Clinical Trials In Pancreatic Cancer Research Articles

Abstract 5176: TIGIT expression increases with advancing clinical stages and does not differ across racial groups in resected pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a dismal 12% 5-year survival rate (SEER) due to a lack of early detection biomarkers and resistance to standard therapeutic options (surgery, chemotherapy, radiation). Black African Americans (BAA) have 20% increased incidence of PDAC compared to those with European Ancestry (EA). TIGIT, an immune checkpoint receptor, is a marker of T cell exhaustion and plays a key role in the inhibition of anti-tumor immune responses. Recent studies have demonstrated that immune checkpoint receptor expression (PD-1 and TIGIT) on specific T cell populations correlates to worse overall survival (OS). TIGIT inhibitors are being explored in clinical trials in pancreatic cancer due to implications of its ligand (CD155) promoting immune evasion. We hypothesize that targeted anti-TIGIT therapy, in conjunction with other therapies targeting the tumor microenvironment, could reverse the immune suppression that is characteristic of PDAC. We performed RNAscope in situ hybridization (ISH) with a probe specific for human TIGIT mRNA (combined with a nuclear counterstain) on 79 tissue samples. The cohort of tissue samples included 8 biopsies (endoscopic-guided fine needle biopsies at time of diagnosis), 66 primary (from surgical resection), and 5 metastatic (liver core biopsies from patients with a primary PDAC diagnosis) formalin-fixed paraffin-embedded (FFPE) tissue sections from patients with histologically confirmed PDAC. After cells were segmented based on nuclear recognition, the presence of TIGIT probe within the cytoplasm of each cell was determined and quantified. Percent positive cell values were then exported for statistical analysis in R. De-identified clinical metadata was obtained from REDCap, a cloud-based HIPAA-compliant database used to compile patient data for research purposes. We tested for associations between %TIGIT present and clinical covariates, using linear regression for continuous outcomes, and logistic regression for binary outcomes. ScRNAseq revealed that TIGIT mRNA is enriched in, but not exclusive to the T/NK cellular compartments in PDAC. Staining analysis showed that TIGIT expression did not differ significantly between racial groups (comparing BAA to non-BAA). The mean percentage of TIGIT positive cells was 64.0%. High expression of TIGIT was associated with clinical stage, where an increase in stage was associated with increasing %TIGIT (p < 0.05).The TIGIT biomarker assay can be conducted at time of diagnosis, time of surgical resection, and time of metastatic biopsy. If patients’ samples contain high levels of TIGIT expression, these patients may be candidates for anti-TIGIT drug therapy. Considering that TIGIT expression correlates with advancing clinical stage, patients with more advanced staging at diagnosis (stage IIB, III, IV) especially may benefit from anti-TIGIT therapy. Citation Format: Madison George, Julie Clark, Kendyll Gartrelle, Georges Nassif, Kailee Hartway, Daniel Long, Daniel Salas-Escabillas, Allison Wombwell, Thais Pichardo, Hui-Ju Wen, Simone Benitz, Samuel Zwernik, Rupen Shah, Hakmin Park, Philip, Gazala Khan, Howard Crawford, David Kwon, Brian Theisen, Nina Steele. TIGIT expression increases with advancing clinical stages and does not differ across racial groups in resected pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5176.

Abstract 7154: Ivospemin/doxorubicin combination modulates polyamine metabolism to improve survival in murine ovarian cancer models

Abstract Polyamines are small polycationic alkylamines that are absolutely required for the continual growth and proliferation of cancer cells. As cancer cells maintain elevated polyamine pools through dysregulated polyamine metabolism, its pharmacological modulation is a promising avenue in cancer therapeutics. The polyamine analogue ivospemin has shown efficacy in slowing pancreatic and ovarian tumor progression in vitro and in vivo and has demonstrated encouraging results in pancreatic cancer clinical trials. Considering nearly 75% of late-stage ovarian cancer patients develop resistant to platinum-based chemotherapies, limiting treatment options, the aim of our study is to determine the potential efficacy of ivospemin in combination with doxorubicin, a common chemotherapeutic used in platinum-resistant ovarian tumors. We have previously shown that ivospemin exposure decreases polyamine content in a variety of cancer cell lines through downregulation of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC) and induction of the polyamine catabolic enzyme spermidine/spermine-N1-acetyltransferase (SSAT). Here we examine the potential of combining ivospemin with doxorubicin. Ivospemin treatment reduces cell viability in ovarian adenocarcinoma cell lines and increases the toxicity of doxorubicin regardless of cisplatin sensitivity. Cells treated with the combination exhibit a greater decrease in polyamine levels than cells treated with either single agent. This increased polyamine depletion and decreased survival is accomplished through modulation of polyamine metabolism, predominately through an additive induction of SSAT activity. Using the syngeneic VDID8+ ovarian murine model, we further evaluated the ability of ivospemin to improve response to doxorubicin at clinical and sub-clinical dosing. Ascites fluid was used as a marker for tumor burden and evaluated for polyamine content. We found that the combination treatment increases median survival, delays tumor onset, and decreases overall tumor burden compared to either clinical or subclinical doxorubicin dosing schemes. Combination treatment also decreases overall polyamine content in the ascites by 75%. N1-acetylated spermidine is enriched in ascites from combination-treated mice, consistent with an upregulation of SSAT in response to treatment. Recognizing the non-representative mutational status of the VDID8+ model as a limitation, we are currently evaluating the combination of ivospemin and doxorubicin in genetically defined murine models that better recapitulate human high-grade serous ovarian carcinomas. Ongoing studies will determine influences on the tumor microenvironment and will mechanistically evaluate the cooperativity of ivospemin and doxorubicin on pathways outside of polyamine metabolism. Citation Format: Cassandra E. Holbert, Jackson R. Foley, Ashley C. Nwafor, Ting-Ann Liu, Elizabeth Bruckheimer, Jennifer K. Simpson, Tracy Murray Stewart, Robert A. Casero. Ivospemin/doxorubicin combination modulates polyamine metabolism to improve survival in murine ovarian cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7154.

