bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of niraparib in combination with EGFR inhibitor panitumumab in patients with advanced colorectal cancer.
Authors: Alese Olatunji B. , Shaib Walid Labib , Akce Mehmet , Wu Christina , Lesinski Gregory B. , El-Rayes Bassel F. 
Published: February 2020

TPS269 Background: Panitumumab (Pmab) is a recombinant monoclonal antibody that binds specifically to the human epidermal growth factor receptor (EGFR), and is indicated for metastatic colorectal carcinoma (mCRC). EGFR inhibition induces synthetic lethality with poly ADP ribose polymerase inhibitors (PARPi) by attenuating DNA repair pathways. This susceptibility to PARPi-induced cell death by EGFR inhibition is associated with deficient Non-homologous end joining (NHEJ), and Homologous recombination (HR) mediated DNA repair and persistence of DNA damage. Furthermore, efficacy of PARPi (such as niraparib) is highly correlated with platinum sensitivity. Cancer cell sensitivity and resistance to both PARPi and platinum have been associated with loss and restoration of HR DNA repair, indicating similar mechanisms of anticancer activity and resistance. Platinum sensitivity in CRC could therefore predict for anticancer properties of PARPi when utilized in the setting of synthetic lethality. Combining PARP and EGFR inhibition has the potential to confer synergistic benefit, while ameliorating resistance mechanism to PARPi. This study aims to evaluate the activity of the combination of niraparib and Pmab in RAS wildtype (WT) mCRC. Methods: Eligible patients for the trial include advanced, RAS WT mCRC who have been intolerant of, progressed on, or failed at least one line of systemic chemotherapy. Those currently on first line oxaliplatin-containing regimen are allowed on the trial if they have remained stable or better (PR or CR) for at least 4 months on that line of treatment, and are being considered for maintenance therapy as standard of care. Patients must also be 18 years old, ECOG PS 0-1 and measurable disease per RECIST 1.1. A safety run-in cohort of 6 eligible patients, and additional 20 patients with the same inclusion criteria will be enrolled. Pmab dose - 6 mg/kg IV on days 1 & 15 of each 28-day cycle; Niraparib - 200mg or 300mg (based on body weight and platelet count) orally continuously. Primary endpoint: clinical benefit rate (CR +PR + SD). Biomarker analysis includes skin biopsies evaluated for p-Caspace-3, PARP, p-MAPK, Ki-67, and p27. The study was activated in Sept. 2019. Clinical trial information: NCT03983993.
Immunotherapy with Y90-radioembolization for metastatic colorectal cancer (iRE-C).
Authors: Kasi Pashtoon Murtaza , Toskich Beau M , Chandrasekharan Chandrikha , Prabhakar Dhivya , Sharif Saima , Berg Daniel James , Miller Ann , Chan Carlos Hou Fai , Laroia Sandeep 
Published: February 2020

TPS276 Background: Immune checkpoint inhibitors have revolutionized the treatment of a number of cancers. In colorectal cancers, their efficacy is limited to mismatch repair deficient or microsatellite stability-high (dMMR/MSI-High) tumors only. These constitute only 4-5% of all metastatic colorectal cancers (mCRC). Novel approaches are needed to make immunotherapy a viable option for mismatch repair proficient or microsatellite stable (pMMR/MSS) tumors. Increasing exposure of neo-antigens to the immune system could be one potential strategy to enhance the response of immunotherapy. Yttrium 90-radioembolization (Y90-RE) in combination with immunotherapy may work synergistically to enhance efficacy of each other. Additionally, radiation can potentially make the tumor microenvironment conducive to effector T-cell recruitment and function. Therefore, we hypothesize and propose the clinical trial of combining immunotherapy with Y90-RE as a feasible and safe strategy that will improve outcomes in patients with mCRC with liver-predominant metastases. Methods: This clinical trial will be conducted as a single-center, open-label, Phase I/II trial to evaluate initially the feasibility and safety of Y90-RE in combination with a fixed dose of immunotherapy (durvalumab) in subjects with liver-predominant, mCRC (Table). It will be offered in the refractory setting. The trial will be performed in 18 subjects with mCRC with liver metastasis and the safety of immunotherapy (durvalumab) with Y90-RE will be investigated in an accelerated titration design. This would allow a maximum tolerated dose with the minimum number of subjects. Correlative studies pertaining to serial circulating tumor DNA (ctDNA - liquid biopsies) testing as well as immune-panel based profiling will be performed alongside pre- and post-biopsies to study changes in the tumor microenvironment. Clinical trial information: NCT04108481. [Table: see text]
A randomized study evaluating tailoring of advanced/metastatic colorectal cancer (mCRC) therapy using circulating cell-free tumor DNA (ctDNA) (TACT-D).
Authors: Raghav Kanwal Pratap Singh , Wang Xin Shelley , Xiao Lianchun , Dasari Arvind , Morris Van K. , Johnson Benny , Shen John Paul Y.C. , Parseghian Christine Megerdichian , Kee Bryan K. , Shureiqi Imad , Fogelman David R. , Wolff Robert A. , Raymond Victoria M. , Odegaard Justin I. , Lanman Richard B. , Overman Michael J. , Kopetz Scott 
Published: February 2020

