bluuebunny/crossref_metadata_2025_split huggingface dataset:
DETERRED: PD-L1 blockade to evaluate the safety of lung cancer therapy using carboplatin, paclitaxel, and radiation combined with MPDL3280A (atezolizumab).
Authors: Lin Steven H. , Lin Yan , Price Justina , Parker Matthew , Gomez Daniel Richard , Welsh James William , Komaki Ritsuko , Kurie Jonathan M. , Simon George R. , Blumenschein George R. , Young Jenean A. , Phan See-Chun , Sandler Alan , Papadimitrakopoulou Vassiliki , Heymach John , Tsao Anne S. 
Published: September 2018

3064 Background: Immune checkpoint blockade in non-small cell lung cancer (NSCLC) may be enhanced when combined with radiation therapy. Atezolizumab (atezo) is a humanized and Fc receptor modified monoclonal antibody that blocks programmed death-ligand-1 (PD-L1) interacting with PD-1 or B7.1 sparing PD-L2, which may result in less pulmonary toxicity. We report the early safety data of combining atezo added sequentially after standard concomitant chemoradiation (CRT) for locally advanced NSCLC (LA-NSCLC). Methods: This is a phase II study in LA-NSCLC assessing the safety and feasibility of adding atezo to CRT in two parts: I) sequentially (N = 10) with CP after completing CRT, or II) concurrently (N = 30) with CRT followed by consolidation atezo with CP. We report on the early toxicity results from part I of the trial. Atezo was given at 1200 mg IV Q3 weeks with consolidation CP for 2 cycles after CRT followed by atezo monotherapy for up to one year. Radiation dose at 60-66 Gy in 30-33 fractions was combined with weekly low dose CP, followed by 2 cycles of full dose CP. Dose limiting toxicities were defined as any adverse events (AEs) ≥ grade 3 within 15 weeks of start of therapy or any immune-related AEs during atezo treatment. Results: From January to December 2016, 10 evaluable patients were enrolled. Seven patients have received consolidation atezo ranging from 1 to 14 doses, with 3 yet to receive atezo after completing CRT. Three patients reported potential immune-related AEs. One patient developed grade 3 arthralgia, and another developed grade 2 radiation-induced pneumonitis, which resolved with steroids. A third patient who experienced grade 3 dyspnea due to COPD exacerbation after 1 dose of atezo discontinued additional therapy. Of the 7 patients who have received atezo, 2 patients developed progression of disease after 6 and 8 doses of atezo. Conclusions: Atezo consolidation with 2 cycles of CP after CRT appears to be feasible and well tolerated with manageable toxicities. Additional data from part I will be reported. Conditions for proceeding after part I are met and part II of the study which adds atezo to CRT followed by atezo-CP consolidation is open for accrual. Clinical trial information: NCT02525757.
A phase II randomized, double-blind study of sipuleucel-T followed by IDO pathway inhibitor, indoximod, or placebo in the treatment of patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Jha Gautam Gopalji , Gupta Shilpa , Tagawa Scott T. , Koopmeiners Joseph S , Vivek Sithara , Dudek Arkadiusz Z. , Cooley Sarah A. , Blazar Bruce R. , Miller Jeffrey S. 