Perceptions of Pancreatic Surgeons and the Current Status of Palliative Care for Pancreatic Cancer in China: A Multi-Center Online Questionnaire Survey

Objective: To investigate the perceptions of pancreatic surgeons regarding palliative care for pancreatic cancer and the current status of palliative care for pancreatic cancer patients in China. Methods: An online questionnaire consisting of thirty-five questions in five domains, including basic information of the respondents, personal interest, training and experiences of palliative care, recognition of the importance of palliative care, palliative care in the hospital of the respondents, and advice to improve the service of palliative care for pancreatic cancer, was distributed to pancreatic surgeons by the WeChat APP. All the data were automatically recorded and can be downloaded. The respondents' perceptions of palliative care and the current status of palliative care were depicted, and the factors influencing the perceptions of the respondents and palliative care in hospitals were further analyzed. Results: Responses from 429 pancreatic surgeons were validated. 81.4% were from tertiary hospitals, and 18.6% were from secondary hospitals. 94.2% were from general hospitals, and 5.8% were from cancer hospitals. Most surgeons have worked for over five years (93%), 72% had senior titles, and 54.5% held administrative positions. 49% have not read papers on palliative care before. 73.4% of the hospitals did not have a palliative care team, 77.9% did not have specific ward or bed for palliative care, 76.2% of the surgeons thought palliative care needed more attention in their hospitals. 97.4% of the surgeons thought palliative care was important for pancreatic cancer patients, and 94.9% were willing to join the palliative team. 46.6% of the surgeons thought palliative care should be conducted once pancreatic cancer was diagnosed. Most surgeons thought palliative care was helpful and should be involved in the multidisciplinary team. Regarding the geographical differences, surgeons and hospitals in North China performed better than in other regions. Surgeons with experience in clinical trials of pancreatic cancer performed better. The top three advice from the surgeons to promote palliative care were more education and training, seminars, and public broadcasting. 69.9% of the surgeons have concerns about the legal issue of implementation of palliative care. Conclusion: In general, the majority of pancreatic surgeons in China lack training and experience in palliative care for pancreatic cancer, and the current status of palliative care in most hospitals needs to be further improved. Prevalence of the participants think that palliative care is very important for pancreatic cancer patients. Palliative care should be provided once pancreatic cancer is diagnosed, and palliative care should be involved in the multidisciplinary team. More seminars, education and training, and public broadcasting are practical ways to improve palliative care for pancreatic cancer patients.

Abstract C012: TIGIT expression correlates to worse overall survival in primary and metastatic pancreatic ductal adenocarcinoma

Abstract Pancreatic Cancer has a 12% 5-year survival rate due to late-stage detection and lack of many chemotherapy or targeted therapy options. TIGIT is an immune checkpoint inhibitor being explored in clinical trials in pancreatic cancer due to the implications of its ligand (CD155) promoting immune evasion. TIGIT is a marker of T cell exhaustion and plays a key role in the inhibition of anti-tumor immune responses. We hypothesize that targeted anti-TIGIT therapy, in conjunction with other therapies targeting the tumor microenvironment, could reverse immune suppression that is characteristic of pancreatic ductal adenocarcinoma (PDAC). As such, here we aim to quantify TIGIT expression using automated RNAscope technology and to correlate it with overall patient survival. We performed RNAscope in situ hybridization and immunohistochemistry on 25 primary and 4 metastatic (liver) formalin-fixed paraffin-embedded (FFPE) tissue sections from patients with histologically confirmed PDAC. A nuclear counterstain combined with an RNAscope probe specific for the human TIGIT mRNA was utilized. Slides were scanned at 40X magnification with an automated slide scanner and quantified using the ISH-IHC module of the HALO-v3.5 software. After cells were segmented based on nuclear recognition, the presence of TIGIT probe within the cytoplasm of each cell was determined and quantified. Percent positive cell values were then exported for statistical analysis in SPSS. De-identified clinical metadata was obtained from REDCap, a cloud-based HIPAA-compliant database used to compile patient data for research purposes. Gender, survival months, ethnicity, race, tumor histology, stage, cancer history, treatment status, and comorbidities were evaluated. We analyzed a cohort of 29 histologically-confirmed surgically resected PDACs, comprised of 25 primary pancreatic tumor samples and 4 metastatic liver core biopsies. The mean percentage of TIGIT positive cells was 63%. From this, the TIGIT high versus low threshold was determined to be 70%. High TIGIT was associated with significantly lower overall survival (p=.013), suggesting that expression of TIGIT and T cell exhaustion may predict overall worse survival. The median overall survival months for the TIGIT low group was 321 months versus 106 months for the TIGIT high group. This data leads us to hypothesize that expression of TIGIT and T cell exhaustion may predict worse overall survival. Anti-TIGIT medications are currently in clinical trials for metastatic PDAC. Here we demonstrate that high TIGIT expression is associated with an overall worse prognosis and present a novel, automated TIGIT detection protocol that may be used to determine if patients are candidates for anti-TIGIT therapy. In a clinical setting, this novel, automated biomarker TIGIT detection protocol could be used to select candidates for anti-TIGIT therapy. This may lead to improved overall patient survival. Citation Format: Madison George, Julie Clark, Kendyll Gartrelle, Georges Nassif, Donald Rempinski, Daniel Long, Hui-Ju Wen, Simone Benitz, Samuel Zwernik, Rupen Shah, Hakmin Park, David Kwon, Philip Philip, Gazala Khan, Howard Crawford, Brian Theisen, Nina Steele. TIGIT expression correlates to worse overall survival in primary and metastatic pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C012.