TPS277 Background: Identifying non-responders to expensive salvage therapies with modest benefits and substantial treatment related adverse events (TRAEs) (e.g. regorafenib/TAS102 in mCRC) is necessary to maximize benefits and limit toxicities. Serial ctDNA sequencing is reliable for tracking tumor dynamics and appears to predict resistance to therapy earlier than radiographic progression. Methods: TACT-D is a randomized study (N = 100) to validate the ability of changes in ctDNA (ΔctDNA) to predict resistance early and in limiting toxicities. We hypothesize that increase in ctDNA (measured by variant allele fraction) at 2 weeks (wk) into treatment can predict resistance earlier than standard radiographic means [at 8-12 wk] and detecting resistance early can enable prompt change in therapy resulting in reduction of TRAEs. Pts with mCRC eligible for either regorafenib/TAS102 are randomized 2:1 to either standard of care (SOC) or ctDNA arm. On SOC arm, treatment is given as per current paradigm i.e. for 8 wk and then restaging. On ctDNA arm, decision to continue therapy is based on ctDNA change between baseline and 2 weeks [ΔctDNA = ctDNA (C1D15 – C1D1)]. Increase in ctDNA triggers early radiographic staging (4 wk). Treatment is continued for disease stability/regression and discontinued for progression. Study has 2 co-primary endpoints: 1) Association of Δ ctDNA and radiographic progression [62 pts on SOC arm, have 94% power (2-sided α 0.05) to detect difference of 95% vs. 58% in progressive disease between pts with increase vs decrease in ctDNA] and 2) Compare proportion of pts experiencing TRAEs within 4 months between study arms [67 in SOC arm and 33 in ctDNA arm have 82% power (2-sided α 0.05) to detect a 30% decrease in toxicity]. Key secondary endpoints include: patient-reported outcomes (MD Anderson Symptom Inventory and PRO-CTCAE), OS, clinical events of special interest (hospitalizations/ER visits/medical interventions such as blood transfusions/IV hydration), clinical trial referral and cost effectiveness. Study is now actively accruing pts (NCT03844620). Funding: MD Anderson Cancer Center, Houston, TX & Guardant Health Inc., Redwood City, CA. Clinical trial information: NCT03844620.
Phase II study of nanoliposomal irinotecan (nal-IRI) with 5-fluorouracil (5-FU)/folinic acid (FA) in refractory advanced high-grade neuroendocrine cancer (HG-NEC) of gastroenteropancreatic (GEP) or unknown origin.
Authors: Gupta Medhavi , Choi Minsig , Ramirez Robert A. , Attwood Kristopher , Mukherjee Sarbajit , Iyer Renuka V. 
Published: February 2020