Published: September 2018

3066 Background: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism exploited by tumors in order to prevent and defeat anti-tumor immunity. Sipuleucel-T has overcome this tumor mediated anergy only in part by its ex-vivo sensitization. Small-molecule inhibitors of the IDO pathway, such as indoximod, are an increasingly validated class of potential cancer therapeutics. We tested the hypothesis whether targeting the IDO pathway by indoximod will inhibit Treg and abrogate tumor-mediated immunosuppression permitting a robust and sustained immune response to sipuleucel-T. Methods: Patient (pts) with mCRPC received either indoximod or placebo orally for 10 weeks after completion of sipuleucel-T therapy. In the absence of radiographic or clinical progression, pts were continued on study drug for 3 more months. Immune monitoring was done similar to IMPACT study (NEJM 2010; 363:411-422) starting prior to sipuleucel-T therapy. The primary endpoint was augmentation of immune response to PA2024 measured at 14 weeks. Secondary endpoints include safety, clinical efficacy (PFS, OS) and HR-QOL Results: Of the 63 pts with CRPC screened, 46 eligible pts were randomized to indoximod (n = 22) or placebo (n = 24). Pts tolerated therapy with indoximod with no significant difference in adverse events between two arms. There was no difference in PSA progression nor difference in the primary endpoint of immune response to PA2024 for 35 pts who have completed study and have samples analyzed. Median OS has not yet been reached in the study. Median radiographic PFS was 10.3 months in the treatment arm vs 4.1 months in placebo arm (p = 0.011), 4.1 months being similar to PFS in the pivotal ‘IMPACT’ study. More Pts continued to complete maximum treatment on indoximod arm (40.9% vs 25%). Conclusions: Treatment with indoximod post sipuleucel-T therapy is well tolerated and led to a significant improvement in radiographic and clinical progression. Augmentation of immune response to PA2024 by ELISPOT or ELISA might not be right biomarker for augmented response assessment while studying inhibition of IDO pathway. Clinical trial information: NCT01560923.
Phase 1 study to evaluate the safety and tolerability of MEDI4736 (durvalumab, DUR) + tremelimumab (TRE) in patients with advanced solid tumors.
Authors: Callahan Margaret K. , Odunsi Kunle , Sznol Mario , Nemunaitis John J. , Ott Patrick Alexander , Dillon Patrick Michael , Park Andrew J. , Schwarzenberger Paul , Ricciardi Toni , Macri Mary J. , Ryan Aileen , Venhaus Ralph Rudolph , Wolchok Jedd D. 
Published: September 2018

3069 Background: DUR is a human IgG1 monoclonal antibody (mAb) that blocks PD-L1. TRE is a human IgG2 mAb inhibitor of CTLA-4. Blocking these checkpoints can result in antitumor activity in some solid tumors. The targets for DUR and TRE are non-redundant, providing sound rationale for clinical testing of the combination. Methods: This is an ongoing Phase 1, multicenter, open label study (NCT01975831) with a dose escalation (3+3 design) and subsequent expansion phase. Patients (pts) with renal cell carcinoma (RCC), cervical (CC), colorectal (CRC), non-triple-negative breast (NTNBC), ovarian (OC), non-small cell lung, or head and neck cancer are eligible. Primary endpoints are safety/tolerability and identification of maximum tolerated dose (MTD) of the combination. Secondary objectives include tumor response and progression-free/overall survival. Results: As of 16 Dec 2016, 105 pts were treated. DUR 1500 mg every 4 weeks (Q4W) and TRE 75 mg Q4W X 4 was the regimen used for opening the expansion phase. Dose-limiting toxicities were reported in 4 pts: diarrhea, colitis, abnormal liver function tests (abn LFTs), and hyponatremia. The majority of treatment-related AEs (TRAEs) were Grades (Gr) 1 and 2. TRAEs ≥ Gr 3 were reported in 12 pts; the majority were diarrhea/colitis (n = 5) and abn LFTs (n = 4) and responded to established treatment algorithms. There was 1 Gr 5 TRAE: multi organ failure. No new toxicities were identified. The preliminary responses by tumor type with n ≥ 10 pts are shown in the table below. Responses were seen in OC and RCC at the Cohort 2 dose escalation level (DUR 1/TRE 3 mg/kg). There were 4 cases of SD > 24 weeks: CC, n=2; CRC, n=1; OC, n=1. PD-L1 status was not tested. Conclusions: The DUR + TRE combination has a manageable safety profile, with preliminary evidence of clinical activity. These data support continued study of the combination therapy; the study is ongoing. Clinical trial information: NCT01975831. [Table: see text]
An open-label, multi-center phase I study of the safety and tolerability of the novel immunomodulatory agent PG545 in subjects with advanced solid tumors.