Toxicity reporting consistency and subjective minimizing language use in colorectal cancer (CRC) and pancreatic cancer (PaC) clinical trials: A systematic review of phase III randomized controlled trials (RCTs) presented at ASCO between 2012-2022.

1567 Background: Objective and complete toxicity reporting in clinical trials is critical for patient-centered shared decision-making. Conference abstracts inform initial impressions of practice-changing treatments. Methods: We performed a systematic review of all abstracts of CRC and PaC phase 3 RCTs presented at ASCO annual meetings between 2012 – 2022; long-term follow-up, supportive care, and solely non-pharmacological studies were excluded. Objective minimization of adverse event (AE) reporting was defined as absent and/or incomplete reporting of cumulative grade 3-5 CTCAE (common terminology criteria for AE). We also assessed the use of subjective minimizing language (Chin-Yee et al ASH 2022), defined as use of “acceptable,” “tolerable”, “manageable”, “favorable” (primary minimization terms), or “feasible”, “safe”, “patients did well”, “limited” (secondary minimization terms), terms that falsely imply patients deemed the therapy as such. Presence/absence of PRO or QOL data was also assessed. Results: 63 RCTs met entry criteria (42 CRC, 21 PaC), detailed in Table. Most trials studied chemotherapy +/- other drugs (52; 83%). 17% of all abstracts did not provide any information on AE. Quantitative data on AEs were reported by 38 (60%) of abstracts. However, serious AE reporting was frequently absent (Table), with some trials reporting only specific toxicities (e.g. cytopenias) instead of cumulative CTCAE. Only 7 (11%) of abstracts noted the occurrence or absence of fatal AE. Any subjective-minimizing language was used in 15 (24%) abstracts. Notably, none of the abstracts using subjective-minimizing language provided information on fatal AE rates, nor reported on the patient perspective via QOL or PRO. Average grade ≥ 3 AE in the experimental arm were similar in abstracts with vs without minimizing language (44% vs 45%). Conclusions: Our systematic review of ph 3 RCTs in GI oncology presented at ASCO annual meetings reveals that subjective minimizing language is often used to describe serious toxicities, and without formally assessing the patient voice. Serious AE reporting is frequently absent or incomplete.[Table: see text]

Clinical trials for pancreatic cancer

Clinical trials for pancreatic cancer

Abstract 4944: Evaluating the efficacy of spermine analogue ivospemin (SBP-101) in combination with chemotherapy in ovarian cancer

