bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study evaluating safety and efficacy of niraparib in patients with previously treated homologous recombination (HR) defective or loss of heterozygosity (LOH) high-metastatic esophageal/GEJ/proximal gastric adenocarcinoma: A Big Ten Cancer Research Consortium study.
Authors: Mamdani Hirva , Mehta Rutika , Fountzilas Christos , Radovich Milan , Perkins Susan , Jalal Shadia Ibrahim 
Published: February 2020

TPS472 Background: Adenocarcinoma of esophagus (EAC) and GEJ is the fastest rising cancer in the US. The outcomes are extremely poor with median overall survival (OS) being 12 mo in patients (pts) with metastatic disease. The standard first line treatment for metastatic EAC is platinum-based regimen with median progression free survival (PFS) of 6 mo. Second line options are associated with limited efficacy. An analysis of TCGA has shown 40% of EAC harboring abnormalities in HR genes, most likely resulting from chronic acid reflux induced DNA damage. HR dysregulation is commonly associated with high LOH. Sensitivity to PARP inhibition has been shown to be a surrogate for HR defects or BRCAness phenotype. Clinically PARP inhibitors have shown activity in HR defective prostate and ovarian cancers. These findings provide the basis for this study. Methods: Pts with metastatic esophageal/GEJ/proximal gastric adenocarcinoma, previously treated with 1 line of platinum containing chemotherapy, and harboring high LOH and/or deleterious alteration(s) in HR genes ( BRCA1/2, PALB2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, NBN, ARID1A, GEN1) are eligible for this study. Pts can be prescreened at the time of diagnosis of locally advanced or metastatic disease by genomic analysis of the most recent available tumor tissue. Pts will receive oral niraparib until disease progression or unacceptable toxicity. Primary objective is response rate (RR). Secondary objectives are safety and tolerability, progression free survival (PFS), and disease control rate (DCR). Exploratory objectives include correlation between high LOH and response to niraparib, mechanisms of resistance to PARP inhibition, EZH2 expression and its correlation with response and resistance to PARP inhibition, and analysis of germline HR gene mutations and correlation with response to niraparib. Estimated sample size is 43. The study has recently opened to accrual at Indiana University with intended collaboration with 2 additional sites. Clinical trial information: NCT03840967.
A phase II clinical trial of the phosphatidylserine targeting antibody, bavituximab, in combination with pembrolizumab in patients with advanced hepatocellular carcinoma.
Authors: Beg Muhammad Shaalan , Zhu Hao , Hsieh David , Kazmi Syed Mohammad Ali , Sanjeevaiah Aravind , Singal Amit G. , Kainthla Radhika , Khosama Leticia , Crane Kimberli , Brekken Rolf A. , Yopp Adam Charles 
Published: February 2020

TPS599 Background: Phosphatidylserine (PS) is an immunosuppressive lipid segregated to the inner leaflet of the plasma membrane of normal cells. PS is externalized to the outer leaflet of the plasma membrane on cells that line tumor blood vessels, tumor cells and exosomes in the tumor microenvironment creating a specific target for anticancer treatments. Bavituximab is a PS targeting antibody that binds to PS via β2 glycoprotein-1 (β2GP1), an abundant serum glycoprotein. Bavituximab can modulate the tumor immune microenvironment to promote anti-tumor immune activity. This clinical trial is evaluating the effect of combining bavituxumab and the checkpoint inhibitor pembrolizumab in patients with advanced hepatocellular carcinoma (HCC). Methods: This is a single arm phase 2 clinical trial for patients with histologically confirmed HCC which is not eligible for curative and/or loco-regional therapy. No prior systemic therapy for HCC is allowed. Patients should be > 18 years, have Child-Pugh Score A, ECOG 0-1 and meet the following laboratory criteria: total bilirubin ≤ 2.0, INR ≤ 1.7; Hgb ≥ 8.5 g/dl; AST, ALT ≤5 times ULN; platelet ≥ 50,000/mm3; and albumin ≥ 2.5 g/dl. Major exclusion criteria include thromboembolic event within the last 6 months, clinically evident ascites, GI bleeding within 2 months, uncontrolled hypertension, HIV and autoimmune disease (except DM1, childhood allergies and thyroid abnormalities if adequately controlled. Dosing is as follows: Bavituximab: 3 mg/kg IV weekly, pembrolizumab: 200 mg IV every 3 weeks. The primary objective is to determine the overall response rate (ORR) of therapy. Secondary objectives are to determine the safety, tolerability and other measures of clinical efficacy (overall survival, 6 month PFS, and duration of response). Tumor and blood samples are being collected to assess for pharmacodynamic biomarkers. A minimax two-stage method will be used to analyze ORR after the first 15 patients are accrued. If 3 or more of the first 15 patients have either a complete or partial response, 13 additional patients will be enrolled. ORR will be analyzed by RECIST 1.1 criteria. Clinical trial information: NCT03519997.
A phase III study of futibatinib (TAS-120) versus gemcitabine-cisplatin (gem-cis) chemotherapy as first-line (1L) treatment for patients (pts) with advanced (adv) cholangiocarcinoma (CCA) harboring fibroblast growth factor receptor 2 (FGFR2) gene rearrangements (FOENIX-CCA3).
Authors: Borad Mitesh J. , Bridgewater John A. , Morizane Chigusa , Shroff Rachna T. , Oh Do-Youn , Moehler Markus H. , Furuse Junji , Benhadji Karim A. , He Helen , Valle Juan W. 
Published: February 2020