Authors: Dredge Keith , Brennan Todd , Brown Michael Paul , Lickliter Jason D. , Bampton Darryn , Hammond Edward , Lin Liwen , Yang Yiping , Millward Michael 
Published: September 2018

3083 Background: PG545 (pixatimod, pINN) is a novel immunomodulatory agent which stimulates dendritic cells (DC) via TLR9/IL-12 pathway to activate natural killer (NK) cells. It also inhibits tumour-associated macrophages in cancer models. We report on safety, PK, PD, and antitumor activity of PG545 monotherapy. Methods: In this dose escalation (3+3 design) study, eligible pts (ECOG≤1) with advanced solid malignancies who failed standard therapies received PG545 once weekly as a 1-hour i.v. infusion until disease progression or discontinuation due to intolerability. The primary objective was determination of the maximum tolerated dose (MTD). Secondary objectives evaluated safety, antitumor activity based on RECIST (1.1) criteria, PK and PD (plasmacytoid DC & NKp46+NK cells from PBMC, and plasma cytokines/chemokines). Results: The study recruited 23 subjects across four cohorts (25, 50, 100 & 150 mg). Three dose limiting toxicities (DLTs) - hypertension (2), epistaxis (1) - occurred in the 150 mg cohort, which was identified as a non-tolerated dose level. No DLTs occurred in the 100 mg cohort, which was identified as the MTD. Six SAEs were reported to be possibly or likely related to PG545 treatment. No RECIST 1.1 objective responses were reported; best response was prolonged stable disease up to 24 weeks (mCRC), with disease control rate in evaluable subjects of 38% (6/16) at eight weeks. Exposure (AUC0-last) was proportional up to 100mg and mean half-life was 144 hours. At 50 and 100mg dose levels, two subjects in each cohort exhibited up to 4-fold increased numbers of NKp46+NK cells, IFN-α-producing pDCs, and increases (up to 25-fold) in plasma IFN-γ, TNF-α, IP-10 and MCP-1. Conclusions: PG545 is well tolerated up to 100 mg once-weekly via i.v. infusion. Human exposure data at 50mg and 100mg reach exposures consistent with those required for preclinical efficacy. Preliminary PD data support the proposed mechanism of action, which represents a promising approach to improve the efficacy of existing therapies. These data, and the absence of toxicities associated with chemo- or immunotherapies, support the development of PG545 in combination clinical trials. Clinical trial information: NCT02042781.
Results of a first-in-human phase I study of INVAC-1, an optimized plasmid DNA encoding an inactive form of human telomerase reverse transcriptase (hTERT), in patients with advanced solid tumors.
Authors: Teixeira Luis , Medioni Jacques , Doucet Ludovic , Culine Stephane , Oudard Stephane , Adotevi Olivier , Dragon Durey Marie-Agnès , Kiladjian Jean-Jacques , Brizard Mara , Bourré Ludovic , Wain-Hobson Simon , DeFrance Rémy , Huet Thierry , Langlade-Demoyen Pierre 
Published: September 2018

3087 Background: INVAC-1 is an optimized plasmid encoding an inactive form of human telomerase reverse transcriptase (hTERT). hTERT is a prototype of shared tumor antigen expressed in more than 85% of human tumors. Telomerase activation is associated with maintenance of telomere length and accounts for the unlimited proliferative capacity of cancer cells. In preclinical models, INVAC-1 triggered Th1-polarized hTERT-specific CD8+ and CD4+T-cell immune responses and anti-tumor effects. Here, we report clinical and pharmacodynamics results of the first clinical study with INVAC-1 as a single agent in solid tumors. Methods: A 3+3 design phase 1 First in Human study evaluating INVAC-1 given monthly for 3 cycles using electroporation-based intra-dermal (ID) injection was conducted. Primary objectives included safety, tolerability and dose limiting toxicities to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives included immune response and anti-tumor activity. Results: 20 patients (pts) with refractory/progressive solid tumors were enrolled in two centers. 3 escalating doses were studied: 100 µg (3 pts), 400 µg (3 pts) and 800 µg (14 pts). At 3-month data cut-off, no dose limiting toxicities or treatment related SAEs have been reported; no MTD was defined. The most common treatment-related adverse events were grade 1 or 2: asthenia and local reaction at injection site. 12 pts experienced stable disease and clinical benefit. For 10 pts, the treatment was extended beyond the per-protocol 3-month duration, up to nine months for 2 pts. IFN-g polarized anti-hTERT immune responses were detected in 55% of pts, in response to INVAC-1 treatment. Conclusions: Results from this study indicate that INVAC-1 ID was safe, well tolerated and strongly immunogenic at the doses and schedule tested. Early anti-tumor activity has been observed. The RP2D of INVAC-1 is therefore a monthly ID injection of 800 µg. These results encourage a future evaluation of INVAC-1 is solid tumors, as well as in hematologic malignancies, either as monotherapy or in combination with various immunotherapeutic drugs. Clinical trial information: NCT02301754.
