Citations

Abstract Pancreatic adenocarcinoma generally presents with a poor prognosis and an extremely low response rate to first line therapies. There is a critical unmet need to discover and implement effective diagnostic panels to stratify outcomes and tailor treatment strategies to improve survival. The BERG Interrogative Biology® platform utilizes Artificial Intelligence to analyze and integrate multi-omic profiles with clinical annotation to define novel biomarkers and improve treatment interventions. Herein, we analyzed the serum proteome, signaling lipidome, structural lipidome, and metabolome of 163patients at multiple timepoints (pancreatic cancer: 115; pancreatitis: 15; and age-matched healthy controls: 33). Utilizing the power of the Bayesian Network learner, bAIcis™ (BERG Artificial Intelligence Clinical Information System), multi-omic profiles were aligned to the longitudinal clinical information and subjected to AI-algorithms to infer probabilistic cause-and-effect relationships among molecular and clinical variables explicitly explaining pancreatic cancer status, cancer progression, and survival, and defining the interconnectivity of molecular features with clinical phenotype. Network features linking into clinical endpoints and key network pressure points were identified as molecular drivers. The drivers of clinical endpoints were analyzed to rank potential biomarkers. Novel biomarkers were discovered that demonstrate diagnostic potential for pancreatic cancer detection, disease prognosis including metastatic disease progression, patient stratification associated with survival, and response to standard chemotherapy agents like Gemcitibine. A prospective study is underway to validate the biomarkers and discover additional diagnostic and therapeutic molecules to improve the outcomes for patients affected by adenocarcinoma of the pancreas. Citation Format: Niven R. Narain, A James Moser, Ramesh Ramanathan, John Crowley, Amy Stoll-D’Astice, Yezhou Sun, Leonardo O. Rodrigues, Eric M. Grund, Emily Chen, Vivek K. Vishnudas, Michael A. Kiebish, Viatcheslav R. Akmaev, Rangaprasad Sarangarajan. Project Survival: Interrogative Biology® platform mediated discovery of molecular markers for detection, stratification and outcomes in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 786.

Abstract Background: The genomes of metastatic pancreatic cancers contain a myriad of intrachromosomal aberrations indicating a likely high prevalence of DNA repair deficiencies indicating sensitivity to DNA damaging agents such as the platinum’s. Because of this, the drug cisplatin was added to an albumin-bound paclitaxel + gemcitabine regimen, which has already been determined to improve survival over gemcitabine alone in a randomized phase III trial (NEJM 2013; 369:1691-1703). Objectives: To determine the efficacy and safety of albumin-bound paclitaxel and gemcitabine plus cisplatin for patients with advanced pancreatic cancer Methods: Eligibility criteria included Stage IV pancreatic cancer, no prior chemotherapy for systemic disease, KPS ≥ 70; life expectancy ≥ 12 weeks and measurable disease. The doses were albumin-bound paclitaxel 125 mg/m2 undiluted, gemcitabine 1000 mg/m2 in 500 ml of normal saline (NS), each infused over 30 minutes on days 1 and 8 of a 21 day cycle, along with 3 different dose levels of cisplatin (25, 37.5 or 50 mg/m2) in 500 ml of NS infused over 60 minutes, after the nab-paclitaxel infusion. Pre and post cisplatin hydration was given. Results: To date, 10 patients have been entered on study with all patients being evaluable, (baseline and at least one follow up CT scans completed). There have been 2 complete responses (20%), 6 partial responses (PR), (60%), 1 stable disease (10%), and 1 patient with progressive disease (10%), by RECIST 1.1 criteria. An exponential decrease in CA19-9 correlating with the t1/2 of the marker was noted. Response was seen rapidly with PR observed at the first staging evaluation at 9 weeks in 7 of 10 patients. The 8th patient achieved a PR at 18 weeks. Serious adverse events occurred in 4 patients: non-neutropenic sepsis/pneumonia (n = 1), and non-neutropenic bacteremia (n = 1) in the cisplatin 25 mg/m2 cohort; clostridium difficile colitis (n = 1) with cisplatin 37.5 mg/m2; and neutropenic fever/pneumonia (n = 1) with cisplatin 50mg/m2. Discussion: The study has completed phase Ib and will be expanded at the phase II dose of cisplatin 25 mg/m2 for a total of 25 patients. If this favorable response rate is confirmed, this 3 drug regimen could be further developed both for patients with advanced disease as well as in neoadjuvant and adjuvant settings. Supported by grants from the Seena Magowitz Foundation and the SU2C Dream Team Citation Format: Gayle S. Jameson, Erkut Borazanci, Elizabeth Poplin, Michael T. Barrett, John Crowley, Adam Rosenthal, Amy Stoll-D'Astice, Karen L. Ansaldo, Steven Boone, Leticia Lebron, Ramesh K. Ramanathan, Ronald L. Korn, Daniel D. Von Hoff. High complete and partial response rate in a phase Ib pilot trial with cisplatin plus albumin-bound paclitaxel and gemcitabine in patients with advanced pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-003. doi:10.1158/1538-7445.AM2015-LB-003