TPS636 Background: The incidence of GEP HG-NEC is increasing and the prognosis is poor. Etoposide–platinum (EP) combination is considered the standard (std) therapy (Rx), but survival is less than 1 year. There is an unmet need for an optimal 2nd line Rx in these patients (pts). Nal-IRI has shown efficacy in small cell lung cancer (pathologically similar to HG-NEC) and in 2nd line pancreatic adenocarcinoma. In a retrospective study, HG-NEC pts with progression on 1st line EP when treated with 2nd line FOLFIRI (FA+5-FU+ IRI) had a good response and a tolerable safety profile (Hentic et al, 2012). Based on this data and the fact that no std 2nd line Rx option exists in HG-NEC, we are evaluating the efficacy of nal-IRI+ 5-FU/FA in a prospective single-arm multicenter study. Methods: Advanced GEP or unknown origin HG-NEC pts with progressive disease/intolerance to 1st line Rx with EP or temozolomide/capecitabine; ECOG PS 0-2 would receive nal-IRI 70 mg/m2, FA 400 mg/m2 followed by 5-FU 2400 mg/m2 on D1 & 15 of 28-days cycle. Rx to continue till disease progression or unacceptable toxicity. Tumor assessment by CT/MRI per RECIST 1.1 q6 wks. Primary end point is to measure ORR (CR+PR). Secondary endpoints include PFS, TTP, OS, safety and QOL changes. Assuming a historic ORR of 15% with std Rx, 37 pts (upto 41 pts considering non-evaluable pts) are required to show an ORR of 30% at a power of 80% at 1-sided significance of α = 0.1. In stage 1, n1= 18 pts will be enrolled. If 3 or more responses are seen, an additional n2= 19 pts to be enrolled. If 8 or more responses are observed of the n = 37 evaluable pts, the Rx would be considered promising for further study. Genomic mutational profiling to be conducted on pre-study tumor samples and correlated with circulating tumor DNA (CT DNA). CT DNA level, assessed serially, will be correlated with Rx response and disease recurrence. We plan to accrue over 3 years at 3 sites. As of August 2019, 1-patient has been enrolled. The trial is funded by Ipsen Pharmaceuticals and the North American Neuroendocrine Tumor Society through the Clinical Investigator Scholarship. Clinical trial information: NCT03736720.
A pilot study of intratumoral SD-101 (toll-like receptor 9 agonist), nivolumab, and radiotherapy for treatment of chemotherapy-refractory metastatic pancreatic adenocarcinoma.
Authors: Chen Justin , Huynh Jasmine , Monjazeb Arta , Cho May Thet , Kim Edward Jae-Hoon 
Published: February 2020

TPS782 Background: Pancreatic adenocarcinoma is an aggressive disease projected to be the second leading cause of cancer-related death. A majority of patients have advanced disease on diagnosis. Combination chemotherapy is first-line for advanced disease but limited by toxicity and median survival under 1 year. SD-101 is a toll-like receptor 9 agonist that is injected intratumorally to increase immunogenicity in the tumor microenvironment. Localized radiation can further enhance this via antigen release and potential abscopal effects. Immunotherapy has revolutionized care for various solid organ malignancies but not yet for pancreatic cancer. Therefore, the combination of SD-101, localized radiation, and checkpoint inhibitor is a promising therapeutic strategy for metastatic pancreatic adenocarcinoma. Methods: Six patients with chemotherapy-refractory, liver-metastatic pancreatic adenocarcinoma will be evaluated for combination SD-101, radiation, and nivolumab. SD-101 is injected intratumorally into a liver metastasis on days 1, 8, 15, 29 with optional dosing days 43 and 57. Localized radiation (6-10 Gy per fraction) to the injected lesion will be given on days 1, 3, 5, 8, and 10. Nivolumab will be given at 240 mg every 2 weeks starting day 2 until progression or unacceptable toxicity. Blood samples will be collected at baseline and at regular intervals while on treatment. Biopsies will be obtained at baseline and on day 29. Primary objectives are to evaluate safety and tolerability, defined so if ≥5 patients reach day 29 without experiencing grade ≥3 treatment-related toxicity. Secondary objectives include preliminary efficacy as defined by disease control rate, duration of response, progression-free survival, and overall survival. Exploratory objectives include objective response rate and biomarker correlatives (T-cell clonality, tumor mutational burden, tumor infiltrative immune cell subsets, and immune-related gene expression profile). Blood and biopsy specimens will be analyzed using flow cytometry, qRT-PCR, RNA sequencing, and whole exome sequencing including immunohistochemistry on biopsy specimens. Clinical trial information: NCT04050085.
TRYbeCA-1: A randomized, phase III study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441).
Authors: Hammel Pascal , Berardi Rossana , Van Cutsem Eric , Feliu Jaime , Greil Richard , Wasan Harpreet Singh , Metges Jean-Philippe , Nygren Peter , Osterlund Pia J. , Noel Marcus Smith , Seufferlein Thomas , Creemers Geert-Yan , Gupta Anu , Salesse Sophie , Biswas-Baldwin Nigel , Dion Hedy , Youssoufian Hagop , Garzon Felix Tomas , El-Hariry Iman , Hidalgo Manuel 
Published: February 2020