Total neoadjuvant chemotherapy to facilitate delivery and tolerance of systemic chemotherapy and response in locally advanced rectal cancer.
Authors: Cercek Andrea , Roxburgh Campbell SD , Strombom Paul , Smith Jesse Joshua , Temple Larissa K. F. , Nash Garrett Michael , Guillem Jose G. , Paty Philip , Yaeger Rona , Stadler Zsofia Kinga , Segal Neil Howard , Reidy Diane Lauren , Shia Jinru , Vakiani Efsevia , Wu Abraham Jing-Ching , Crane Christopher H , Gollub Marc Jeffrey , Garcia-Aguilar Julio , Saltz Leonard , Weiser Martin R. 
Published: September 2018

3519 Background: The most common therapy for locally advanced (T3/4 or N+) rectal cancer (LARC) consists of preoperative chemoradiotherapy (chemoRT) followed by surgery and adjuvant chemotherapy. Recently, use of total neoadjuvant therapy (TNT) with preoperative chemotherapy in addition to chemoRT prior to resection has been accepted as an alternative. Methods: Of 811 consecutive patients (pts) who presented with LARC at our cancer center in 2009-2015, 320 received chemoRT with planned adjuvant chemotherapy, and 308 received TNT (induction FOLFOX/CAPOX chemotherapy followed by chemoRT). Treatment and outcome data for those two cohorts were compared. Results: Pts in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort (p < 0·005 and p < 0·001, respectively). The complete response (CR) rate, which includes pathological CR (pCR) and clinical CR (cCR) at 6 months post-treatment, was 21% in the chemoRT with planned adjuvant chemotherapy cohort and 36% in the TNT cohort. The median follow-up was 40 months in the chemoRT with planned adjuvant chemotherapy cohort and 23 months in the TNT cohort. Fewer distant recurrences were seen in patients who had T downstaging (p < 0·001), N downstaging (p < 0·005), a cCR (p = 0·005), or a pCR (p < 0·005). There was no statistically significant difference in distant-recurrence-free survival between the two cohorts. Conclusions: Our findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines for rectal cancer treatment, which categorizes TNT as a viable treatment strategy that facilitates superior compliance and delivery of systemic therapy. Given its high CR rate, TNT may be beneficial as part of a nonoperative treatment strategy aimed at organ preservation.
Circulating tumor DNA (ctDNA) utilizing a high-sensitivity panel to detect minimal residual disease post liver hepatectomy and predict disease recurrence.
