DLL4 in metastatic gastrointestinal (GI) cancer.
Authors: Lee Jeeyun , Kim Seung , Lee Su Jin , Park Se Hoon , Park Joon Oh , Ha Eunsin , Park Doo-Hong , Park Neunggyu , Kim Hoon-Kyo , Lee Sang Hoon , You Weon-Kyoo , Lim Ho Yeong , Park Young Suk , Kang Won Ki
Published: May 2019

3023

Background: Antiangiogenic therapy has been a successful clinical strategy for the treatment of various cancer types. To date, all approved antiangiogenic drugs primarily inhibit the VEGF/VEGFR pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis. A dual blockade of both VEGF and DLL4 could be a promising strategy to overcome anti-VEGF therapy resistance. ABL001 (NOV1501) has been developed as a bispecific antibody to bind and inhibit both DLL4 and VEGF thereby significantly suppressing tumor angiogenesis. Methods: In a classical 3+3 dose-escalation design, ABL001 was administered IV at doses ranging from 0.3, 1, 2.5, 5, and 7.5 mg/kg biweekly (NCT03292783: the next doses of ABL001 are 10 and 12.5 mg/kg). After the first administration of ABL001 in each cohort, DLT (dose limiting toxicity) was observed for 3 weeks. Tumor assessments were performed every 6 weeks and cardiac assessments were performed every cycle. Results: From 2017 November to February 2019, 18 patients were enrolled on this trial. All patients were heavily pre-treated with at least 3 prior lines of chemotherapy. All patients in cohort 4 and 5 were either metastatic colorectal cancer or gastric cancer. Of the 5 cohorts, there was no DLT observed during dose escalation. In addition, there was no maximum tolerated dose identified up to 7.5 mg/kg dose. The most common treatment-related adverse events (AEs) (including all dose levels and all grades) occurred were hypertension, anorexia, general weakness, headache and anemia. Preliminary results of pharmacokinetic (PK) analysis demonstrated slightly shorter mean half-life than conventional monoclonal tantibodies due to the bispecific nature of the ABL-001. In addition, preliminary pharmacodynamic (PD) biomarker analysis using PBMC and plasma samples showed engagement of both VEGF/VEGFR and DLL4/Notch1 pathway modulation after ABL001 administration. One gastric cancer patient at 7.5 mg/kg achieved unconfirmed partial response at the time of this writing. Conclusions: ABL001 therapy has been well tolerated up to 7.5 mg/kg with no significant treatment related adverse events and showed preliminary anti-tumor activity in heavily pre-treated cancer patients. After completion of this ongoing phase 1a study, phase 1b/2a study is planned in combination of ABL001 with chemotherapy or anti-PD-1 antibody. Clinical trial information: 03292783.
PDX validation of a 3D microtumor platform.
Authors: Sampson Ellen , Nikolov Katya , Henderson Paul T. , Apfel Christian , Pan Chong-xian , Zimmermann Maike , Ma Ai-Hong
Published: May 2019

3029

Title: Patient-derived xenograft validation of a 3D microtumor platform Background: Patient-derived xenograft (PDX) mouse models are thought to most closely reflect the biology of a patient’s cancer. Unfortunately, growing sufficient tumor in a PDX model takes several months and more often than not, the tumor fails to grows at all. The SAGE Direct Platform, an in-vitro model, can create hundreds of live microtumors from virtually every patient’s viable biopsy and test a panel of clinically relevant drugs within no more than 1 week. Thus, concordance of results from a PDX model with results of the SAGE Direct Platform would support a rational for the platform to be potentially useful to predict tumor response in cancer patients. Methods: A bladder cancer from a 77 year old female was used to establish a PDX model. Mice were divided into three groups receiving either saline (control), cisplatin, or gemcitabine intraperitoneal on the days 1, 8, and 13, and tumor growth was observed. One tumor sample was used to create 3D microtumors and those were tested using the same drugs. Results: Tumor growth (exceeding 1,000 mm3) was similar after cisplatin compared to control (4.8 vs. 3.7 weeks). After gemcitabine tumors initially shrank and only started growing a couple of weeks after the end of treatment so that 1,000 mm3 was only reached after 10.2 weeks (p<0.001 compared to cisplatin and control). In the SAGE Direct Platform the EC50 of cisplatin was 97.3 µM and thus two orders of magnitudes higher than the EC50 of gemcitabine, which was 0.7 µM. Conclusions: Both the PDX model and the SAGE Direct Platform have shown this bladder cancer to be virtually resistant to cisplatin while very sensitive to gemcitabine. The next steps of these preliminary data could be to repeat this experimental design with other tumors and/or to start an observational cohort study in patients correlating the SAGE Direct Platform results to patient outcomes.
Anticancer activity in patients with advanced ovarian and biliary tract cancers treated with NUC-1031 and a platinum agent.
Authors: Blagden Sarah Patricia , Bré Jennifer , Mullen Peter , Gnanaranjan Chathunissa , Ghazaly Essam Ahmed , McNamara Mairead Geraldine , Valle Juan W.
Published: May 2019