Abstract Polyamines are small cationic alkylamines that play critical roles in essential cellular processes governing growth and proliferation. As such, cancers are fully reliant on increased polyamine pools maintained through dysregulation of polyamine metabolism. Pharmaceutical modulation of polyamine metabolism is a promising avenue in cancer therapeutics and has been attempted with enzyme inhibitors, including DFMO (difluoromethylornithine), and polyamine analogues. Ivospemin is a spermine analogue that has shown efficacy in slowing pancreatic and ovarian tumor progression both in vitro and in vivo and demonstrated encouraging results in pancreatic cancer clinical trials. We have shown that ivospemin decreases polyamine content through depression of the activity of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC) in a variety of cancer cell lines. Treatment of the VDID8+ murine ovarian cancer model with ivospemin resulted in a marked increase in survival. Here we examine the potential of combining ivospemin and chemotherapeutic agents that are used to treat cisplatin-resistant ovarian cancer. Treatment with gemcitabine, topotecan, and doxorubicin increased the in vitro toxicity of ivospemin, while paclitaxel and docetaxel did not have any added benefit over ivospemin alone. Using the VDID8+ model, we further evaluated the efficacy of ivospemin in combination with gemcitabine, topotecan, and doxorubicin in vivo. Ascites fluid was used as a marker of tumor burden and evaluated for polyamine content. Addition of ivospemin improved the survival of mice treated with any of the three chemotherapeutics. The ivospemin and doxorubicin combination mice had the greatest median survival time; this combination is being further evaluated in mechanistic studies and additional murine studies. Ovarian cancers have extremely immunosuppressive tumor microenvironments (TME) and metabolic reprogramming of the TME to reduce immunosuppressive phenotypes is a promising approach for treatment. Sustained elevation of polyamine levels supports an immunosuppressive TME, and evidence suggests that pharmacologic depletion of polyamines may reduce immunosuppressive phenotypes. DFMO treatment in the immunosuppressive VDID8+ model influences the immune cells of the TME, and we therefore are investigating the combination of ivospemin and DFMO in ovarian cancer. In addition to the cooperativity of ivospemin and chemotherapeutic agents, we have observed a cooperative antiproliferative response in ovarian cancer cells following DFMO and ivospemin cotreatment. Together, these studies suggest the potential of polyamine modulation by ivospemin and DFMO in combination with standard of care chemotherapy. Future studies will determine influences on the immune microenvironment and will evaluate cooperativity between ivospemin, DFMO, and chemotherapy. Citation Format: Cassandra E. Holbert, Jackson R. Foley, Tracy Murray Stewart, Michael J. Walker, Elizabeth Bruckheimer, Jennifer K. Simpson, Robert A. Casero. Evaluating the efficacy of spermine analogue ivospemin (SBP-101) in combination with chemotherapy in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4944.

Transcriptomic analysis of pancreatic adenocarcinoma specimens obtained from Black and White patients.

In pancreatic cancer clinical trials, Black patients are under-represented while having higher morbidity and mortality rates as compared to other racial groups. Multiple factors, including socioeconomic and lifestyle factors may contribute to this disparity, but genomic contributions remain unclear. In an exploratory project to identify genes that may contribute to differences in survival between Black (n = 8) and White (n = 20) patients with pancreatic cancer, transcriptomic sequencing of over 24,900 genes was performed in human pancreatic tumor and non-tumor tissue obtained from Black and White patients. Over 4,400 genes were differentially expressed in tumor and non-tumor tissue, irrespective of race. To validate these results, the expression of four genes (AGR2, POSTN, TFF1, and CP) reported to be up-regulated in pancreatic tumor tissue as compared to non-tumor tissue were confirmed using quantitative PCR. Transcriptomic analysis that compared pancreatic tumor tissue from Black and White patients revealed differential expression in 1,200 genes, while a comparison of the non-tumor and tumor gene expression differences within each race revealed over 1,500 tumor-specific differentially expressed genes in pancreatic tumor and non-tumor tissue from Black patients. We identified TSPAN8 as a potential tumor-specific gene significantly overexpressed in pancreatic tumor tissue in Black patients as compared to White patients. Using Ingenuity Pathway Analysis software to compare the race-associated gene expression profiles, over 40 canonical pathways were identified to be potentially impacted by the gene expression differences between the races. Heightened expression of TSPAN8 was associated with poor overall survival, suggesting TSPAN8 as one potential genetic factor contributing to the differential outcomes in Black patients with pancreatic cancer, supporting the potential utility of larger genomic studies to further explore the role of TSPAN8 in pancreatic cancer.

Call to action: overcoming enrollment disparities in cancer clinical trials with modernized eligibility criteria.

Traditional clinical trial eligibility criteria restrict study populations, perpetuating enrollment disparities. We aimed to assess implementation of modernized eligibility criteria guidelines among pancreatic cancer (PC) clinical trials. Interventional PC trials in the United States since January 1, 2014, were identified via clinicaltrials.gov with December 31, 2017, as the transition for pre- and postguidance eras. Trials were assessed for guideline compliance and compared using Fisher exact test. In total, 198 trials were identified: 86 (43.4%) were pre- and 112 (56.6%) postguidance era. Improvements were seen in allowing patients with history of HIV (8.6% vs 43.8%; P < .0001), prior cancer (57.0% vs 72.3%; P = .034), or concurrent and/or stable cancer (2.1% vs 31.1%; P < .0001) to participate. Most (>95%) trials were compliant with laboratory reference ranges, QT interval corrected for heart rate (QTc) cutoffs, and rationalizing excluding prior therapies both pre- and postguidance eras. However, overall compliance with modernized criteria remains poor. We advocate for stakeholders to update protocols and scrutinize traditionally restrictive eligibility criteria.

Transparency of clinical trials in pancreatic cancer: An analysis of availability of trial results from the ClinicalTrials.gov database.