Authors: Overman Michael J. , Vauthey Jean-Nicolas , Aloia Thomas A. , Conrad Claudius , Chun Yun Shin , Pereira Allan Andresson Lima , Jiang Zhiqin , Crosby Shadarra , Wei Steven , Raghav Kanwal Pratap Singh , Morris Van Karlyle , Tan Michelle , Maslan Annie , Talasaz AmirAli , Mortimer Stefanie , Kopetz Scott 
Published: September 2018

3522 Background: Preliminary data suggests that ctDNA can serve as a marker of minimal residual disease following colorectal cancer (CRC) tumor resection. Applicability of current ctDNA testing is limited by the requirement of sequencing known individual tumor mutations. We explored the applicability of a multi-gene panel ctDNA detection technology in CRC. Methods: Plasma was prospectively collected from CRC patients (pts) undergoing hepatic resections with curative intent between 1/2013 to 9/2016. In a blinded manner 5ml of preoperative (preop) and immediate post-operative (postop) plasma were tested using a novel 30kb ctDNA digital sequencing panel (Guardant Health) covering SNVs in 21 genes and indels in 9 genes based on the landscape of genomic alterations in ctDNA from over 10,000 advanced cancer pts with a high theoretical sensitivity (96%) for CRC. Median unique molecule coverage for this study is 9000 for cfDNA inputs ranging from 10 – 150 ng (media input preop = 27 ng, median input postop = 49 ng) with 120,000X sequencing depth on an IIlumina HiSeq2500. Results: A total of 54 pts underwent liver metastectomies with curative intent with a median follow-up of 33 months. Preop blood was a median of 49 days from last systemic chemotherapy and 3 days prior to surgery; postop blood was a median of 17 days after resection. Tumor mutations from standard of care hotspot multigene panel testing (at MDACC) were identified in 46 of 54 pts (85%). Preop ctDNA mutation detection rate was 80% (43/54) and 44% (24/54) in postop setting, with postop median allele frequency of 0.16% (range 0.01% to 20%). In pts with a minimum of 1 year follow up, sensitivity of postop ctDNA for residual disease was 58% (95%CI; 41%-74%), and specificity was 100% (66%-100%). In 43 patients who underwent successful resection of all visible disease, postop detection of ctDNA significantly correlated with RFS (P = 0.002, HR 3.1; 95% CI 1.7-9.1) with 2-year RFS of 0% vs. 47%. Recurrence was detected in ctDNA a median of 5.1 months prior to radiographic recurrence. Conclusions: The detection of postop ctDNA using an NGS panel-based approach is feasible and is associated with a very high rate of disease recurrence.
Variability in genomic alterations between right- and left-sided microsatellite stable (MSS) metastatic colorectal cancer and impact on survival.
Authors: Yaeger Rona , Chatila Walid , Lipsyc Marla , Sanchez-Vega Francisco , Hechtman Jaclyn Frances , Cercek Andrea , Stadler Zsofia Kinga , Middha Sumit , Kundra Ritika , Syed Aijazuddin , Zehir Ahmet , Varghese Anna M. , Segal Neil Howard , Vakiani Efsevia , Ladanyi Marc , Berger Michael F. , Kemeny Nancy E. , Shia Jinru , Saltz Leonard , Schultz Nikolaus 
Published: September 2018

3534 Background: Metastatic colorectal cancers (mCRCs) with a right-sided primary site are associated with shorter survival and insensitivity to EGFR inhibitors compared to those originating in the left side of the colon or rectum. Methods: We performed targeted gene sequencing of 928 consecutive MSS mCRCs. Primary tumor site was divided into right-sided for cecum to distal transverse colon (n = 242), left-sided for splenic flexure to rectum (n = 673), or unknown colonic location (n = 13). Histologic subtypes were conventional (adenocarcinoma not otherwise specified), conventional with mucinous features ( < 50% mucinous), mucinous, signet ring, and poorly differentiated. To evaluate receptor tyrosine kinase (RTK) signaling, we analyzed ligand mRNA expression in TCGA. Results: Overall survival from time of metastasis was shorter for right-sided than left-sided primary site (survival at 5 years: 45% v 67%, p < 0.001). Right-sided tumors had more mutations (5.60 v 4.62 per MB, p < 0.001) but fewer copy-number changes (0.18 v 0.22 fraction genome altered, p = 0.001) compared to left-sided tumors. Alterations of KRAS, BRAF, PIK3CA, PTEN, AKT1, RNF43, and SMAD4 were significantly enriched in right-sided tumors, and of APC and TP53 in left-sided tumors. In a multivariate model, APC (HR = 0.7, p = 0.03), BRAF (HR = 3.7, p < 0.001), and KRAS (HR = 1.7, p < 0.01) alterations predicted for survival, but primary site did not (HR = 0.74, p = 0.07). Amphiregulin, epiregulin, neuregulin, and HGF expression was significantly higher in left-sided tumors. We found a higher proportion of conventional histology (83% v 63%) and moderate differentiation (82% v 69%) for left versus right-sided cases. Conclusions: We find that within MSS mCRC there are significantly more oncogenic mutations in right-sided tumors, and the difference in survival between right- and left-sided mCRC is primarily driven by differences in mutations. Left-sided tumors more commonly exhibit a “simpler” conventional histology that is lower grade and may rely on native RTK signaling, such as EGFR, for growth, providing a potential mechanism for the differential sensitivity to EGFR inhibitors seen by primary tumor site.
