bluuebunny/crossref_metadata_2025_split huggingface dataset:
Machine learning-based identification of predictive features of the tumor micro-environment and vasculature in NSCLC patients using the IMpower150 study.
Authors: Taylor-Weiner Amaro , Beck Andrew , Cowan James Donovan , Elliott Hunter , Fridlyand Jane , Glass Benjamin , Guardino Ellie , Hegde Priti , Kerner Jennifer K , Khosla Aditya , Lee Mark , Liu Yi , McCleland Mark , Montalto Michael , Schulze Katja , Shames David S. , Srinivasan Ramprakash , Zou Wei , Wapinski Ilan , Giltnane Jennifer Margaret 
Published: May 2020

3130 Background: IMpower150 is a phase 3 study measuring the effect of carboplatin and paclitaxel (CP) combined with atezolizumab (A) and/or bevacizumab (B) in patients with advanced nonsquamous NSCLC, testing the hypothesis that anti-PD-L1 therapy may be enhanced by the blockade of VEGF. Here, we apply a machine-learning based approach to quantify the tumor micro-environment (TME) and vasculature and identify associations with clinical outcome in IMpower150. Methods: Digitized H&E images were registered onto the PathAI research platform (n=1027). Over 200K annotations from 90 pathologists were used to train convolutional neural networks (CNNs) that classify human-interpretable features (HIFs) of cells and tissue structures from images. Blood vessel compression (BVC) indices were calculated using the long versus short axes for each predicted blood vessel. HIFs were clustered to reduce redundancy, and selected features were associated with progression free survival (PFS) within each arm (ABCP, ACP, and BCP) using Cox proportional hazard models. Results: We used the trained CNNs to generate 4,534 features summarizing each patient’s histopathology and TME. After association with survival and correction for multiple comparisons we identified clusters that were significantly associated with survival in at least one arm. Among patients receiving treatments that target PD-L1 (ABCP and ACP), high lymphocyte to fibroblast ratio (LFR) was associated with improved PFS (HR=0.64 (0.51, 0.81), p < 0.001) and showed no significant association with PFS among patients treated with BCP alone (HR=1.13 (0.85, 1.51), p=0.4). Among BCP treated patients, a higher average BVC within the tumor tissue was associated with improved PFS (HR=0.67 (0.50,0.90), p=0.01) and worse PFS among patients treated with ACP (HR=1.50 (1.10,2.06), p=0.009). Conclusions: We developed a deep learning-based assay for quantifying pathology features of the TME and vasculature from H&E images. Application of this system to Impower150 identified an association between high LFR and improved PFS among patients receiving PD-L1 targeting therapy, and between low BVC and improved PFS among patients receiving BCP. These findings support the importance of the TME and vasculature in determining response to PD-L1 and VEGF-targeting therapies.
Multi-antigen active specific immunotherapy induced long-term remission and prevent colorectal cancer relapse.
Authors: Marquez-Manriquez Juan Pablo , Lucero-Diaz Pedro Alejandro , Camacho-Hernandez Alejandro , Gallardo-Rincon Dolores , Rosas-Delgado Martin Orlando , Perez-Astorga Mario Alberto , Fernandez-Felix Daniel Adrian , Cisneros-Ruiz Jorge Alberto ALBERTO , Banuelos Maria Olga Rocha , Durazo Alberto 
Published: May 2020

3138 Background: Clinical effective multi-antigen active immunotherapy for colorectal cancer (CRC) is still limited and most studies have failed. We consider this is because the targets in some of the studies are not oncogenic drivers. This is especially important for patients that progressed to standard of care treatment. Also, most of the studies with Immune checkpoint inhibitors (ICH) have failed in CRC but potentially may impact and provide better outcomes if used as combination therapies. We treated CRC patients with progressive disease in a pilot study n = 15 and found clinical responses that correlate with the CD8, delayed-type hypersensitivity (DTH) and Th1 parameters. After patients achieved remission we used the same peptides to prevent relapse with clinical and statistics significance. Methods: N = 15 CRC patients were enrolled in this pilot trial after approval for the ethic IRB committee from CICS Mexico. Patients were treated with an intradermal vaccine every week for four weeks, every two weeks four times in axillary and inguinal lymph nodes (LN) areas, and finally subcutaneously every month six times in the sites with tumor activity. Previously to the treatment we perform Granzyme B ELISPOT, ELISA, DTH and CT scan as initial controls. We delivered intradermal four peptides from sixteen peptides predicted from four proteins such as Fascin-1, Ape-1, VCP and RCAS1. Results: 86% of the patients had an objective clinical responses and 14% stable disease. All the patients had a correlation with the immunological assays as following. 58% of patients had an increased in the CD8 cells demonstrated by Granzyme B; DTH reactions were gradually increasing and by the first month of treatment the DTH were positive for Fascin-1 (78%), Ape-1 (85%), VCP (95%) and RCAS1 (83%) peptides. The more immunogenic peptides by ELISA were Fascin-1 A (P = 0.001), Fascin-1 D (P = 0.005), Ape-1 C (p = 0.001), VCP A (P = 0.003), RCAS1 A (p = 0.001) and RCAS1 B (P = 0.01). Conclusions: The treatment was effective with CR and SD responses. Once we validate this data we are planning a clinical study combining the treatment with low dose of ICH. Currently all the patients with CR are now under relapse prevention. We are still treating the patients with SD until disease progression. Importantly we believe that this data may impact the PFS and OS in CRC patients who have Karnoksky > to 80% despite progressive disease to standard of care.