Pancreatic cancer (PC) is a highly malignant tumor of the digestive system. As clinical trials involving PC are increasingly being conducted, the transparency of the generated data has become an important issue of concern. In other areas of medicine, clinical trial transparency presents a worrying state of affairs. However, at present, there has been no study examining the transparency of data derived from PC clinicaltrials. A comprehensive search was conducted in the ClinicalTrial.gov database for clinical trials investigating pancreatic cancer as of June 2022. We examined the availability of clinical trial results and recorded the characteristics of the trials. A total of 856 trials were included in this study, of which 668 were completed and 188 were terminated or suspended. The results of 626 trials (73.13%) were available, of these 230 trials (26.87%) did not disclose any information on the trial data in any form. The publication rate for trials with available results was 86.10%, but the report rate on ClinicalTrial.gov was only39.78%. Although approximately 90% of clinical trial investigating interventions on patients with PC have published study results, 30% of trials did not report any findings, and the disclosure of trial results from ClinicalTrial.gov was unsatisfactory. In general, there is still room for improvement in the transparency of PC clinical trials.

Racial disparities in pancreatic cancer clinical trials: Defining the problem and identifying solutions.

Underrepresented minority patients with pancreatic cancer have differential access to cancer treatments, including clinical trials. The successful conduct and completion of clinical trials is critical to improve outcomes for patients with pancreatic cancer. Therefore, it is essential to consider how to maximize eligibility of patients for both therapeutic and non-therapeutic clinical trials. It is important for clinicians and for the health system to understand individual-, clinician-, and system-level barriers to recruitment, enrollment, and completion of clinical trials to alleviate bias. Understanding strategies that lead to improved enrollment of underrepresented minorities, socioeconomically disadvantaged individuals, and underserved communities will improve generalizability of cancer clinical trials and advance health equity.

Abstract 2636: Targeting Autotaxin to suppress stromal signaling in the tumor microenvironment to improve outcome to therapy in fibrotic tumor types

Abstract Recent findings indicate that in cancer, host immune suppression and resistance to therapy is orchestrated by the presence and activity of stromal cells in the tumor microenvironment. Therefore novel approaches to overcome stromal mediated resistance to therapy represent a potential strategy to improve the outcome to chemotherapy and immune checkpoint blockade, particularly in tumors that have a fibrotic microenviroment. Autotaxin is an enzyme that converts Lysophosphatidylcholine (LPC) to Lysophosphatidic Acid (LPA), a key pathway that is aberrantly activated in fibrosis. LPA has also been described to act directly on tumor cells, promoting their growth and proliferation via G protein-coupled LPA Receptors (LPARs). IOA-289 is a novel, potent, selective and orally bioavailable inhibitor of Autotaxin, a target with known clinical application in fibrotic diseases and with a strong rationale for exploration in cancer. In preclinical models, IOA-289 modulated levels of circulating LPA in a dose dependent manner. At doses achieving at least 50% reduction of circulating LPA, IOA-289 showed monotherapeutic efficacy in in vivo mouse models of cancer. Notably the effects were most prominent in orthotopic models that recapitulate the stromal components of the microenvironment. In vitro studies investigated the mechanism of action of IOA-289, and it was shown to be driven by: (i)Direct anti-tumor activity on cancer cell lines in vitro (ii)Modulation of the secretory profile of fibroblasts(iii)Increased T cell infiltration in vitro and in vivo In a healthy volunteer study following a single oral ascending dose, IOA-289 showed a dose dependent increase in plasma and a corresponding decrease in circulating LPA. We also demonstrated that ATX was elevated in plasma from pancreatic cancer patients compared to samples from healthy volunteers and are correlated with soluble CA19-9. Based on our preclinical data we postulate that inhibition of the ATX/LPA pathway with IOA-289 may be a beneficial therapeutic strategy for cancer patients with fibrotic tumor microenvironments. The predicted biologically effective dose of IOA-289 has been calculated using PK/PD modelling combining data from preclinical studies and from the phase Ia healthy volunteer study. IOA-289 is scheduled to enter a phase Ib clinical trial in pancreatic cancer. Citation Format: Zoe Johnson, Marcel Deken, Ragini Medhi, Lauren Maggs, Alan Carruthers, Anne Cheasty, Alessia Tagliavini, Andrea Nizzardo, Marco Pergher, Karolina Niewola, Amy Fraser, Lars van der Veen, Pritom Shah, Luigi ZIviani, Stefano Milleri, Michael Lahn. Targeting Autotaxin to suppress stromal signaling in the tumor microenvironment to improve outcome to therapy in fibrotic tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2636.

Abstract 299: Self-assembling nanoparticles: A novel approach for targeted cancer treatment using tumor treating fields