Final results of the McCAVE trial: A double-blind, randomized phase 2 study of vanucizumab (VAN) plus FOLFOX vs. bevacizumab (BEV) plus FOLFOX in patients (pts) with previously untreated metastatic colorectal carcinoma (mCRC).
Authors: Bendell Johanna C. , Sauri Tamara , Cubillo Antonio , López-López Carlos , Garcia Alfonso Pilar , Hussein Maen A. , Limon M. Luisa , Cervantes Andres , Montagut Clara , Santos Cristina , Bessudo Alberto , Modiano Manuel R. , Moons Veerle , Andel Johannes , Bennouna Jaafar , Van Der Westhuizen Andre , Samuel Leslie M. , Krieter Oliver , Rossomanno Simona , Hurwitz Herbert ,   McCAVE Study Group
Published: September 2018

3539 Background: VEGF-A and ANG-2 have complementary roles in regulation of tumor angiogenesis. Targeting VEGF-A with BEV in combination chemotherapy (CT) in mCRC has proven to increase PFS and OS. ANG-2 is overexpressed and associated with poor outcome of mCRC pts receiving BEVcontaining treatment. Hence, dual blockade of VEGF-A and ANG-2 by the bispecific mAb VAN with standard CT may improve clinical activity in mCRC. Methods: All pts received mFOLFOX-6 and were randomized 1:1 to also receive intravenous VAN 2000 mg every other week (Q2W) (Arm A) or BEV 5 mg/kg Q2W (Arm B). The primary end point was investigator assessed progression-free survival (PFS). Key eligibility criteria included pts with non-resectable mCRC, no prior therapy for advanced disease, PS 0-1, adequate organ functions, and no history of GI fistula/perforation or intraabdominal abscess within the last 6 months. Results: 192 pts were randomized (Arms A/B, n = 95/97) by 39 sites in 7 countries, between Oct 2014 and May 2016. Median follow-up was 17.6 months (range 2.8 – 20.7). In the ITT population (n = 189; Arms A/B, n = 94/95), median PFS in Arms A and B was 11.3 and 11.0 months (stratified hazard ratio (HR) 1.00 (95%CI 0.64-1.58; p = 0.985)), respectively. Objective response rate was 52.1% vs 57.9%. Relevant prognostic factors incl. RAS/BRAF status and tumor sidedness were balanced between arms and did not significantly influence outcome. Baseline plasma ANG-2 levels were prognostic in both arms but not predictive for response to VAN. The overall incidence of adverse events (AEs) grade ≥ 3 was similar (Arms A/B, 83.9%/82.1%); AEs grade ≥ 3 attributed to the mode of action of VAN/BEV included hypertension (37.6%/18.9%), hemorrhage (2.2%/1.1%), thromboembolic events (venous 6.5%/2.1%; arterial 1.1%/3.2%) and GI perforations incl. GI fistula & abdominal abscess (10.6%/8.4%). Conclusions: The combination of VAN and FOLFOX did not improve PFS and was associated with a marked increase in hypertension compared with BEV plus FOLFOX. Our results strongly suggest that ANG-2 is not a relevant therapeutic target in the setting of first line mCRC. Clinical trial information: NCT02141295.