TPS600 Background: Pts with adv CCA have poor survival outcomes, and chemotherapy offers limited survival benefit (5-year survival rates, 5–10%; median overall survival [OS], 8–12 months). FGFR2 gene rearrangements are known to be early drivers of oncogenesis in ~15% of pts with intrahepatic (i) CCA. Futibatinib, an oral, highly selective, irreversible FGFR1-4 inhibitor has shown antitumor activity against a broad spectrum of FGFR-deregulated tumors in preclinical studies. In a previous study, futibatinib demonstrated clinical activity and tolerability in heavily pretreated pts with adv CCA harboring FGFR2 gene rearrangements. This phase 3 trial (FOENIX-CCA3) is designed to evaluate futibatinib vs gem-cis as 1L therapy for pts with adv iCCA harboring FGFR2 rearrangements. Methods: FOENIX-CCA3 is a multicenter, open-label, randomized phase 3 study that will be conducted in pts with metastatic or unresectable iCCA harboring FGFR2 rearrangements (assessed at screening by a central laboratory). Pts must have an ECOG performance status of 0 or 1 and should not have received previous systemic anticancer therapy for adv disease (adjuvant/neoadjuvant therapy ≥6 mo prior to randomization is permissible). Pts with clinically-significant alterations in calcium-phosphorus homeostasis or ectopic mineralization/calcification will be excluded. Approximately 216 pts will be randomized (1:1 ratio) to receive 20 mg futibatinib once daily until disease progression or other discontinuation criteria are met or gem-cis (on days 1 and 8 of a 21-day cycle) for 8 cycles or until disease progression, whichever occurs first. Pts will be stratified by prior surgical excision (yes vs no), geographic region, and locally adv vs metastatic disease. The primary endpoint is progression-free survival (PFS) assessed by independent central review (ICR). Secondary endpoints include objective response rate and disease control rate based on ICR, OS, PFS per investigator assessment, and safety. The anticipated start date is in April, 2020.
Improving cascade genetic testing for families with inherited pancreatic cancer (PDAC) risk: The GENetic Education, Risk Assessment and TEsting (GENERATE) study.
Authors: Yurgelun Matthew B. , Ukaegbu Chinedu I. , Furniss C. Sloane , Kenner Barbara , Klein Alison , Lowy Andrew M. , McAllister Florencia , Mork Maureen E , Nelson Scott H. , Robertson Alison , Stopfer Jill E. , Underhill Meghan , Ocean Allyson J. , Madlensky Lisa , Petersen Gloria M. , Garber Judy Ellen , Lippman Scott Michael , Goggins Michael , Maitra Anirban , Syngal Sapna 
Published: February 2020