Abstract Tumor Treating Fields (TTFields) are used in cancer treatment as they offer increased efficacy, safety, and low adverse effects. They have shown significant potential in pancreatic cancer (PC) clinical trials when combined with chemotherapy. It is pertinent to know that although TTFields-chemotherapy combination definitely enhances the treatment efficacy, it also results in chemotherapy induced severe adverse effects. To resolve this, we earlier reported development of Gemcitabine loaded self-assembling cationic-anionic polymer nanoparticles (S-CAP NPs) capable of achieving TTFields-triggered targeted drug release at the PC tumor site. Initially, four S-CAP NPs [C4 and C7 from chitosan- bovine serum albumin (Chitosan-BSA) S-CAP NPs; P5 and P8 from polyethylenimine- bovine serum albumin (PEI-BSA) S-CAP NPs] were shortlisted [Table 1 - particle size: ~ 200 nm; % encapsulation efficiency (EE): 55-65%]. For proof-of-concept studies, effect of TTFields on the % EE and % cumulative drug release of the S-CAP-NPs was investigated. The studies revealed (Table 1) significant reduction (p value &amp;lt; 0.05) in the % EE of S-CAP NPs within 48h TTFields treatment, confirming that the TTFields destabilize the NPs triggering targeted drug release. Similarly, In vitro drug release studies showed significant increase (p&amp;lt; 0.01) in rate of drug release from S-Cap NPs in presence of TTFields. The cell inhibition assay confirmed the synergism in cell apoptosis wherein PEI-BSA S-CAP NPs showed higher efficacy compared to chitosan-BSA S-CAP NPs. Further, additional stability studies continued over a period of 18 months confirmed stable formulations. In vivo acute and chronic toxicity studies are underway to identify the most optimum dose of S-CAP NPs for further in vivo efficacy studies. To summarize, S-CAP-NPs present a promising avenue to achieve targeted chemotherapy in conjunction with TTFields. This work is supported by AACR-Novocure tumor treating fields research fellowship. Table 1. Effect of TTFields on % encapsulation efficiency (n=3). Data represented as Mean ± SD. Batch Particle size (nm) Encapsulation efficiency (%) - 0h Encapsulation efficiency (%) - 24h - 150 KHZ Encapsulation efficiency (%) - 48h - 150 KHZ Chitosan-BSA S-CAP NPs C4 210.54 ± 38.96 61.26 ± 5.11 36.21 ± 3.53 24.86 ± 3.19 C7 215.67 ± 32.55 65.31 ± 5.84 32.19 ± 2.68 21.86 ± 4.64 PEI-BSA S-CAP NPs P5 198.29 ± 41.05 58.83 ± 3.33 27.66 ± 3.31 18.96 ± 3.96 P8 209.92 ± 31.33 64.31 ± 5.13 24.83 ± 4.29 19.42 ± 2.73 Citation Format: Preshita Prafulla Desai, Sunil Prabhu. Self-assembling nanoparticles: A novel approach for targeted cancer treatment using tumor treating fields [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 299.

Use of modernized eligibility criteria in pancreatic cancer clinical trials.

6545 Background: In 2017, ASCO + Friends recommended modernized eligibility criteria to improve generalizability of clinical trial results. Traditional criteria contribute to disparities in trial participation, yet modernized criteria can equalize eligibility rates. We aimed to assess use of modernized eligibility criteria in pancreatic ductal adenocarcinoma (PDAC) clinical trials since the updated guidelines. Methods: Modernized eligibility criteria were obtained from ASCO + Friends guidelines. Clinicaltrials.gov was queried for “pancreas adenocarcinoma” trials from Jan. 1, 2018 onward and eligibility criteria were assessed for compliance with modernized criteria. Kruskal-Wallis and Fisher’s exact tests were used to determine differences in compliance based on disease stage(s), starting year, phase, and funder. Results: In total, 108 clinical trials were identified - 31.5% for resectable, 56.5% for unresectable, 12.0% for both resectable/unresectable disease. Most trials were phase 1 (24.1%), phase 1|2 (15.7%) or phase 2 (45.4%). Funding sources included industry (38.0%), NIH (22.2%) and other sources (39.8%). No trial was compliant with all modernized criteria. Only 34.7% of trials allowed patients with ECOG performance status of 2. HIV+ patients were not allowed in 56.5% of trials. Only 7 trials (6.5%) were compliant with assessing renal function whereas 64.8% appropriately used upper limit of normal cutoffs for labs. Among trials that excluded patients for CHF, 59.6% used a classification system for exclusion. Specific cardiac abnormalities were excluded in 60.2% of trials. Prior malignancy was allowed in 71.3% of trials if treated &gt; 2 years prior and concurrent malignancy, if stable, was allowed in 21.3% of trials. Prior PDAC treatment was allowed for 38.0% and required for 24.1% of trials. If prior treatment was allowed, 94% justified drug exclusions, 40.3% did not require a washout period, and 35.8% required recovery from prior adverse events. Stable/treated brain metastases were allowed in 33.8% of trials for unresectable cancer. Compliance with prior malignancy criteria improved from 2018-2019 to 2020-2022 (56.0% vs 84.5%, respectively; p = 0.001). Requirement of prior PDAC treatment was associated with disease stage (8.8% for resectable, 32.8% for unresectable, and 23.1% for both; p = 0.024), as was exclusion based on prior therapy (58.8% for resectable disease, 14.8% for unresectable, and 30.8% for both; p &lt; 0.0001). Earlier trial phase was associated with prior treatment allowance (p = 0.002), whereas later phase trials were less likely to allow prior treatment (p = 0.021). NIH-funded trials required prior treatment (37.5%) more than industry (29.3%) or other (11.6%) funded trials (p = 0.034). Conclusions: Modernized eligibility criteria are inadequately implemented in PDAC clinical trials. Efforts to improve their use are warranted to produce more generalizable results and advance inclusivity.

