Mansfield, Aaron S.

184 Background: Patients with CLL are at higher risk of developing melanoma and other skin malignancies. The survival of patients with melanoma is worse, stage for stage, in patients with CLL than patients without. It is thought that early diagnosis of skin cancer is critical to improving survival in CLL patients. To promote early diagnosis and education on skin cancer prevention, the Mayo Clinic CLL group has recommended that CLL patients be referred for full body skin evaluation within 6 months of diagnosis. We sought to determine adherence to these guidelines by our group and identify prevalence of skin malignancies within 6 months of diagnosis. Methods: We identified patients who lived within 30 miles of Mayo Clinic who were diagnosed with CLL between 01/01/2004 and 01/01/2012 using the Mayo Clinic CLL database. Charts were reviewed for skin examinations, referrals to dermatology/primary care within 6 months of diagnosis of CLL, and diagnosis of a skin malignancy. Results: There were 107 patients newly diagnosed with CLL included in this study. Of the 79 patients who received their primary care at Mayo Clinic, 40 (51%) had a documented whole body skin exam by either a dermatologist or primary care provider within six months of diagnosis. Nine of these 40 patients (23% of examined patients; 8% overall cohort) had a skin malignancy: 2 patients had basal cell carcinomas, 6 patients had squamous cell carcinomas, and 1 patient had malignant melanoma. Prophylactic skin care recommendations could be documented for only 28 (26%) of patients. Conclusions: At least 8% of patients in this locally dwelling cohort with newly diagnosed CLL had a skin malignancy identified within six months of diagnosis (number needed to screen for 1 skin cancer: 13). Of patients referred to dermatology 23% had a skin malignancy (number needed to screen: 4.3). Referrals for screening skin examinations at diagnosis in patients with CLL could have an immediate impact for this at-risk population.

333 Background: Primary pancreatic small cell carcinoma (SCC) is rare, with just over 30 cases reported in the literature. Only 7 of these patients underwent surgical resection with a median survival of 6 months. Prognosis of SCC is therefore considered to be poor, and the role of adjuvant therapy is uncertain. Here we report two institutions' experience with resectable pancreatic SCC. Methods: Six patients with pancreatic SCC at the Johns Hopkins Hospital (4 patients) and the Mayo Clinic (2 patients) were identified from prospectively collected pancreatic cancer databases and re-reviewed by pathology. All six patients underwent a pancreaticoduodenectomy. Clinicopathologic data was analyzed, and the literature on pancreatic SCC was reviewed. Results: Median age at diagnosis was 50 years (range 27-60). Half of the patients were male, and half were known smokers. All six masses were limited to the pancreatic head. Median tumor size was 3 cm, and all cases had positive lymph nodes except for one patient who only had five nodes sampled. There was no perioperative mortality, although three patients had postoperative complications. All six patients received adjuvant chemotherapy therapy, five of whom were given cisplatin and etoposide. Of these five patients, three were known to have received radiation, while the remaining two had a plan for radiation at an outside facility. Median survival was 20 months with a range of 9-173 months. The patient who lived for 9 months received chemotherapy only, while the patient who lived for 173 months was given chemoradiation with cisplatin and etoposide and represents the longest reported survival time from pancreatic SCC to date. Conclusions: Pancreatic SCC is an extremely rare form of cancer with a poor prognosis. Patients in this surgical series showed improved survival rates when compared to prior experiences with both resected and unresectable cases. Cisplatin and etoposide appears to be the preferred chemotherapy regimen, although its efficacy remains uncertain, as does the role of combined modality treatment with radiation. No significant financial relationships to disclose.

Abstract Purpose: To determine the MTD and to assess the safety, tolerability, and potential activity of LB-100, a first-in-class small-molecule inhibitor of protein phosphatase 2A (PP2A) in adult patients with progressive solid tumors. Experimental Design: LB-100 was administered intravenously daily for 3 days in 21-day cycles in a 3 + 3 dose escalation design. Results: There were 29 patient entries over 7 dose escalations. One patient stopped treatment after one dose because of an acute infection and was reenrolled after recovery; each course was analyzed as a separate patient entry. Two patients had dose-limiting toxicity (reversible increases in serum creatinine or calculated serum creatinine clearance) at the 3.1 mg/m2 level. Probable or possible study drug-related grade 3 adverse events occurred in 6 (20.7%) patients [anemia (n = 2), decreased creatinine clearance, dyspnea, hyponatremia, and lymphopenia]. Ten (50%) of 20 response-evaluable patients had stable disease for four or more cycles. One patient with pancreatic adenocarcinoma had a partial response noted after 10 cycles, which was maintained for five additional cycles. The other patients achieving stable disease had one of the following: fibrosarcoma, chondrosarcoma, thymoma, atypical carcinoid of lung, or ovarian, testicular, breast (n = 2), and prostate cancer. The recommended phase II dose of LB-100 is 2.33 mg/m2 daily for 3 days every 3 weeks. Conclusions: The safety, tolerability, preliminary evidence of antitumor activity, and novel mechanism of action of LB-100 support its continued development alone and in combination with other therapies. Clin Cancer Res; 23(13); 3277–84. ©2016 AACR.

