Citations

299 Background: In 2011, ASCO launched a forum for the oncology research community to facilitate and promote the implementation of quality clinical research. The ASCO Research Community Forum (RCF) was created to provide a solution-oriented venue for research sites to address common challenges with conducting clinical trials. It offers in-person and virtual forums and resources to learn and share best practices with peers on a variety of topics, including site quality assessment and improvement, research site operations, and clinical trial access and accrual. Methods: An assessment was performed to measure the ASCO RCF output and to gather information on its potential impact on the cancer community. Results: The ASCO RCF has provided an in-person venue for physicians and research administrators with a steady increase in attendance, from 52 attendees in 2012 to 159 in 2018. Multi-stakeholder meetings and manuscripts have promoted best practices and solutions to address challenges with implementing quality clinical trials. Tools and resources to facilitate best practices and quality improvement at trial sites have been accessed by a range of types of research sites from across the U.S. and internationally. Its web-based library of resources was accessed over 27,000 times in 2018, alone. An online forum was launched in 2019 to provide a new opportunity to connect and impact the research community. Conclusions: The ASCO RCF is a productive and esteemed resource for the cancer research community. In-person and virtual forums, along with practical tools, promote access and accrual to clinical trials by facilitating networking, developing solutions, and providing education and resources. The ASCO RCF impact has extended from community-based oncology practices to larger research networks and academic centers across the U.S. and internationally. Its efforts to promote and facilitate access to quality clinical trials align with the vision and mission of ASCO to conquer cancer through research, education, and promotion of the highest quality patient care.

Abstract Abstract 3650 Background: Mantle cell lymphoma (MCL) is an aggressive lymphoma with poor prognosis. Cyclin D1 (CCND1) gene amplification is a marker of MCL. Glutathione (GSH) S-transferase pi (GSTP1) is a gene on the same amplicon as CCND1. Alternative splicing of CCND1 is mediated by an A/G single nucleotide polymorphism (SNP) in the exon 4 splice donor region. Inhibition of GSTP1 activity increased the sensitivity of MCL cell lines to cisplatin, cytarabine and bortezomib, but not doxorubicin suggesting its importance for drug resistance (Paret et al, 2005, ASH Abst #2806). Other GSH-related proteins were hypothesized to potentially be predictive biomarkers. We retrospectively analyzed DNA samples from MCL patients in a clinical trial with uniform first line chemoimmunotherapy treatment in order to study potential prognostic and predictive molecular markers including: GST M1/T1 gene copy number as well as SNPs for CCND1, GSTP1 and other GSH metabolism family of genes (described in Moyer et al, 2010 CEBP). Methods: DNA was available from 89 MCL patients treated with R-HyperCVAD from 1999 to 2002 at MD Anderson Cancer Center (MDACC). The CCND1 exon 4 (codon 242) SNP was evaluated using pyrosequencing. GST copy numbers were determined as previously described (Moyer et al., 2007 CCR). GSH-related gene SNP testing was performed at the Mayo Clinic Advanced Genomic Technology Center using an Illumina Golden Gate 384 plex panel [290 GSH-related SNPs (30 genes) and 94 additional SNPs in DNA damage repair and other pathways (19 genes] for GSTs and related GSH metabolism genes including GSH synthetase and GSH transporters. Comparison to ten year clinical data with an 8 year median follow-up was used under an IRB approved protocol (Romaguera et al., 2010, Br J Haematol). For overall survival (OS) and failure free survival (FFS), each SNP was first examined by the method of Kaplan and Meier and the log-rank test. To account for multiple testing (of 300+ SNP), we used a beta-uniform mixture model to model the sets of p-values for OS and FFS separately. SNPs that had a false discovery rate (FDR) adjusted p-value of less than 0.2 were evaluated with Cox proportional hazard models to examine the association between SNP and time to event. When there was evidence of non-proportional hazards, we fitted Bayesian parametric accelerated failure regression model. All tests are two-sided. All analyses were done using SAS (v 9.1, Cary, NC) and the R statistical project (http://www.r-project.org/). Results: Fifteen SNPs were significantly associated with FFS or OS in univariable analysis using a FDR q-value cut off of 0.2 (Table). Ten of these SNPs remained significant with FFS or OS after adjustment for age. Prognostic SNPs included GST (GSTO1, GSTO2, GSTA5) and DNA repair (LIG1, ERCC2, RAD52) genes. GST M1/T1 gene copy numbers and SNPs for GSTP1 and CCND1 were not found to be significantly associated with FFS and OS. Conclusion: DNA repair and GSH-associated gene SNPs correlated with OS and FFS in MCL patients treated with R-HyperCVAD at ten years follow-up. This is the largest MCL molecular marker study of which we are aware in a uniformly treated patient group and includes over 300 SNPs including CCND1, GSTP1, and GSH-associated metabolism pathway genes. Additional clinical trials may look at these SNPs in correlative studies. Statistically Significant SNPs Disclosures: No relevant conflicts of interest to declare.