Phase I/II study of avadomide (CC-122) in combination with R-CHOP for newly diagnosed DLBCL.
Authors: Mehta-Shah Neha , Chavez Julio C. , Abrisqueta Pau , Johnson Nathalie , Bergua Burgues Juan Miguel , Grande-Garcia Carlos , Stewart Douglas , Dunleavy Kieron , Rodriguez Guillermo , Sancho Juan-Manuel , Drew James , Wu Chengqing , Hagner Patrick R. , Delarue Richard , Martin Alejandro 
Published: May 2020

3501 Background: In certain subsets of patients (pts) with diffuse large B-cell lymphoma (DLBCL), the failure rate of standard R-CHOP treatment is high. Pts with high-risk disease (International Prognostic score [IPI] 3-5) have a particularly poor prognosis, with 3-y survival rates of ~62% with R-CHOP alone. The cereblon E3 ligase modulator avadomide (CC-122) showed activity in pts with relapsed or refractory DLBCL. We report results of avadomide plus R-CHOP in previously untreated pts with high-risk DLBCL. Methods: CC-122-DLBCL-002 (NCT03283202) is a phase 1/2 study of avadomide plus R-CHOP-21 in pts newly diagnosed with DLBCL not otherwise specified with IPI scores 3-5 who were aged ≥18 y. Pts received standard R-CHOP and escalating doses (1-3 mg) of oral avadomide for up to six 21-d cycles (Table). All pts received pegfilgrastim support. Primary objectives were to assess safety, tolerability, and complete response (CR) rate. Secondary objectives include evaluation of additional efficacy parameters (objective response rate [ORR], progression-free survival [PFS], and overall survival) and biomarkers. Results: As of July 30, 2019, 35 pts were enrolled in the phase 1 part of the study. Median age was 66 y (range, 20-75), 23 pts (66%) were aged > 60 y, 18 (51%) had an IPI score of 3, and 17 (49%) had an IPI score of 4-5. Thirty-two pts (91%) completed 6 cycles of treatment. Median relative total dose intensity of avadomide was 99% and the average relative dose intensity of R-CHOP was 95%. Six pts had dose-limiting toxicities: 1 pt had neutropenia and bacterial hepatic infection; 1 had pneumonia; 1 had febrile neutropenia (FN); 1 had FN and hypotension; 1 had FN due to skin infections; and 1 had sepsis. The recommended phase 2 dose was 3 mg 2/3 wk. Grade 3/4 adverse events in ≥10% of pts were neutropenia (54%), anemia (20%), leukopenia (20%), lymphopenia (14%), hypophosphatemia (14%), and FN (11%). Among 34 efficacy-evaluable pts, the ORR was 88% (n = 30/34), including a CR rate of 79% (n = 27/34) at the end of treatment. With a median follow-up of 10 mo, the 1-y PFS rate was 80% (95% CI, 58-92). Correlative analyses will be presented at the meeting. Conclusions: Avadomide plus R-CHOP was well-tolerated with no significant additive toxicities. The promising efficacy in this high-risk pt population warrants further evaluation of immunomodulatory drugs combined with immunochemotherapy for pts with previously untreated DLBCL. Clinical trial information: NCT03283202 . [Table: see text]
Phase II study of copanlisib in patients with tumors with PIK3CA mutations (PTEN loss allowed): NCI MATCH EAY131-Z1F.