Eligibility Criteria Perpetuate Disparities in Enrollment and Participation of Black Patients in Pancreatic Cancer Clinical Trials.

PURPOSEClinical trials determine safety and efficacy of cancer therapeutics and establish standards of care. Minority patient participation in cancer clinical trials is dismal. We aimed to determine the impact of eligibility criteria on disparities in pancreatic ductal adenocarcinoma (PDAC) clinical trial candidacy.METHODSTraditional PDAC trial eligibility criteria were obtained from ClinicalTrials.gov. Patients with PDAC who sought care at Virginia Commonwealth University Health from 2010 to 2019 were included. Clinical data were obtained from billing codes and discrete values in the electronic medical record. Eligibility criteria differences between racial groups were determined using chi-squared tests and unconditional maximum likelihood-based odds ratios.RESULTSAmong 676 patients, most identified as Black or White race (42.5% and 51.6%, respectively). Using traditional criteria, Black patients were more likely to be ineligible for participation compared with White patients (42.4% v 33.2%, P = .023) secondary to hypoalbuminemia (14.1% v 7.9%, P = .023), HIV (3.1% v 0.3%, P = .010), hepatitis B (1.7% v 0%, P = .043), and hepatitis C (9.1% v 3.4%, P = .005). Black patients were also numerically more likely to be ineligible because of renal dysfunction, recent coronary stenting, and uncontrolled diabetes mellitus. Prior cancer treatment excluded fewer Black than White patients (9.1% v 14.0%, P = .072), most attributable to lower rates of neoadjuvant chemotherapy received. Strategic eligibility criteria revisions could equalize ineligibility rates between Black and White patients (26.8% v 24.8%, P = .581).CONCLUSIONTraditional eligibility criteria differentially exclude Black patients from participating in PDAC clinical trials. These criteria perpetuate disparities, limit generalizability, and are often not medically justifiable. Revised criteria may improve participant diversity, without compromising safety or study results.

Patient-reported outcomes (PROs) in pancreatic cancer clinical trials (CTs).

534 Background: Incorporating PROs into CTs is critical for patients with pancreatic cancer, as these individuals often experience a high symptom burden and prioritize maximizing quality of life (QOL). Methods: We reviewed protocols of completed U.S. CTs listed on ClinicalTrials.gov that investigated curative/palliative interventions in pancreatic cancer from 1995-2020. We assessed up to August 2021 if CT publications reported PRO results through linked publications and an independent search through PubMed/MEDLINE. We extracted CT details (funding, eligibility, etc), and if PROs (outcome directly reported by patients) were listed as an endpoint (primary/secondary/exploratory). We classified interventions as cancer-directed (e.g. chemotherapy), supportive care (e.g. neurolysis), or other (e.g. curcumin). Results: We reviewed 619 protocols and included 379 in the analysis. Most CTs investigated cancer-directed interventions (317, 83.6%). Only 43 (11.4%) included PROs as endpoints (Table). In these, most of the PROs assessed QOL (34, 79.1%) and pain (15, 34.9%). For the 33/43 (76.7%) protocols that listed a specific PRO instrument, EORTC-QLQ C30 (11/33, 33.3%) was the most common. Only 6 (18.2%) protocols included pancreatic cancer-specific PROs, such as QLQ-PAN26. Supportive care CTs were more likely to assess PROs than cancer-directed CTs (odds ratio, OR= 62.6, 95% CI 16.7-234.3, p&lt;0.0001). Protocols listed PROs as a primary, secondary, and exploratory endpoint in 15 (34.9%), 25 (58.1%), and 3 (6.9%) CTs respectively. Most CTs (13/15, 86.7%) with PROs as a primary endpoint evaluated supportive care interventions. Of 15 CTs with PROs as a primary endpoint, 10 (66.7%) had results published. Of 28 CTs assessing PROs as a secondary/exploratory outcome, 20 (71.4%) had published results and 12 (42.9%) included PRO data. Conclusions: From 1995-2020, only 11.4% of pancreatic cancer CTs incorporated PROs as endpoints. Supportive care CTs were more likely to include PROs than cancer-directed CTs. Our findings underscore the need to improve efforts to incorporate PROs into CTs for patients with pancreatic cancer. Data as number (%).[Table: see text]

Abstract PR-09: Eligibility criteria perpetuate disparities in enrollment and participation in pancreatic cancer clinical trials

