Mansfield, Aaron S.

Purpose: Many cancer clinical trials lack appropriate representation of specific patient populations, limiting their generalizability. Therefore, we determined the representation of ethnic minorities and women in cancer clinical trials. Methods: Enrollment data from all therapeutic trials reported as completed in ClinicalTrials.gov from 2003 to 2016 were analyzed. We calculated enrollment fractions (EFs) for each group, defined as the number of enrollees divided by the 2013 Surveillance, Epidemiology, and End Results (SEER) database cancer prevalence. Results: Of 1,012 clinical trials, 310 (31%) reported ethnicity with a total of 55,689 enrollees. Participation varied significantly across ethnic groups. Non-Hispanic whites were more likely to be enrolled in clinical trials (EF, 1.2%) than African Americans (EF, 0.7%; P < .001) and Hispanics (EF, 0.4%; P < .001). A decrease in African American (6% v 9.2%) and Hispanic (2.6% v 3.1%) enrollment was observed when compared with historical data from 1996 to 2002. Younger patients (age younger than 65 years) were more likely to be enrolled in clinical trials than the elderly (64% v 36%; P < .001). Low recruitment of female patients was observed in clinical trials for melanoma (35%), lung cancer (39%), and pancreatic cancer (40%). Conclusion: We observed a decrease in recruitment of minorities over the past 14 years compared with historical data. African Americans, Hispanics, and women were less likely to be enrolled in cancer clinical trials. Future trials should take extra measures to recruit participants that adequately represent the US cancer population.

AbstractWomen diagnosed with cutaneous melanoma have a survival advantage compared to men, which has been hypothesized to be due to difference in behavior and/or biology (sex hormones). It remains controversial whether this advantage is dependent on age or stage of disease. We sought to compare melanoma‐specific survival between females in pre, peri, and postmenopausal age groups to males in the same age group, adjusting for stage of disease. This is a retrospective population‐based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. Patients diagnosed from 1 January 1992 through 31 January 2011 with primary invasive cutaneous melanoma were included in our cohort. Melanoma‐specific survival was the main outcome studied. Of the 106,511 subjects that were included, 45% were female. Females in all age groups (18–45, 46–54, and ≥55) with localized and regional disease, were less likely to die from melanoma compared to males in the same age group. Among patients with localized and regional disease, the relative risk of death due to melanoma increased with advancing age at diagnosis; this increase was more pronounced among females than males. In contrast, we observed no female survival advantage among patients with distant disease and no effect of age on relative risk of death from melanoma. Females with localized and regional melanoma have a decreased risk of death compared to males within all age groups. Our data show no differences in survival between men and women with metastatic melanoma, indicating that the influence of sex on survival is limited to early stage disease but not confined to pre or perimenopausal age groups.

Abstract Background: Early phase trials (EPCT) provide significant value by evaluating the possible benefits of new agents. The eligibility criteria in EPCT are usually rigorous and may exclude many patients (pts) commonly seen in clinical practice. Our objective was to identify the most common comorbidities excluded in EPCT for NSCLC. Methods: ClinicalTrials.gov was queried on August 1st of 2016. 299 interventional drug trials were extracted from 2010 to 2016. We studied the trial characteristics including: experimental therapy, location, funding and eligibility criteria. Exclusion of CNS metastasis was treated as a binary variable (strict exclusion vs. allowed). Logistic regressions were used for statistical analysis. Results: Of the 299 trials, 164 (55%) were phase II, 81 (27%) phase I and 54 (18%) phase Ib/II. 164 (55%) were conducted in the United States (US), 45 (15%) in Asia, 39 (13%) in Europe and 51 (17%) were international. 171 (57%) trials were funded by the industry, 54 (18%) by government agencies and 74 (25%) were investigator initiated. Survival was an end-point in 97 (32%) trials. 70 (23%) trials required a repeat lung biopsy. 54 (18%) trials excluded pts &gt;75 years of age. 99 (33%) trials required creatinine levels &lt;1.5 mg/dl, 132 (44%) liver enzymes &lt;2.5 and total bilirubin &lt;1.5 of the upper limit of normal. 88 (29%) trials required Hgb&gt;9 g/dl and 141 (47%) excluded pts with platelets &lt;100,000/dl. In terms of comorbidities, 84 (28%) trials excluded pts with atrial fibrillation, 94 (31%) with any anticoagulation therapy and 120 (40%) HIV positive pts. CNS involvement was a significant exclusion factor, 123 (41%) trials excluded pts with CNS metastasis. On univariate analysis, the odds of CNS metastasis exclusion were significantly higher in immunotherapy trials (OR 1.72, 95%CI 1.2-2.4, p&lt;0.01) and lower in European trials (OR 0.76, 95%CI 0.6-0.9, p&lt;0.005). In multivariate analysis, US based trials had higher odds of exclusion of CNS metastasis (OR: 3.2, 95%CI 1.4-7.5, p&lt;0.05). Conclusions: Many of the EPCTs excluded pts with advanced age, cytopenias and other common comorbidities, eliminating the possibility of many of our aging pts from participation. Regarding CNS disease, our analysis suggests the type of agent and location may influence the trial design about CNS metastasis inclusion. Investigators should review whether sufficient justification exists for every exclusion criterion before their incorporation in future trial protocols. Citation Format: Narjust Duma, Yucai Wang, Aaron Mansfield. Comorbidities limiting recruitment of non-small cell lung cancer (NSCLC) patients in early phase trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 766. doi:10.1158/1538-7445.AM2017-766