TPS779 Background: 4-10% of PDAC patients harbor pathogenic germline variants in cancer susceptibility genes, including APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53. For families with such pathogenic variants, the greatest potential impact of germline testing is to identify relatives with the same variant (cascade testing), thereby providing the opportunity for early detection and interception of PDAC and other associated cancers. Numerous factors limit cascade testing in real-world practice, including family dynamics, widespread geographic distribution of relatives, access to genetic services, and misconceptions about the importance of germline testing, such that the preventive benefits of cascade testing are often not fully realized. The primary aim of this study is to analyze two alternative strategies for cascade testing in families with inherited PDAC risk. Methods: 1000 individuals with a confirmed pathogenic germline variant in any of the above genes in a 1st/2nd degree relative and a 1st/2nd degree relative with PDAC will be remotely enrolled through the study website (www.GENERATEstudy.org) and randomized between two methods of cascade testing (individuals with prior genetic testing will be ineligible): Arm 1 will undergo pre-test genetic education with a pre-recorded video and live interactive session with a genetic counselor via a web-based telemedicine platform (Doxy.me), followed by germline testing through Color Genomics; Arm 2 will undergo germline testing through Color Genomics without dedicated pre-test genetic education. Color Genomics will disclose results to study personnel and directly to participants in both arms. All participants will have the option of pursuing additional telephone-based genetic counseling through Color Genomics. The primary outcome will be uptake of cascade testing. Secondary outcomes will include self-reported genetic knowledge, cancer worry, distress, decisional preparedness, familial communication, and screening uptake, which will be measured via longitudinal surveys. Enrollment is underway nationwide as of May, 2019. Clinical trial information: NCT03762590.
Vitamin D receptor agonist paricalcitol plus gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer.
Authors: Perez Kimberly , Cleary James M. , Karasic Thomas Benjamin , Raghavan Srivatsan , Rahma Osama E. , Nowak Jonathan , Borazanci Erkut Hasan , Downes Michael , Drebin Jeffrey A. , Tuveson David A. , Ting David Tsai , Moffitt Richard , Yeh Jen Jen , Aguirre Andrew , Evans Ronald , Von Hoff Daniel D. , Odwyer Peter J. , Wolpin Brian M. 
Published: February 2020

TPS784 Background: Patients(pts) with metastatic pancreatic cancer (PC) have a median survival of less than one year even with use of multiagent chemotherapy programs. Pancreatic tumors are composed of multiple cell types and a dense extracellular matrix that may support cancer cell proliferation and impede chemotherapy delivery. Cancer-associated fibroblasts (CAF’s) in the tumor microenvironment secrete pro-inflammatory factors and components of the extracellular matrix. In PC laboratory models, engagement of the vitamin D receptor (VDR) by VDR agonists shifts CAFs toward a more quiescent phenotype with reduced tumor growth and improved chemotherapy penetration (Sherman. Cell, 2014). Paricalcitol is a synthetic VDR agonist used in patients with secondary hyperparathyroidism due to chronic kidney disease. A prior pilot study evaluated IV paricalcitol with gemcitabine (G) and nab-paclitaxel (A) before surgical resection in patients with resectable PC (NCT02030860). Methods: Pts with previously-untreated metastatic PC will be enrolled in a two-stage study consisting of a safety run-in and a randomized phase 2 study (NCT03520790). In the run-in stage, 36 pts will be randomized 1:1:1 to G (1000 mg/m2) and A (125 mg/m2) given 3 weeks on and 1 week off plus: (a) paricalcitol 25mcg IV thrice weekly, (b) paricalcitol 16mcg oral daily, or (c) placebo oral daily. Grade 3/4 hypercalcemia or genitourinary stones will be considered dose limiting toxicities.Pts will undergo paired pre- and on-treatment tumor biopsies to examine pharmacodynamic (PD) markers by bulk and single cell RNA sequencing and multiplex immunofluoresence.Assuming safety and supportive PD assessments, the phase 2 study will randomize an additional 76 pts to two treatment arms with GA plus: (a) paricalcitol or (b) placebo.Paricalcitol formulation (IV or oral) will be determined based on data from the run-in stage.The primary endpoint of the phase 2 study is overall survival, with a total of 100 pts needed to identify a hazard ratio of 0.6 with 80% power and one-sided alpha of 0.10.Secondary endpoints include safety, response rate, and progression free survival.Trial funding provided by SU2C, CRUK,Lustgarten Foundation, and AACR. Clinical trial information: NCT03520790.
Stereotactic MR-guided on-table adaptive radiation therapy (SMART) for locally advanced pancreatic cancer.
Authors: Parikh Parag , Low Daniel , Green Olga L. , Lee Percy P. 
Published: February 2020