3030

Background: The inhibition of cellular nucleotide metabolism to promote apoptosis is a key principle of cancer therapy. This, in combination with platinum-induced DNA-damage, is key to promoting anti-cancer activity in a variety of tumors, including ovarian, biliary tract, lung, breast and bladder. NUC-1031, a phosphoramidate transformation of gemcitabine is designed to overcome resistance mechanisms that limit the efficacy of this nucleoside analog. NUC-1031 has shown broad clinical activity across multiple solid tumors as both a single agent and in combination with platinum agents. We show potential synergism between NUC-1031 and a platinum agent in advanced ovarian (OC) and biliary tract (BTC) cancers. Methods: PRO-002 was a phase Ib study; 25 patients (pts) with recurrent OC who had exhausted all other therapy options received NUC-1031 + carboplatin. 17 pts were considered platinum resistant (10) or platinum refractory (7). ABC-08 is a phase Ib study, 14 pts with advanced BTC treated in the first-line setting with NUC-1031 + cisplatin. Results: In PRO-002, strong efficacy signals were observed in non-platinum-responsive patients. Of the 17 response-evaluable platinum-resistant or refractory pts, 5 partial responses (PRs) and 11 stable diseases (SDs) were achieved, resulting in an ORR of 29% and a DCR of 94%. NUC-1031 + carboplatin was well-tolerated with no unexpected AEs; DLTs were myelosuppression and fatigue. Encouraging response rates were also observed in ABC-08 compared to historical standard of care (ABC-02). One CR (7%), 6 PRs (43%) and 1 SD (7%) were observed, resulting in an ORR of 50%. NUC-1031 + cisplatin was well-tolerated, with no unexpected AEs or DLTs. Complementary in vitro evidence suggests that the beneficial interaction occurs whereby platinum treatment sensitizes cells to NUC-1031. Conclusions: Increasing evidence suggests that NUC-1031 in combination with a platinum agent may have synergistic properties, leading to enhanced anti-cancer activity. In both OC and BTC, durable tumor shrinkage was observed. This was particularly encouraging in a platinum resistant/refractory OC population. Future studies utilizing both NUC-1031 plus a platinum agent will further elucidate the potential of this therapeutic combination.
Dynamic monitoring of circulating tumor DNA next-generation gene sequencing as a predictive biomarker of response and progression-free survival after pembrolizumab monotherapy in patients with advanced NSCLC.
Authors: Aggarwal Charu , Thompson Jeffrey C. , Chien Austin , Quinn Katie , Lefterova Martina , Nagy Rebecca , Yee Stephanie , Ciunci Christine Agnes , Alley Evan W. , Bauml Joshua , Cohen Roger B. , Langer Corey J. , Carpenter Erica L.
Published: May 2019