Abstract Expression of DLL3 was examined in additional tumor types, as it was found to be highly expressed in tumor-initiating cells (TIC) in small cell lung cancer (SCLC), where a DLL3-targeted antibody drug conjugate (ADC), rovalpituzumab tesirine (Rova-T; SC16LD6.5; Saunders et al. 2015 Sci Transl Med 7:302ra136)) exerted clinically meaningful anti-tumor effects in a phase I trial (Spigel et al. 2016 Lancet Oncology; In Press). DLL3 expression was profiled by qRT-PCR, ELISA and immunohistochemistry in multiple tumor types. Patient-derived xenografts (PDX) from melanoma and ovarian small cell carcinoma were established and used for efficacy studies to determine the ability of Rova-T to impact tumor growth and TIC frequency. DLL3 expression was seen in metastatic melanoma (55%), low grade gliomas (90%), glioblastoma (70%), medullary thyroid cancer (65%), carcinoids (33%), dispersed neuroendocrine tumors in the pancreas (9%), bladder (57%) and prostate (24%), testicular cancer (90%), and lung adenocarcinomas with neuroendocrine features (80%). Unlike SCLC, where DLL3 does not predict clinical outcome on standard therapies, DLL3 expression negatively correlates with overall survival in melanoma and small cell bladder cancer. In mice bearing DLL3 positive melanoma PDX, treatment with a single dose of Rova-T resulted in effective and durable responses (&gt;100 days), which correlated with a significant impact on TIC frequency. Similarly, in mice bearing DLL3-positive ovarian small cell PDX, a single dose of Rova-T resulted in effective and durable responses (&gt;100 days). Our results show that DLL3 is expressed in many neuroendocrine tumors (lung, ovarian, prostate, bladder, etc), metastatic melanoma, medullary thyroid cancer, low-grade gliomas and glioblastoma. Given pre-clinical results showing efficacy of Rova-T in melanoma and ovarian small cell carcinoma, as well as encouraging clinical data with Rova-T in patients with recurrent/refractory SCLC, clinical evaluation of Rova-T in DLL3-positive melanoma, glioblastoma, medullary thyroid cancer and other high-grade neuroendocrine carcinomas is warranted. A “basket” trial enrolling patients with DLL3-positive solid tumors is now recruiting patients (NCT02709889). Citation Format: Laura R. Saunders, Samuel A. Williams, Sheila Bheddah, Kumiko Isse, Sarah Fong, Marybeth A. Pysz, Himisha Beltran, Loredana Puca, Verena Sailer, Juan M. Mosquera, Yu Yin, Jiaoti Huang, Andrew J. Armstrong, Jorge Garcia, Cristina Magi-Galluzzi, Vadim Koshkin, Petros Grivas, Farhad Kosari, John Cheville, Justin C. Moser, Thomas J. Flotte, Thorvardur Halfdanarson, Aaron Mansfield, Konstantinos N. Leventakos, Julian R. Molina, Douglas W. Ball, Barry D. Nelkin, Jill E. Shea, Courtney L. Scaife, Scott J. Dylla. Expression of DLL3 in metastatic melanoma, glioblastoma and high-grade extrapulmonary neuroendocrine carcinomas as potential indications for rovalpituzumab tesirine (Rova-T; SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody drug conjugate (ADC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3093. doi:10.1158/1538-7445.AM2017-3093

SummaryThe Glivec International Patient Assistance Programme makes Glivec (Imatinib mesylate) available to Philadelphia chromosome/BCR‐ABL1 positive patients with chronic myeloid leukaemia (CML) in Lower and Middle Income Countries (LMIC). We have established a large cohort of 211 CML patients who are eligible for Imatinib, in Kathmandu, Nepal. Thirty‐one patients were lost to follow‐up. We report on 180 CML patients with a median age of 38 years (range 9–81). Of these 180 patients, 162 underwent cytogenetic testing and 110 were investigated by reverse transcription polymerase chain reaction. One hundred and thirty‐nine of the 180 patients (77·2%) had at least one optimal response. Taken together, our cohort has a 95% overall survival rate and 78% of the patients were still taking Glivec at a median time of 48·8 months (range 3–140 months). The number of patients who actually failed therapy, as defined by the LeukaemiaNet 2013 criteria, was 39 (21·7%). While our cohort has some differences with those in North America or Europe, we have shown Glivec is effective in inducing an optimal response in our patients in Nepal and that it is possible to deliver a clinical service for CML patients using tyrosine kinase inhibitors in resource‐poor settings.