AbstractWe compiled and analyzed a database of cooperative group trials in advanced pancreatic cancer to develop historical benchmarks for overall survival (OS) and progression-free survival (PFS). Such benchmarks are essential for evaluating new therapies in a single-arm setting. The analysis included patients with untreated metastatic pancreatic cancer receiving regimens that included gemcitabine, between 1995 and 2005. Prognostic baseline factors were selected by their significance in Cox regression analysis. Outlier trial arms were identified by comparing individual 6-month OS and PFS rates against the entire group. The dataset selected for the generation of OS and PFS benchmarks was then tested for intertrial arm variability using a logistic-normal model with the selected baseline prognostic factors as fixed effects and the individual trial arm as a random effect. A total of 1,132 cases from eight trials qualified. Performance status and sex were independently significant for OS, and performance status was prognostic for PFS. Outcomes for one trial (NCCTG-034A) were significantly different from the other trial arms. When this trial was excluded, the remaining trial arms were homogeneous for OS and PFS outcomes after adjusting for performance status and sex. Benchmark values for 6-month OS and PFS are reported along with a method for using these values in future study design and analysis. The benchmark survival values were generated from a dataset that was homogeneous between trials. The benchmarks can be used to enable single-arm phase II trials using a gemcitabine platform, especially under certain circumstances. Such circumstances might be when a randomized control arm is not practically feasible, an early signal of activity of an experimental agent is being explored such as in expansion cohorts of phase I studies, and in patients who are not candidates for combination cytotoxic therapy. Clin Cancer Res; 20(16); 4176–85. ©2014 AACR.

AbstractA panel of members of the 2009 International Myeloma Workshop developed guidelines for risk stratification in multiple myeloma. The purpose of risk stratification is not to decide time of therapy but to prognosticate. There is general consensus that risk stratification is applicable to newly diagnosed patients; however, some genetic abnormalities characteristic of poor outcome at diagnosis may suggest poor outcome if only detected at the time of relapse. Thus, in good-risk patients, it is necessary to evaluate for high-risk features at relapse. Although detection of any cytogenetic abnormality is considered to suggest higher-risk disease, the specific abnormalities considered as poor risk are cytogenetically detected chromosomal 13 or 13q deletion, t(4;14) and del17p, and detection by fluorescence in situ hybridization of t(4;14), t(14;16), and del17p. Detection of 13q deletion by fluorescence in situ hybridization only, in absence of other abnormalities, is not considered a high-risk feature. High serum β2-microglobulin level and International Staging System stages II and III, incorporating high β2-microglobulin and low albumin, are considered to predict higher risk disease. There was a consensus that the high-risk features will change in the future, with introduction of other new agents or possibly new combinations.

Abstract The optimal design of phase II studies continues to be the subject of vigorous debate, especially studies of newer molecularly targeted agents. The observations that many new therapeutics “fail” in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of clinical trials, further emphasize the critical importance of robust and efficient phase II design. The Clinical Trial Design Task Force (CTD-TF) of the National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on phase II trial design in Clinical Cancer Research. The IDSC has developed formal recommendations about aspects of phase II trial design that are the subject of frequent debate, such as endpoints (response versus progression-free survival), randomization (single-arm designs versus randomization), inclusion of biomarkers, biomarker-based patient enrichment strategies, and statistical design (e.g., two-stage designs versus multiple-group adaptive designs). Although these recommendations in general encourage the use of progression-free survival as the primary endpoint, randomization, inclusion of biomarkers, and incorporation of newer designs, we acknowledge that objective response as an endpoint and single-arm designs remain relevant in certain situations. The design of any clinical trial should always be carefully evaluated and justified based on characteristic specific to the situation. Clin Cancer Res; 16(6); 1764–9