Abstract PURPOSE: Previous mutational analyses have failed to identify a predictive or prognostic marker for pulmonary carcinoid tumors (PCT). The heterogeneity of PCTs coupled with a lack of detailed information about the tumor biology, impedes patient stratification into groups based on tumor phenotypes or treatment response. We sought to use high-throughput next-generation sequencing to improve prognostication. METHODS: We stratified 37 patients with resected PCTs as low risk (n = 17) and high risk (n = 20) based on a 5 year long follow up for recurrence. Patients with no recurrence within 5 years from initial treatment were deemed low risk. Macrodissection was followed by genomic DNA isolation and next-generation sequencing was performed using an Illumina Mate Pair library protocol. Sequence reads were mapped to the human genome, and primers spanning the fusion junctions were used for validation polymerase chain reaction. RESULTS: Carcinoids commonly harbor rearrangements (median 3.5, range 1-167). Large chromosomal gains or losses were found in 24 of the cases (64.8%). We developed a prognostic score that included the total amount of genetic alterations (deletions and translocations). ROC analysis revealed an AUC of 0.76. High risk patients had a mean score of 20 and low risk patients had a mean score of 5.45 (p value = 0.03, Welch Two Sample t-test). Further analysis of the specific genetic alterations harbored by high and low risk PCTs and correlation with the pathologic and immunohistochemical information is currently underway. CONCLUSION: Large chromosomal rearrangements and aneuploidy portend a poor prognosis for patients with PCTs. Mate Pair sequencing of PCTs provides valuable prognostic information for this highly heterogeneous group of cancers. Citation Format: Konstantinos Leventakos, Aaron S. Mansfield, Stephen J. Murphy, Sarah H. Johnson, Sarah E. Kerr, Marie Christine Aubry, George Vasmatzis, Julian R. Molina. A prognostic model for pulmonary carcinoid tumors based on large chromosomal alterations. [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 4513.

Abstract Lung cancer accounts for about 27% of the cancer related deaths in the USA annually. Pathologically, it is a very complex disease broadly classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLCs are further classified into squamous cell carcinoma, large cell carcinoma and adenocarcinoma. Achaete-scute homolog 1 (ASCL1), an important transcription factor essential in the development of neuroendocrine cells (NE) in lungs is shown to be specifically expressed in lung NE cancers and 10-20% of adenocarcinomas (AD) with NE differentiation (NED), thus suggesting a role in the pathogenesis of these tumors. Our previous study showed that ASCL1 is a regulator of the RET oncogene in AD with NED. RET is a receptor tyrosine kinase with two isoforms in humans: RET9 (short) and RET51 (long). We performed survival analysis to study implications of RET isoforms in ASCL1+ tumors and found that elevated expression of the long RET mRNA was associated with poor survival. Subsequent in vitro experiments demonstrated that treatment with EGF robustly induced phosphorylation of RET in HCC1833 and H1755 cell lines which have high endogenous levels of ASCL1 and RET but not in VMRC-LCD cell line which has high level of ASCL1 but low level of RET. EGF induced phosphorylation of RET was diminished by gefitinib and by EGFR siRNA. Immunoprecipitation results indicated direct binding between EGFR and RET in presence of EGF. Furthermore, a high throughput drug screening found 8 EGFR inhibitors that were 10 - 250 fold more cytotoxic in ASCL1+ compared with ASCL1- AD cells. These results implicate EGFR as a key regulator of RET activation in ASCL1+ AD and suggest that EGFR inhibitors may be therapeutic for this population of patients. Citation Format: Kaustubh N. Bhinge, Yang Lin, Hamed Rahi, Marie Christine Aubry, Aaron Mansfield, Irina Kovtun, Stephen Murphy, Ping Yang, Dennis Wigle, Joanne (Eunhee) Yi, Aqsa Nasir, Simone Terra, Julian Molina, George Vasmatzis, Farhad Kosari. EGFR-mediated activation of RET in ASCL1+ lung adenocarcinoma. [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 1129.