Abstract Mutations in the EGFR gene or transcript fusion involving EML4-ALK result in oncogenic activation of these oncogenes driving lung adenocarcinoma growth in tumors carrying such an alteration. For lung adenocarcinoma with these genetic changes, small-molecule tyrosine kinase inhibitors have been highly effective at reducing tumor burden and improve the outcome of the patients. Unfortunately, drug resistance eventually develops in these tumors and challenges remain in controlling lung cancer recurrence after targeted therapy. To overcome recurrence, we initiated a prove-of-principle study to evaluate the feasibility of an integrated strategy utilizing genomic profiles of the tumor and patient-specific tumor xenografts derived (PDX) from biopsies for ex vivo evaluation of antitumor drugs to help guide personalized treatment of lung cancer in patients who have developed resistance to targeted therapy drugs. Our study has three main objectives. 1) Use tumor biopsies obtained at the time of recurrence for oncogene mutation and RNAseq analyses to identify molecular changes in oncogenes and gene pathways that can be potentially targeted. 2) Evaluate drug efficacy and optimize personalized therapy for each patient using PDX models. 3) Assess clinical feasibility and our experience using integrated approaches for lung cancer patients who failed targeted therapy. This study was approved by the Mayo Clinic Institutional Review Board (IRB) and utilizes both clinical and research biopsies. A dedicated nurse study coordinator reviews clinical patient list and history on weekly basis and informs the study team of each potential candidate patient. A total of 30 patients having ALK positive lung cancers have been identified and followed up from nearly 500 potentially ALK positive cases between April 2014 to Sept. 2015. Most patients were never smokers but six were former smokers and two were current smokers. Age at diagnoses ranged from 27-78 years (median = 61). Seven patients (23%) were 45 years or younger at the time of diagnosis. A total of 22 patients are currently being treated with crizotinib while eight are on ceritinib or alectinib. For each biopsy, tumor tissues are obtained using a 20 gauge needle, transferred on ice in preserving media and implanted within one hour into 6-8 week old NOD/SCID mice. Many patients have been on treatment for 2-3 years with stable disease so they do not require biopsy. Using a similar strategy, we also obtained biopsies from patients with EGFR gene mutations in their tumors and have progressed while on targeted therapy. A total of seven cases have been implanted. We will report our experiences in patient selection, clinical follow up, patient consent, PDX development, time from biopsy to tumor establishment, and the results of molecular analyses. Our study enabled us to gain new insights regarding the molecular changes associated with recurring tumors after they have failed targeted therapy as well as clinical experiences on how to utilize state-of-the art approaches and comprehensive genomic information to further improve cancer patient care upon disease progression. Acknowledgements: This work is supported in part by the Hillsberg Award from the National Foundation for Cancer Research and by the Biomarker Discovery Program at the Mayo Clinic Center for Individualized Medicine. Citation Format: Jin Jen, Aaron Mansfield, Patrick W. Eiken, Shawn Stoddard, Karlyn Pierson, Xiaonan Hou, Hong Zheng Ren, Julian Molina, Joanne Yi, Ping Yang. Integrated Approaches to Treating Lung Adenocarcinoma Resistant to Targeted Therapy. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B34.

82 Background: Metastatic malignant melanoma is a nearly uniformly fatal disease. Systemic therapy has notable but limited success. Novel therapeutic strategies are urgently needed. To that end, we’ve pursued combinatorial therapeutics using conventional chemotherapy added to an inhibitor of angiogenesis (bevacizumab) with some evidence of clinical benefit. Preliminary analysis of one of our trials suggested a previously unrecognized immunomodulatory effect of bevacizumab when added to chemotherapy in patients with metastatic melanoma, and this may have a potential impact on clinical outcome. Herein we evaluate the immunomodulatory effect of bevacizumab when added to chemotherapy in patients with metastatic melanoma. Methods: We measured levels of peripheral blood mononuclear cell phenotypes in addition to 42 cytokines, chemokines and growth factors in plasma of 55 patients who received albumin-bound paclitaxel and carboplatin (AC) and of 73 patients who received AC with bevacizumab (ACB) on clinical trials N057e and N0775 respectively. The relative percent change in PBMC cell counts and cytokine levels were determined from baseline at their restaging evaluation after two cycles of therapy. The Mann Whitney U test was used to compare responses between the groups. Results: There was a significant increase in CD197+type 1 macrophages in the group that received ACB (35.3%, -11.8-142.7%) compared to AC (-11.6%, -45.9-38.3%; p=0.004). There was a significant decrease in IL-6 in the group that received ACB (-42.4%, -87.7-0.0%) compared to AC (28.4%, -37.4-480%; p=0.0018). Conclusions: The addition of bevacizumab to chemotherapy for the treatment of metastatic melanoma modulates cellular immunity and a pro-inflammatory cytokine. Patients who received bevacizumab had a significant increase in CD197+ type 1 macrophages and a significant decrease in IL-6. Clinical significance of these findings is the subject of ongoing work.