TPS783 Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study inpatients with advanced pancreatic cancer whose disease progressed following first-line treatment. Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is a randomized, open-label Phase 3 trial (N = ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage III-IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. A hazard ratio in OS of 0.725 is being targeted which represents a conservative estimate based on the Phase 2b data and is viewed as being highly clinically relevant. An IDMC will be established to review safety at regular intervals andto review efficacy data at the planned interim and final analyses. Clinical trial information: NCT03665441.
PCRT16-001: Phase II study of PEGPH20 plus pembrolizumab for patients (pts) with hyaluronan (HA)-high refractory metastatic pancreatic ductal adenocarcinoma (mPDA).
Authors: Chiorean E. Gabriela , Ritch Paul S. , Zhen David Bing , Poplin Elizabeth , George Ben , Hendifar Andrew Eugene , Dragovich Tomislav , Coveler Andrew L. , Stoll-D'Astice Amy C. , Edwards Stephanie , Rosenthal Adam , Thorsen Shelley M. , Hingorani Sunil R. 
Published: February 2020

TPS785 Background: PDA is characterized by invasiveness and therapeutic resistance in part due to a desmoplastic stroma and an immunosuppressive microenvironment ( Provenzano PP, Hingorani S. Br J Cancer 2013). PD1/PD-L1 inhibitors have no single agent activity in PDA, except for pts with mismatch repair defects. There is high need to overcome resistance to immune targeted therapies and develop biomarkers for pts selection. Stromal HA poses a physical barrier and protects tumor cells from immune surveillance ( Kultti A, et al Biomed Res Int 2014). By remodeling the tumor stroma, PEGPH20 allows infiltration of cytotoxic T lymphocytes, and improves delivery of chemotherapy and PD1/PD-L1 antibodies ( Singha NC, et al Mol Cancer Ther 2015). mPDA pts refractory to 1st line therapy have median overall survival (OS) of 6 mos. We hypothesize that stroma remodeling with PEGPH20 sensitizes PDA to immune therapy, and stroma and immunologic biomarkers will identify pts most likely to benefit. In this trial we will evaluate the efficacy, safety and translational biomarkers of PEGPH20 plus pembrolizumab in HA-high refractory mPDA. Methods: Eligible pts have ECOG PS 0-1, ≤ 2 prior therapies for mPDA, life expectancy ≥ 12 wks, able/willing to have tumor biopsies at baseline and after 6 wks of treatment. PEGPH20 dosing is 3 µg/kg iv QW and pembrolizumab 200 mg iv Q3W (2-4 hrs after PEGPH20 on wk 1) in 3-wk cycles. All pts receive prophylactic low molecular weight heparin. Primary endpoint: progression-free survival (PFS). Secondary endpoints: safety, OS, response rates. Translational endpoints: flow cytometry of peripheral and intratumoral immune cells, T-cell receptor sequencing, immune transcriptome, immune subsets IHC, circulating cytokines, serial plasma and tumor HA levels. For the primary endpoint of PFS, with a sample size of 31 evaluable pts, a one-sided α-level of 0.05, assuming 12 mos of accrual and 6 mos of follow-up, this study has 80% power to detect a difference between the null hypothesis median PFS 3 mos, versus the alternative hypothesis median PFS 6 mos. The study was activated in May 2019 and is open to accrual; 6 pts were enrolled as of 24Sept 2019. Clinical trial information: NCT03634332.
Trends in PRO reporting in clinical trials leading to cancer immunotherapy drug approvals from 2011 to 2019.
Authors: Safa Houssein , Tamil Monica , Diab Adi , Semaan Adele , Chahoud Jad 
Published: February 2020