3040

Background: Circulating tumor DNA next generation sequencing (ctDNA NGS) is increasingly being used to detect mutations (MT) in patients (pts) with metastatic (m) NSCLC. Limited data exist on the correlation of baseline ctDNA NGS profile and serial ctDNA NGS monitoring to response to immunotherapy. Methods: We conducted a prospective study in pts with mNSCLC receiving pembrolizumab monotherapy. Plasma was collected at weeks 0 (T0), 9 (T1), and 18 (T2). ctDNA NGS was performed using a 73 gene panel. Number of MTs and variant allelic fraction (VAF) were determined at baseline, and serially; change in mean VAF was calculated between T1-T0, and T2-T0. Response rate (RR) was assessed using RECIST 1.1. Correlations were made for pt characteristics, RR, progression free survival (PFS), and overall survival (OS). Results: We analyzed 95 samples from 33 pts, 21 female, median age 69 (range 51-89 years), smokers (n = 29), adenocarcinoma (n = 23), 25 pts enrolled at initial diagnosis, majority had high PD-L1 ≥50% (n = 29, 88%). At T0, 32 pts had detectable MT, median number of MTs was 4 (range 0-21), (non-synonymous MT = 3), most common MT was TP53 (n = 21). Confirmed PR was 27% (n = 9), clinical benefit rate (SD+PR) was 64% (n = 21), and 2 pts were not evaluable for response. Smokers were more likely to have higher number of MT at T0 (4 vs. 1 p = 0.003); there was no correlation with smoking and overall RR (p = 0.17). RR was not related to number of MT at T0, p = 0.37. A decrease in ctDNA VAF was seen in 6/9 pts with PR (mean VAF change range -0.11 to -0.001); 2/5 pts with PD showed an increase in mean VAF while 3 showed decrease. At median follow up of 9.26 months (mos), median PFS and OS were 7.4 and 10.5 mos, respectively. Median PFS was longer for pts with a decrease in ctDNA VAF at both T1-T0 (8.9 vs. 5 mos, p = 0.02) and T2-T0 (9.1 vs. 5.5 mos, p = 0.006). OS and additional biomarker analyses including correlation of response to a 2mb ctDNA plasma-based NGS panel will be reported at the meeting. Conclusions: Our results demonstrate that it is feasible to serially monitor plasma NGS, decline in mean ctDNA VAF correlates with radiographic response and PFS on immunotherapy with pembrolizumab.
NMR-metabolite-resonance signature to predict HR+ breast cancer patient response to CDK4/6 inhibitors.
Authors: Zhang Bo , Warner Jason , Pinto Christopher , Juric Dejan , ODay Elizabeth
Published: May 2019

3043

Background: Advanced ER+ breast cancer patients have reported prolongation of stable disease when treated with a CDK4/6 inhibitor as a monotherapy or in combination with endocrine treatment. However ~20% of patients are intrinsically resistant and all patients eventually acquire resistance to these therapies. There is a critical need to identify biomarkers that accurately predict response and resistance to CDK4/6 inhibitors. ER-positivity, luminal patterns of gene expression, Rb function, overexpression of cyclin D1, cyclin E, CDK6 and low levels of p16 are biomarkers that do not accurately match clinical outcomes. Methods: We performed a retrospective study analyzing plasma-based metabolites from a baseline (pre-dose) and ~2 months post treatment of 21 women with estrogen-receptor-positive (ER+) metastatic breast cancer treated with CDK4/6 inhibitors. Results: By correlating the metabolite expression profiles to clinical outcomes we were able to identify a metabolic signature that could differentiate the CDK4/6 responders and resistant patients with a predictive accuracy of > 90%. Further we were able to identify independent signatures predictive of response for individual CDK4/6 inhibitors palbociclib and ribociclib. Conclusions: The results of this study could lead to a paradigm shift in the administration of CDK4/6 inhibitors wherein prior to treatment and during treatment patient plasma is screened to determine whether that individual patient is responsive or resistant to a CDK4/6 inhibitor.
Identification and validation of a serum microRNA panel for detection of early-stage breast cancer.
Authors: Zou Ruiyang , Zhou Lihan , Loke Sau Yeen , Too Heng-Phon , Lee Ann
Published: May 2019