Abstract Introduction: Clinical trials determine efficacy and safety of cancer therapeutics and set the standard of care. Inequitable representation of participants leaves gaps in our knowledge, limits opportunities to investigational therapeutics and subsequently perpetuates disparities in survivorship. Clinical trial eligibility criteria have been postulated to differentially impact certain racial/ethnic groups which have higher prevalence of infectious and chronic diseases. We aimed to determine the impact of eligibility criteria on disparities in pancreatic cancer clinical trial candidacy. Methods: Common eligibility criteria for Phase 2 and 3 pancreatic cancer trials listed in clinicaltrials.gov were compiled for simulation of a clinical trial screening process. Patients with pancreatic ductal adenocarcinoma who sought care at VCU Massey Cancer Center (Richmond, VA) from 2010-2019 were included. Clinical variables pertaining to eligibility criteria were obtained from billing codes and discrete values in the medical record. Inclusion/exclusion criteria were applied to determine overall eligibility and for individual criterion. Chi-squared tests were utilized to identify statistically significant differences in patient eligibility between racial groups. Results: A total of 676 patients with pancreatic cancer were identified, with Black (42%) and White (52%) patients comprising the majority of the patient population. Black patients were significantly more likely than White patients to be deemed ineligible based on Creatinine (6.08% vs 2.27%, p = 0.036), HIV (3.136% vs 0.286%, p = 0.01), Hepatitis B (1.742% vs 0%, p = 0.043), and Hepatitis C (9.06 vs 3.43%, p = 0.005). Black patients were also more likely to be ineligible based on Albumin (12.45% vs 7.47%, p = 0.076), history of coronary stenting in the past 6 months (1.39% vs 0%, p = 0.087), and uncontrolled diabetes (8.96% vs 6.07%, p = 0.244), although differences in these criteria did not achieve statistical significance at 5% level. History of prior cancer treatment was the only variable that excluded less Black patients than White patients (9.06% vs 14.0%, p = 0.072) and was attributable to more White patients initiating neoadjuvant chemotherapy for their pancreatic cancer prior to seeking care at VCU. After applying all criteria, Black patients were more likely to be ineligible for participation compared to White patients (42.0% vs 33.3%, p = 0.039). Conclusion: Standard pancreatic cancer clinical trial eligibility criteria differentially exclude Black patients from participating in clinical trials. These criteria perpetuate racial disparities, limit generalizability to real world clinical scenarios, and are often not medically justifiable. Alternative eligibility criteria can improve representation of diverse participants, provide more equitable access to investigational therapeutics and reduce disparities in survivorship, without compromising patient safety or study results. Citation Format: Andrea N. Riner, Selamawit Girma, Nevena Skoro, Tamas S. Gal, Kelly M. Herremans, Nitai Mukhopadhyay, Vignesh Vudatha, Shreya Raman, Thomas George, Jose G. Trevino. Eligibility criteria perpetuate disparities in enrollment and participation in pancreatic cancer clinical trials [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PR-09.

More efficient clinical trials in pancreatic cancer: develop better treatment options, faster

Clinical development of new treatment options for patients with pancreatic cancer has been slow and expensive and resulted in few effective therapies. With a dismal five-year survival rate of 11% in the U.S., pancreatic cancer remains the third leading cause of cancer-related deaths and is poised to move to second by 2030. Standard clinical trials typically compare one investigational treatment to one standard of care, encompass one phase of clinical investigation at a time, and treat one patient population. Accrual and data analysis are often very slow, and unfortunately, the vast majority of clinical trials targeting pancreatic cancer patients are unsuccessful. More efficient clinical trial designs can include combining phases I and II or phases II and III, and trials that involve a master protocol approach can also answer multiple clinical questions simultaneously. These modern clinical trial designs can allow a faster, more efficient and cost-effective approach to testing investigational therapies in patients with pancreatic cancer and, most importantly, fewer patients may be required to determine the efficacy of treatment. Herein we summarize some of the recent innovative clinical trials in pancreatic cancer to provide meaningful data toward developing new treatment options to benefit patients with a dismal disease like pancreatic cancer.

Understanding pancreatic cancer stem cells and their role in carcinogenesis: a narrative review.

The purpose of this review article is to describe the pathogenesis of pancreatic cancer and to better understand the role of abnormal stem cells in the development of pancreatic cancer. Pancreatic cancer is a highly fatal disease that is caused by the uncontrolled proliferation of pancreatic exocrine or neuroendocrine glands. It is believed that pancreatic cancers arise from a small population of abnormal cancer stem cells (CSCs) that promote tumorigenesis, tumor metastasis and therapeutic resistance. The molecular markers CD133, CXCR4, DCLK1, c-MET, ABCG2 and Lgr5 are routinely used to detected and observe the behaviours of pancreatic cancer stem cells (PCSCs). A comprehensive search was performed on PubMed, Google Scholar, Scopus, Clinicaltrials.gov and Web of Science using related keywords. Articles focusing on PCSCs and pancreatic cancer pathogenesis, biochemistry and clinical trials were selected. Although very little is known about the exact cause of pancreatic cancer, PCSCs seem to play an important role in carcinogenesis. Mutated biochemical cascades include Sonic Hedgehog, K-RAS-JNK, DLL4/Notch and Nodal/Activin. Several clinical trials are trying to determine if the transplantation of hematopoietic stem cell or peripheral stem cells could be useful for the treatment of such an aggressive tumor.

Racial Disparity Between Whites and African Americans in Incidence and Outcome of Pancreatic Cancer: Have We Made a Difference?

Racial Disparity Between Whites and African Americans in Incidence and Outcome of Pancreatic Cancer: Have We Made a Difference?