Authors: Damodaran Senthil , Zhao Fengmin , Deming Dustin A. , Mitchell Edith P. , Wright John Joseph , Doyle Laurence A , Gray Robert James , Li Shuli , McShane Lisa , Rubinstein Larry V , Patton David R , Williams Mickey , Hamilton Stanley R. , Suga Jennifer Marie , Conley Barbara A. , Arteaga Carlos L. , Harris Lyndsay , O'Dwyer Peter J. , Chen Alice P. , Flaherty Keith 
Published: May 2020

3506 Background: The NCI-MATCH (EAY131) is a platform trial that enrolls patients (pts) with solid tumors, lymphomas, or multiple myeloma to targeted therapies based on matching genomic alterations of interest (NCT02465060). Arm Z1F evaluated copanlisib, a highly selective, pan-Class 1 PI3K inhibitor with predominant activity against both the δ and α isoforms in pts with PIK3CA mutations. Methods: Pts received copanlisib (60 mg IV) on days 1, 8, and 15 in 28-day cycles until progression/toxicity. Tumor assessment was every 2 cycles. The primary endpoint was objective response rate (ORR); secondary endpoints were PFS, 6-month PFS, and predictive biomarkers. Pts with KRAS mutations, HER2+ve breast cancers, lymphomas were excluded. Results: 35 pts were enrolled (from 8/2/18 to 12/27/18), of which, 28 pts were available for analysis (7 patients, not eligible or did not start therapy). Multiple histologies were enrolled with gynecologic (n = 7), gastrointestinal (n = 6), and genitourinary (n = 5) the most common tumors. Median age 61 (range 42-78). 75% of pts had ≥ 3 lines of prior therapy. 54% of PIK3CA mutations were located in the helical domain, 32% in kinase domain and 14% in other domains. Twenty-six pts had co-occurring gene alterations (median 3; range 1-9), with 9 patients having 4 or more gene alterations. The ORR was 11% (3/28, 90% CI: 3%-25%). Partial responses were seen in uterine cancer, clear cell carcinoma of anterior abdominal wall, and liposarcoma. 6 pts had > 6 months of stable disease and clinical benefit rate was 32% (9/28). Two pts are still on treatment. The most common reason for protocol discontinuation was disease progression (n = 18, 69%). Thirty pts were included for toxicity analysis. Ten pts (33%) had grade 1 or 2 toxicities, 16 pts (53%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity (CTCAE v5.0). Most common toxicities include hyperglycemia (n = 19), fatigue (n = 11), hypertension (n = 10), diarrhea (n = 10), and nausea (n = 9). Total of 5 deaths were reported, none related to treatment. Conclusions: Copanlisib showed meaningful clinical activity across various tumors with PIK3CA mutation in the late-line refractory setting. Further study either alone or in combinations in select tumors is warranted. G3/4 toxicities observed were consistent with reported toxicities for PI3K pathway inhibition. Clinical trial information: NCT02465060 .
First-in-human study of palcitoclax (APG-1252), a novel dual Bcl-2/Bcl-xL inhibitor, demonstrated advantages in platelet safety while maintaining anticancer effect in U.S. patients with metastatic solid tumors.
Authors: Lakhani Nehal J. , Rasco Drew W. , Zeng Qi , Tang Yuefen , LIANG ZHIYAN , Wang Hengbang , Lu Ming , Chen Jason , Fu Lei , Wang Cunlin , Yang Dajun , Zhai Yifan 
Published: May 2020

3509 Background: Targeting Bcl-2/Bcl-xL proteins is considered as an important approach for anticancer drug development. Palcitoclax (APG-1252) was being developed to reduce on-target platelet toxicity without diminishing antitumor potency. Methods: The phase 1 study was to evaluate the safety/tolerability, pharmacokinetics (PK), and preliminary efficacy (assessed per RECIST 1.1) of palcitoclax in US patients with metastatic small-cell lung cancer (SCLC) or other solid tumors (NCT03080311). A standard “3+3” design was applied to the dose-escalation stage. Palcitoclax was administered IV infusion for 30 minutes, twice a week (BIW) or once a week (QW) for 3 weeks in a 28-day cycle. Once the maximum tolerated dose / recommended phase 2 dose (MTD/RP2D) was determined, additional patients were treated in a dose-expansion stage. Results: The dose-escalation phase has been completed with 42 patients (31 on BIW and 11 on QW) who received palcitoclax at 8 dose cohorts ranging 10 mg - 400 mg. Most adverse events (AEs) were grade 1 or 2 (G1 or G2), and 26.2% patients had ≥ G3 TRAEs. The most common TRAEs were platelet count decreased (14.3%), aspartate aminotransferase increased (9.5%), and alanine aminotransferase increased (7.1%). Rapid platelet drop was observed in patients treated at 320 mg and 400 mg, which was transient and resolved rapidly within 2-6 days. Palcitoclax at 240 mg once weekly was determined to be MTD/RP2D. Of 36 efficacy-evaluable patients, 3 patients with SCLC, neuroendocrine prostate cancer, and ovarian cancer respectively achieved partial response (PR) and 8 patients had stable disease (SD) as their best overall response. One patient with SCLC had a PR that lasted over 21 cycles. Preliminary PK analyses showed that Cmax and AUC were approximately dose proportional over the range of 10 mg to 320 mg following the IV infusion on Day 1, with a mean T1/2 of 3.0-13.0 hours. Conclusions: Palcitoclax is safe and well tolerated, with a favorable platelet toxicity profile. Its promising antitumor effect supports its further development in combination therapies for treatment of patients with SCLC and other solid tumors. Clinical trial information: NCT03080311 .