TPS786 Background: Standard dose radiation therapy has been unsuccessful in inoperable pancreatic cancer; with a negative study (LAP07) for conventional chemoradiation and dropping of the stereotactic body radiation therapy arm in Alliance A021501. Recently, reports of using high dose ablative radiation therapy has been associated with increased survival in retrospective studies. Moreover, technological advances with MRI-guided radiation therapy offer improved targeting and the ability to change the radiation delivery on a daily fashion; allowing ablative radiation doses over one week. However, it is not clear whether this can be done safely on a multiinstitutional basis. Methods: We are conducting the largest prospective study of ablative radiation therapy in pancreatic cancer. The study is a single arm, multi-institutional phase II, industry sponsored study to investigate the safety and efficacy of Stereotactic, MR guided, on-table-Adaptive Radiation Therapy (SMART). Eligibility criteria include locally advanced and borderline resectable pancreatic cancer patients with ECOG PS of 0 or 1; who have non-metastatic disease after a minimum of 3 months of any systemic therapy; including investigational agents. Patients will receive MR-guided radiation therapy to a dose of 50 Gy / 5 fractions; with maximum tumor coverage delivered each fraction that allows keeping the gastrointestinal organs at risk to a dose of 33 Gy or less. Primary endpoint is grade 3 of higher gastrointestinal toxicity at 90 days. Secondary endpoints are overall survival at 2 years, distant progression free survival at 6 months, and changes in patient related quality of life at 3 and 12 months. Target sample size was calculated to show at a significance level 0.05, a reduction of the toxicity rate to 8% or lower by using SMART compared with 15.8%, the toxicity rate of conventionally delivered chemoradiation at a power level 0.8. Given an expected 15% drop-out, the enrollment goal is 133. Descriptive statistics will be used for secondary objectives. The study opened in January, 2019 and is currently opened at 4 centers; with other US and international sites pending. Sponsored by Viewray, Inc. Clinical trial information: NCT03621644.
A pilot study of liposomal irinotecan plus 5-FU/LV combined with paricalcitol in patients with advanced pancreatic cancer progressed on gemcitabine-based therapy.
Authors: Grierson Patrick , Wang-Gillam Andrea , Park Haeseong , Pedersen Katrina , Tan Benjamin R. , Amin Manik A. , Suresh Rama , Trikalinos Nikolaos , Liu Jingxia 
Published: February 2020

TPS793 Background: Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second leading cause of cancer-related death by 2030, and is characterized by resistance to chemo- and radiotherapy and a highly fibrotic tumor microenvironment. Front-line therapies for advanced PDAC include FOLFIRINOX and gemcitabine/nab-paclitaxel with median overall survival ranging from 8.5 to 11 months. After progression on gemcitabine-containing therapy, 5-FU/LV/liposomal irinotecan is a standard second-line option, however outcomes are still poor. Retrospective studies demonstrate superior survival of advanced PDAC in patients with high serum levels of 25(OH) vitamin D. Notably, the PDAC tumor microenvironment is enriched in cancer-associated fibroblasts that favorably respond to vitamin D, prolonging survival in combination with chemotherapy in mouse models. Furthermore, vitamin D suppresses catabolism of irinotecan in gastrointestinal cancer cells, potentiating its efficacy. Therefore, we are conducing an investigator-initiated study of 5FU/LV/liposomal irinotecan with paricalcitol as second-line therapy in advanced PDAC. Methods: This is a pilot study of 5FU/LV/liposomal irinotecan combined with paricalcitol in patients with advanced PDAC progressed on gemcitabine-based therapy. All patients receive liposomal irinotecan, LV, 5-FU and paricalcitol. Liposomal irinotecan is given at 70 mg/m2 IV over 90 minutes, LV at 400 mg/m2 IV over 30 minutes, and 5-FU at 2400 mg/m2 continuous IV infusion over 46 hours, on Day 1 of each 14-day cycle. Paricalcitol IV infusion will precede the above, given according to assigned cohort (75 mcg weekly or 7 mcg/kg weekly). The primary objective of this study is to determine the tolerability between two different dose levels of paricalcitol added to the combination regimen of 5-FU/LV/liposomal irinotecan in patients with advanced PDAC. Secondary objectives are measures of efficacy (ORR, PFS, OS, CA19-9 biochemical response rate). Clinical trial information: NCT03883919.
Real-world data validation for differential expression of immunoregulatory molecules and targetable cancer genes may provide therapeutic insights into agnostic-driven trial designs.
Authors: Adashek Jacob J. , Szeto Christopher W. , Reddy Sandeep K. , Spiess Philippe E. 
Published: February 2020