3051

Background: The implementation of mammogram-based screening has significantly improved the early detection of breast cancer in the west. However, the use of screening mammography is less prevalent in Asia partly due to social and cultural reasons. The aim of this study was to determine if a serum microRNA (miRNA) panel could be used as biomarkers to assist in the early detection of breast cancer. Methods: We conducted a multi-center, multi-ethnic study to identify and validate miRNA biomarkers for the early detection of breast cancer. A total of 1070 subjects including 550 breast cancer cases (predominantly stage 1 and 2) and 520 matched controls from 6 independent sources were included in this study. Among these, there were 768 American and European subjects recruited by biobanks and 302 Singaporean Asian Subjects recruited at the National Cancer Centre Singapore and the National University Hospital. The study was conducted in 3 phases. First, 119 European Caucasian serum samples (Discovery Cohort) were interrogated to identify differentially expressed miRNAs between early-stage breast cancer cases and matched controls, among 520 circulating miRNA candidates by quantitative RT-PCR using MiRXES assays. The remaining 951 subjects from 5 independent sources were assigned into two groups for biomarker optimization/algorithm development (Optimization Cohort, n = 451) and validation (Validation Cohort, n = 500). Results: Among the 520 circulating miRNAs measured, 241 were quantified in absolute copy numbers for 119 subjects in the Discovery Cohort. Thirty-two candidate miRNAs were identified. These miRNAs consistently showed differential expression between cancer and control subjects in the Optimization Cohort. A multi-variant panel of 8 miRNAs and an algorithm was developed using the combined Discovery and Optimization Cohorts, with an AUC of > 0.90. When validated in the independent Validation Cohort, the panel demonstrated an AUC of > 0.85. Conclusions: We developed and validated a serum miRNA panel that is both sensitive (~70%) and specific (~90%) in detecting early-stage breast cancer.
Changes in DNA hydroxymethylation for the detection of multiple cancers in plasma cell-free DNA.
Authors: Bergamaschi Anna , Collins Francois , Ellison Chris , Ning Yuhong , Guler Gulfem , Phillips Tierney , McCarthy Erin , Wang Wendy , Antoine Michael , Ku Jeremy , Scott Aaron , Lloyd Paul , Ashworth Alan , Levy Samuel
Published: May 2019

3058

Background: Methylation and hydroxymethylation of cytosines enable the epigenomic regulation of gene suppression and activation. 5-hydroxymethyl-cytosine (5hmC) is globally decreased in tumor tissue. However, genome-wide analysis using precise 5hmC labelling techniques reveals more nuanced changes upon tumorigenesis and raises the possibility that this loss could be exploited for developing a cancer biomarker. This suggests that 5hmC profiles might enable discrete classification of not only tumor tissue but also of tumor cell-free DNA (cfDNA). We sought to identify genome-wide 5hmC changes in plasma based cfDNA from cancer patients representing multiple disease types, stages and clinical characteristics in comparison with non-cancer patients. Methods: cfDNA was isolated from plasma, enriched for the 5hmC fraction using chemical labelling, sequenced, and aligned to the genome to determine 5hmC counts per genomic feature. Regularized regression models were constructed to classify cancer samples (age matched or corrected for smoking status) on non-overlapping training (80% of all samples) and test sample sets (20% of all samples). Results: 226 non-cancer patients and 278 cancers across four cancer types (breast, colorectal, lung-squamous and pancreas) were included in this study, where more than 60% of cancer samples were early stage disease (I or II). Upon comparison with non-cancer samples, 5hmC peaks have reduced enrichment in exons in breast, colorectal and lung cancer but not in pancreatic cancer. Further, 5hmC peaks in pancreas show different patterns of enrichment in 3’UTR, translational termination sites, promoters and LTR. Overall 5hmC signal density was reduced in late stage cancers across all four diseases. The ability to classify non-cancer versus cancer patients was evaluated via cross-validation of out of fold prediction in the training set with AUC > 0.84 for all four cancer types. Further, test set sensitivity across all four cancer types was found to be > 66% with 98% specificity. Conclusions: These findings suggest that 5hmC changes in plasma cfDNA enable classification of early stages of breast, colorectal, lung-squamous and pancreas cancer and are promising biomarkers for disease detection.