Purpose To assess the impact of age on outcome and to analyze the projected years of life lost in patients with multiple myeloma. Patients and Methods Ten thousand five hundred forty-nine patients were evaluated; 6,996 patients were treated with conventional chemotherapy, and 3,553 patients were treated with high-dose therapy with autologous stem-cell transplantation. Results Mean observed and relative overall survival times in the entire cohort were 3.7 and 3.9 years, respectively. Observed survival decreased steadily from 6.4 years in patients younger than age 50 years to 2.5 years in patients ≥ age 80 years. A similar decrease was noted for relative survival. Higher age correlated significantly with higher International Staging System (ISS) stage. Relative excess risk of death differed significantly between 10-year age cohorts beginning from age 40 years (P < .001 for age 50 to 59 v age 40 to 49, P < .001 for age 60 to 69 v age 50 to 59, P < .001 for age 70 to 79 v age 60 to 69, and P = .009 for age ≥ 80 v 70 to 79). The average years of life lost per patient was 16.8 years in the entire patient cohort and decreased steadily from 36.1 years in patients younger than 40 years old to 4.6 years in patients ≥ age 80 years. Conclusion Age is associated with higher ISS stage and is an important risk factor for early mortality. Survival declined continuously by each decade from age 50 to age ≥ 80 from more than 6 to less than 3 years. The average of years of life lost in patients with myeloma is higher than in many other cancers and amounts to more than 30 years in patients younger than 40 years old but decreases to less than 5 years in patients age 80 years or older.

Purpose Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC. Patients and Methods Patients were randomly assigned to IP (irinotecan 60 mg/m2 on days 1, 8, and 15; cisplatin 60 mg/m2 day 1, every 4 weeks) or EP (etoposide 100 mg/m2 on days 1 through 3; cisplatin 80 mg/m2 day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients. Results Of 671 patients, 651 were eligible (324 and 327 patients in the IP and EP arms, respectively). Response rates with IP and EP were 60% and 57%, respectively (P = .56). Median progression-free survival for IP and EP was 5.8 and 5.2 months, respectively (P = .07). Median overall survival for IP and EP was 9.9 and 9.1 months, respectively (P = .71). Severe diarrhea was more common with IP (19% v 3%); severe neutropenia and thrombocytopenia were higher with EP versus IP (68% v 33% and 15% v 4%, respectively). PG analysis showed that ABCB1 (C3435T)T/T (membrane transport) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated with IP-related neutropenia. Conclusion This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients. Both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP. These results emphasize the potential importance of PG in interpreting trials of cancer therapy.

Abstract As the use of molecularly targeted agents, which are anticipated to increase overall survival (OS)and progression-free survival (PFS) but not necessarily tumor response, has increased in oncology, there has been a corresponding increase in the recommendation and use of randomized phase II designs. Such designs reduce the potential for bias, existent in comparisons with historical controls, but also substantially increase the sample size requirements. We review the principal statistical designs for historically controlled and randomized phase II trials, along with their advantages, disadvantages, and statistical design considerations. We review the arguments for and against the use of randomization in phase II studies, the situations in which the use of historical controls is preferred, and the situations in which the use of randomized designs is preferred. We review methods used to calculate predicted OS or PFS values from historical controls, adjusted so as to be appropriate for an experimental sample with particular prognostic characteristics. We show how adjustment of the type I and type II error bounds for randomized studies can facilitate the detection of appropriate target increases in median PFS or OS with sample sizes appropriate for phase II studies. Although there continue to be differences among investigators concerning the use of randomization versus historical controls in phase II trials, there is agreement that each approach will continue to be appropriate, and the optimal approach will depend upon the circumstances of the individual trial.

Abstract Recently, many new drugs have been developed for the treatment of Waldenström macroglobulinemia (WM). To optimize the treatment according to the prognosis and to facilitate the comparison of trials, we developed an International Prognostic Scoring System for WM in a series of 587 patients with clearly defined criteria for diagnosis and for initiation of treatment. The median survival after treatment initiation was 87 months. Five adverse covariates were identified: advanced age (>65 years), hemoglobin less than or equal to 11.5 g/dL, platelet count less than or equal to 100 × 109/L, β2-microglobulin more than 3 mg/L, and serum monoclonal protein concentration more than 7.0 g/dL. Low-risk patients (27%) presented with no or 1 of the adverse characteristics and advanced age, intermediate-risk patients (38%) with 2 adverse characteristics or only advanced age, and high-risk patients (35%) with more than 2 adverse characteristics. Five-year survival rates were 87%, 68%, and 36%, respectively (P < .001). The ISSWM retained its prognostic significance in subgroups defined by age, treatment with alkylating agent, and purine analog. Thus, the ISSWM may provide a means to design risk-adapted studies. However, independent validation and new biologic markers may enhance its significance.