Phase Ib study of a novel, small-molecule MDM2 inhibitor APG-115 combined with pembrolizumab in U.S. patients with metastatic solid tumors.
Authors: Tolcher Anthony W. , Karim Raghad , Tang Yuefen , Wang Hengbang , Ji Jiao , Chen Jason , Kaiser Angela , Sheladia Piyush , Ahmad Mohammad , LIANG ZHIYAN , Yang Dajun , Zhai Yifan 
Published: May 2020

3512 Background: APG-115 activates p53-mediated apoptosis in tumor cells retaining wild-type TP53. It also functions as a host immune modulator and enhances antitumor activities when combined with PD-1 blockade preclinically. MDM2 amplification is associated with hyperprogression in patients treated with checkpoint inhibitors. Methods: The Phase Ib / II study was designed to evaluate APG-115 combined with pembrolizumab in patients with metastatic solid tumors (NCT03611868). APG-115 was administered orally every other day for 2 weeks, at dose ranging from 50 mg – 200 mg, with pembrolizumab at 200 mg IV on Day 1 of a 21-day cycle. Study objectives were to assess safety including dose-limiting toxicity (DLT), serious adverse events (SAEs), treatment-related AEs (TRAEs), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy (assessed by RECIST v1.1), to determine recommended phase 2 dose (RP2D). Results: As of December 25, 2019, the enrollment of phase 1b study was completed. Total 19 patients had been treated in four APG-115 cohorts: 50 mg (n = 3), 100 mg (n = 3), 150 mg (n = 6), and 200 mg (n = 7). No DLT was observed, The TRAEs (≥15%) were nausea (47.4%), fatigue (36.8%), decreased platelet count (26.3%), and decreased appetite (21.1%), as well as diarrhea, vomiting, decreased neutrophil or white blood cell count, and hypothyroidism in 15.8% each. Grade > 3 TRAEs included decreased neutrophil and thrombocytopenia in 15.8% each. Two SAEs were treatment related: G3 febrile neutropenia and G3 adrenal insufficiency. No new safety finding from combination with Pembrolizumab. The RP2D of APG-115 was 150 mg. One patient with ovarian cancer has a CR lasting for 15 months, 2 patients had PR for 8-9 months: one NSCLC failed IO therapy, another with appendix cancer, and 7 had SD for 1.5-7 months. The objective response rate was 15.8%, and the disease control rate (DCR) was 52.6%. PK data indicated an approximately dose-proportional increase in APG-115 exposure over the range of 50-200 mg on Day 1. PD-PK analyses showed that serum macrophage inhibitory cytokine-1 (MIC-1) increase was time and dose dependent, the MIC-1 elevation correlated with APG-115 exposure, indicating p53 activation in these patients. Conclusions: APG-115 in combination with pembrolizumab is well tolerated. Encouraging antitumor effects were observed in several tumor types. The phase II study is ongoing in the cancer patients with specific bio-marker profiling. Clinical trial information: NCT03611868 .
Lurbinectedin (LUR) in combination with Irinotecan (IRI) in patients (pts) with advanced solid tumors: Updated results from a phase Ib-II trial.
Authors: Ponce Aix Santiago , Cote Gregory Michael , Falcon Gonzalez Alejandro , Sepulveda Juan Manuel , Jimenez Aguilar Elizabeth , Sanchez-Simon Inmaculada , Flor Maria José , Nuñez Rafael , Gonzalez Eva Maria , Insa Monica , Siguero Mariano , Cullell-Young Martin , Kahatt Carmen Maria , Zeaiter Ali Hassan , Paz-Ares Luis G. 