105 Background: Patient-reported outcomes (PROs) are a primary tool to evaluate the effect of a given drug on the health-related quality of life from a patient’s perspective and to maximize the value of patient-centeredness in drug development and approval. In this study, we aimed to evaluate the current trend in reporting, analysis and interpretation of PRO data. Methods: We conducted a systematic review of the FDA archives, identifying all cancer immunotherapy drug approvals between the years 2011 and 2019. We then retrieved the clinical trials that respectively led to these drug approvals from PubMed and ClinicalTrials.gov. We systematically screened for PROs and assessed their analytic tools and interpretation methods that were collected from the published journal articles and their study protocols. If one FDA approval was supported by more than one clinical trial, we included all studies in our review. An FDA approval was considered to include PROs if they were reported in at least one of the supporting trials. Results: Thirty-seven clinical trials leading to 35 immunotherapy drug approvals were identified. More than half (54%) did not publish any PROs. While PROs were reported in the primary clinical outcomes manuscript of 4 trials (11%) and in a secondary separately published paper for 13 trials (35%). The median time between the primary and secondary papers was 22 months (range: 5 - 40). In the 17 published PROs, the hypothesis was broad in 12 (71%), not reported in 4 (24%) and specific in only 1 (6%). Ten (59%) were reported as exploratory endpoints, five (29%) as secondary endpoints, and two (12%) did not specify the PRO reporting in their endpoints. The most common PRO instruments were EQ-5D (71%) and QLQ-C30 (65%). Control for type I error was needed but not done in 15 (88%). Fourteen (82%) described an approach for dealing with missing PRO assessments. None reported on significant differences based on race and ethnicity of participants. Conclusions: Suboptimal reporting and delays in publication of PROs occur regularly in cancer immunotherapy trials. Increased efforts are needed to enhance standardization and quality reporting of PROs to maximize the value of this data in cancer immunotherapy drug approval.
Alternative measure of therapy impact (TXI): Length of sojourn on treatment—Value of early restaging imaging for prediction of response to nivolumab among patients with advanced cancer.
Authors: Janicek Milos Josef 
Published: February 2020

106 Background: Cross-sectional Imaging (CI) plays an essential role in early assessment of patients on immune checkpoint inhibitors (ICIs), yet often remains inconclusive in the setting of advanced disease, prior cancer treatment, toxicity, and cancer unrelated findings. We propose a robust, reproducible imjScore based on measurable tumor response on the first two re-staging scans that may predict TXI. We are testing prognostic value of early imaging, time lag of ICIs effect, against Duration of clinically effective treatment as a Measure of Treatment Impact. Methods: Retrospective review of CI studies in 92 patients with advanced stage solid tumors treated with Nivolumab (Nivo) during 6/2015-8/2018 at BMC on standard clinical protocols. Time on therapy (TOTx) was used as a surrogate marker of therapy impact. Modified imRECIST score utilizing ∑ of 5 discrete cancer lesions at baseline, 1st, and 2nd CI since initiation of Nivolumab were adjusted for TOTx. Our imjSCORE averages "predicted days on therapy" from best fit function of tumor change/day [%] at each time point vs. TOTx and ratios between 1st and 2nd scan. Results: Median TOTx was 70 days (range 1-1029). Differences in imRECIST scores derived from two early restaging CI studies adjusted for TOTx were able to identify with high statistical significance two groups of "SHORT" vs "LONG" sojourn on Nivolumab around Median of 70 days. Early Progression curve was associated with shorter benefit of Nivo; Pseudo-progression curve showed significantly shorter sojourn on Nivolumab compared to initial Regression or Stable score curves (P < .002). Conclusions: The imjScore may differentiate with high likelihood patients with short versus long sojourn on Nivo as a novel measure of TXI. Our CI-based imjSCORE validates early imaging with a response curve and standardized analysis of the 1st and 2nd post-treatment scans. If validated with other ICIs, this scoring tool may allow early prediction of ICIs treatment response and clinical outcome. Further correlation with clinical biomarkers may lead to development of predictive nomograms of "short" versus "long" TXI.