10 Background: Targeting actionable genes and using immunotherapy have increased treatment options. We previously reported that some immunoregulatory molecules are found differentially regulated in the presence of certain gene mutations regardless of cancer subtype. Here we validated a subset of these associations in an independent, real-world dataset with distinct clinicopathological characteristics. Methods: Previously, 2740 TCGA patients were identified to have at least one potentially oncogenic mutation (mt) within an established 50-gene hotspot panel. Differential expression of 10 immunoregulatory molecules (IRM) was analyzed between mutant (mt) vs. wild-type (wt). To ensure observed significant associations were not confounded by tumor-type, differential IRM expression within mt-enriched tumor-types was compared to that of mt vs. wt. Now, using the NantHealth external database of 2739 unselected clinical cases these associations were validated. Results: Within the TCGA cohort 19/50 gene mutations were found to be significantly associated with ≥1 IRM expression. In many, the mt effect-size was larger than that of tumor-type; e.g. head & neck carcinomas (HNSCC) are highly enriched for CDKN2A mt (OR = 4.9, p = 4.3e-9), yet CDKN2A mt are more associated with CTLA4 expression than HNSCC histology (t = 7.0 vs. 5.4). Of these 15 associations, 6 were validated within the independent later-stage NantHealth cohort. Most notably, CDKN2A mt was validated as associated with increased PD1 and CTLA4 expression while KRAS and APC mt were validated as associated with decreased PDL1/2 expression. Conclusions: The presented differential checkpoint expression patterns are strongly associated with mutation status and are not primarily driven by tissue-type, which have been further validated by an external database. Strategies combining genomic targets have been shown to yield success as well as using immunotherapies. Our data suggests there may be a role for combining NGS targets along with IRM expression patterns to better guide future design of clinical trials in combatting various cancers in a tissue-agnostic fashion.
Indirect mechanisms of action of a novel IgG1 monoclonal antibody, NEO-201, to enhance immune killing of tumor.
Authors: Arlen Philip M. , Annunziata Christina M. , Fantini Massimo , Morelli M. Pia , Tsang Kwong Y. 
Published: February 2020

17 Background: NEO-201 is an IgG1 mAb targeting variants of CEACAM5/6 that demonstrates tumor sensitivity and specificity. Functional analysis revealed that NEO-201 is capable of engaging innate immune effector mechanism including ADCC and CDC to directly kill tumor cells expressing its target. Previous studies demonstrated safety/tolerability in non-human primates, and an on going clinical trial at the NCI is currently exploring its dosing and safety. We have explored indirect mechanisms of its action that may enhance immune tumor killing. NEO-201 has the ability to enhance NK activity by blocking the binding of CEACAM5 on tumor cells to CEACAM1 on NK cells. In addition NEO-201 can target and eliminate regulatory T cells (Tregs). Methods: In vitro functional assays, using various human tumor cell lines as target cells and NK-92 cells (CEACAM1+/CD16−) as effectors, were conducted to assess the ability of NEO-201to enhance antitumor cytotoxicity of NK-92 cells by blocking the interaction between CEACAM5 on tumor cells and CEACAM1 on NK cells. In addition, flow cytometry analsyis and CDC assays were performed to evaluate the ability of NEO-201 to target and eliminate human Tregs in vitro. Results: Addition of NEO-201 significantly enhanced NK-92 cell cytotoxicity against highly CEACAM5+/NEO-201+ cells, suggesting that its activity is correlated with the level of CEACAM5+/NEO-201+ tumor cells. Furthermore, NEO-201 targets human Tregs and mediates killing of opsonized T-reg cells via CDC. Conclusions: Previously we have demonstrated the ability of NEO-201 as an IgG1 mab to destroy tumor cells expressing its target directly through both ADCC and CDC. This study suggests that in addition, NEO-201may also mediate immune killing through additional mechanisms including blocking the interaction between CEACAM5 on tumor cells and CEACAM1 on NK cells to reverse CEACAM1-dependent inhibition of NK cytotoxicity. In addition, we have shown that NEO-201 is also able to recognize and eliminate human Tregs. Ongoing studies are looking at leveraging this phenomenon by combining NEO-201 with checkpoint inhibitors.