Published: May 2020

3514 Background: LUR is a novel agent that exerts antitumor activity through inhibition of trans-activated transcription and modulation of tumor microenvironment. Preclinical synergism/additivity in combination with IRI has been reported, thus prompting the conduct of this clinical trial. Methods: Phase Ib-II trial to evaluate escalating doses of LUR on Day (D) 1 plus a fixed dose of IRI 75 mg/m2 on D1 and D8 every 3 weeks (q3w) in pts with advanced solid tumors (+/- G-CSF, if dose-limiting toxicities [DLTs] were neutropenia). Starting dose was LUR 1.0 m/m2 + IRI 75 mg/m2. Results: 77 pts have been treated to date at 5 dose levels, 51 of them at the recommended dose (RD). Baseline characteristics of all 77 pts were: 48% females, 68% ECOG PS=1; median age 57 years (range, 19-75 years); median of 2 prior lines (range, 0−4 lines). The maximum tolerated dose (MTD) was LUR 2.4 mg/m2 + IRI 75 mg/m2 with G-CSF, and the RD was LUR 2.0 mg/m2 + IRI 75 mg/m2 with G-CSF. DLTs in Cycle 1 occurred in 2/3 evaluable pts at the MTD and 3/13 evaluable pts at the RD, and comprised omission of IRI D8 infusion due to grade (G) 3/4 neutropenia (n=3 pts) or G2-4 thrombocytopenia (n=2). At the RD (n=51), common G1/2 non-hematological toxicities were nausea, vomiting, fatigue, diarrhea, anorexia and neuropathy. G3 non-hematological toxicities (diarrhea 10%, fatigue 10%) and G3/4 hematological abnormalities (neutropenia 49%, thrombocytopenia 10%) were transient. Conclusions: The combination of LUR and IRI had acceptable tolerance, with no unexpected toxicities. Transient myelosuppression was dose-limiting. The RD is LUR 2.0 mg/m2 on D1 + IRI 75 mg/m2 on D1 and D8 q3w with G-CSF. Antitumor activity was observed at the RD in SCLC pts, as well as in endometrial carcinoma pts. Hints of activity were also observed in STS pts. Updated results will be presented. Clinical trial information: NCT02611024 . [Table: see text]
An open-label, multicenter, phase II study of ceritinib in patients with advanced ALK+ non-lung solid tumors and hematological malignancies (ASCEND-10).
Authors: Moreno Victor , Kim Tae Min , Rha Sun Young , Longo Federico , Sathornsumetee Sith , Zhang Shirong , Hirschberg Yulia , Pramanik Barnali , Wamil Barbara D , Kiss Igor 
Published: May 2020

3520 Background: Prior studies have confirmed the efficacy and safety of ceritinib in patients (pts) with advanced ALK+ non-small cell lung cancer (Soria, et al, Lancet 2017; Shaw et al, Lancet Oncol 2017; Cho et al, JTO 2019). Ceritinib also demonstrated antitumor activity in pediatric pts with ALK+ inflammatory myofibroblastic tumor (IMT) and ALCL (Georger et al, ASCO 2015 [abstract#10005]). Long-term clinical benefits of ceritinib treatment were shown in pts with anaplastic large cell lymphoma (ALCL) (Richly et al, Blood 2015). The aim of the current study was to examine ceritinib efficacy and safety in pts with advanced ALK+ non-lung solid tumors and hematological malignancies. Methods: In this open-label, multi-arm, phase 2 (NCT02465528) trial, adult pts with ALK gene abnormalities who had received ≥1 prior systemic therapy were administered oral ceritinib 750 mg/day, under fasted conditions. Primary endpoint: investigator assessed disease control rate (DCR); secondary endpoints: investigator assessed overall response rate (ORR), duration of response (DOR), time to response (TTR), progression-free survival (PFS), and safety. Results: Overall, 22 pts (ALCL [n = 1], IMT [n = 4], glioblastoma multiforme [GBM, n = 12] and others [n = 5]) were enrolled; median (m) age: 52.5 years; male: 50%; Stage ≥IV: 95.4%. Key efficacy results are shown in the Table. mTTR in pts with confirmed complete response (CR) or partial response (PR) [n = 4] was 7.4 (range, 6–25) weeks. mDOR was not reached. mPFS (95% CI) was 2.6 (1.6, 3.7) weeks. Most common adverse events (AEs; ≥30%) were: diarrhea and nausea (59.1% each), vomiting (50.0%) and increased alanine aminotransferase (31.8%). Most common grade ≥3 AEs (≥10%): hyperglycemia (18.2%), increased gamma-glutamyl transferase, thrombocytopenia, and anemia (13.6% each). Clinical trial information: NCT02465528 . Conclusions: Ceritinib 750 mg/day under fasted conditions showed antitumor activity in pts with ALK+ ALCL and IMT; however, data interpretation is limited due to the small sample size. Safety findings were consistent with the known ceritinib safety profile. [Table: see text]