Abstract Background Protein phosphatase (PP2A) is a multifunctional protein involved in regulation of cell cycle, DNA-damage response, and apoptosis. LB-100, a novel small molecule inhibitor of PP2A, inhibits the growth of a broad spectrum of leukemic and solid tumor cell lines. In addition, LB100 potentiates the effectiveness of cytotoxic drugs (cisplatin, docetaxel, doxorubicin, temozolomide) and radiation without significant increases in toxicity. The predominant mechanisms responsible for potentiation are inhibition of mitotic exit and homologous recombination repair. Methods This is an open label, first-time-in-human, multicenter, phase 1 study of LB-100 in patients with advanced cancer refractory to standard therapies. The first part of the study determines the maximum tolerated dose (MTD) of LB-100 as a single agent when given intravenously days 1-3 every 21 days. Utilizing a standard 3+3 design, patients (pts) are evaluated for dose limiting toxicities (DLT) through 2 cycles. Once the single agent MTD is determined, the dose will be reduced by 2 dose levels (DL) and combined with docetaxel given on day 2. Escalation will continue until the MTD of the combination is determined. Plasma sampling for pharmacokinetics of LB-100 will be collected on days 1 and 3 of cycle 1 in the MTD confirmation cohort. Results The starting dose of LB-100 was 0.25 mg/m2 and 21 pts have enrolled in part 1 of the study through six dose levels. At DL6, pts received 2.33 mg/m2 and no DLTs have been observed. One pt with metastatic colon cancer at DL6 had a grade 2 creatinine after 2 doses that resolved with hydration. This was related to LB-100 and the study was amended to increase the volume and infusion time. One pt on DL3 with stage 4 pancreas cancer had stable disease through 15 cycles of treatment and another pt on DL5 with metastatic thymoma remains on treatment through 8 cycles. Stable disease for 4-6 cycles was also observed in breast, ovarian, carcinoid and testicular cancer patients. Conclusions Rb and p53 mutations are common in malignancies leading to chromosomal instability and overexpression of the mitotic checkpoint gene Mad2. PP2A inhibition results in synthetic lethality of cancer cells overexpressing Mad2 which may be a biomarker for LB100 responsiveness. Through 6 DLs, LB-100 has been well tolerated without any DLTs and early activity has been observed with stabilization of disease in a wide variety of cancers. Correlative studies for biomarkers of response are planned. Clinical trial identifier: NCTO1837667 Citation Format: Vincent Chung, Donald Richards, Fadi Braiteh, John S. Kovach, Aaron Scott Mansfield. A phase 1 study of a novel inhibitor of protein phosphatase 2A alone or in combination with docetaxel. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A175.

Abstract Purpose: The NCI Cancer Therapy Evaluation Program sponsors hepatic dysfunction phase I clinical trials (HDCT) and phase 1 clinical trials (P1CT) to determine safe doses and schedules of antineoplastic therapeutics. We sought to compare clinical outcomes between these trial types while stratifying by hepatotoxic agents. Experimental Design: Individual subject data were extracted from the records of 51 NCI-sponsored HDCT and P1CT. The NCI's Organ Dysfunction Working Group's hepatic impairment categorization and two drug-induced liver injury (DILI) scales (FDA R ratio and Hy's law) were used to classify subjects. The number of cycles administered and treatment discontinuation reason were also evaluated and compared between groups. Results: There were 513 and 1,328 subjects treated on HDCT (n = 9) and P1CT (n = 42), respectively. There were differing patterns of DILI with significant worsening of total bilirubin in subjects on HDCT, and worsening of alanine aminotransferase (ALT) in subjects on P1CT. Cholestatic peak patterns of liver impairment (predominant increases in alkaline phosphatase rather than transaminases) were more frequent in HDCT. Criteria for Hy's law were met by 11 subjects on P1CT, but not by any subjects on HDCT. Disease progression was the most common reason for treatment discontinuation, followed by adverse events at similar frequencies in both HDCT and P1CT. Conclusions: The differential effects on hepatotoxicity suggest that underlying hepatic function may affect susceptibility to and patterns of DILI. The incorporation of additional measures of hepatic function may help identify those at highest risk of hepatotoxicity in future trials because baseline liver tests did not. Clin Cancer Res; 22(22); 5472–9. ©2016 AACR.

Immune checkpoint therapy with PD-1 blockade has emerged as an effective therapy for many advanced cancers; however, only a small fraction of patients achieve durable responses. To date, there is no validated blood-based means of predicting the response to PD-1 blockade. We report that Bim is a downstream signaling molecule of the PD-1 pathway, and its detection in T cells is significantly associated with expression of PD-1 and effector T cell markers. High levels of Bim in circulating tumor-reactive (PD-1 + CD11a hi CD8 + ) T cells were prognostic of poor survival in patients with metastatic melanoma who did not receive anti–PD-1 therapy and were also predictive of clinical benefit in patients with metastatic melanoma who were treated with anti–PD-1 therapy. Moreover, this circulating tumor-reactive T cell population significantly decreased after successful anti–PD-1 therapy. Our study supports a crucial role of Bim in both T cell activation and apoptosis as regulated by PD-1 and PD-L1 interactions in effector CD8 + T cells. Measurement of Bim levels in circulating T cells of patients with cancer may provide a less invasive strategy to predict and monitor responses to anti–PD-1 therapy, although future prospective analyses are needed to validate its utility.