Abstract BACKGROUND: S-adenosyl-L-methionine (AdoMet or SAM-e®) is a commonly used nutritional supplement available in the United States since 1999. AdoMet is metabolized to homocysteine (Hcy), a potential cardiovascular risk factor. A few open-label, single-arm studies have reported on the effect of exogenous AdoMet on the levels of Hcy in humans; however, this has not been tested in a double-blind, randomized clinical trial. As a nutritional supplement, AdoMet is subject only to limited regulation by the FDA, despite being used to treat clinical diseases such as depression and osteoarthritis. AdoMet is the methyl donor for small molecule, DNA, RNA, and protein methylation reactions; therefore, further understanding the biology of the AdoMet/Hcy system is important. We hypothesized that exogenous AdoMet would increase plasma Hcy levels. METHODS: In a double-blind, placebo-controlled, randomized clinical trial, 93 healthy human subjects were screened and 52 were treated with placebo (26) or 800 mg per day AdoMet (26) pills for 4 weeks. Pre- and post-treatment Hcy levels were measured. The primary endpoint was change in Hcy level. Secondary endpoints included an interim Hcy level, high sensitivity C-reactive protein (hsCRP) levels, lipid profile, and transaminases. Exclusion criteria included pregnancy and concurrent use of medications associated with changes in Hcy. RESULTS: Of 52 subjects enrolled, 45 were evaluable at the end of treatment. Subject characteristics and dropout rates were similar between placebo and control groups. Adverse events were minor and were not different between placebo and AdoMet. The primary endpoint, change in Hcy, was not significantly different between the groups (mean (umol/L), baseline: 7.43 (placebo), 8.25 (AdoMet), P=0.358; 4 week: 7.66 (placebo), 8.06 (AdoMet), P = 0.683; Baseline − 4 week: 0.23 (placebo), −0.19 (AdoMet), P = 0.427). No statistically significant difference in change in Hcy or hsCRP at 2 or 4 weeks was noted. This was true for both absolute differences as well as relative percent changes. A small decrease in ALT was observed at 2 weeks in the AdoMet group compared to the placebo group (P = 0.027). AdoMet is used in the treatment of liver diseases. There was a small, but statistically significant (P = 0.028) decrease in total cholesterol in the AdoMet group as compared to the placebo group. Interestingly, a subject with the highest baseline Hcy level had a decline in Hcy on AdoMet. Study limitations include no evaluation of AdoMet serum levels or measurement of the effect of AdoMet on DNA methylation patterns. CONCLUSIONS: AdoMet seems well tolerated and in a dose of 800 mg/day for 4 weeks does not appear to significantly affect Hcy levels in the blood. Future clinical trials of AdoMet should monitor Hcy levels with extended use of AdoMet to confirm its safety with long term use. Clinicaltrials.gov ID: NCT00284011.

Abstract Abstract 1856 Background: Lenalidomide has proven to be a highly effective treatment in relapsed multiple myeloma (MM), particularly when used in combination with dexamethasone. However, over 30% of patients with myeloma have renal insufficiency and as lenalidomide is renally excreted, little information is available about its use in myeloma patients with impaired kidney function. Defining a safe and effective dose of lenalidomide in this context is critical. Objective: We undertook this study to establish the maximum tolerated dose of lenalidomide in three cohorts of patients with different levels of impaired renal function: Group A - patients with creatinine clearance (CrCl) between 30 and 60 mL/min, Group B - patients with CrCl <30 mL/min not on dialysis, and Group C - patients with CrCl < 30mL/min who are on dialysis. Secondary endpoints included response rate, progression free survival and overall survival. Methods: Eligible patients had previously treated MM with renal impairment defined as creatinine clearance < 60 mL/min measured within 21 days prior to registration. Patients previously treated with lenalidomide were required to demonstrate clinical response (any duration) or stable disease with progression-free interval of > 6 months from start of that therapy. All patients received dexamethasone 40 mg orally on days 1, 8, 15 and 22 of a 28-day cycle. Prophylactic anticoagulation consisted of either 81 mg or 325 mg per day of aspirin. Patients also received lenalidomide orally every 1 or 2 days on days 1 through 21 of a 28-day cycle, as described below (Table 1). Starting doses were as in US Product Insert. Dose escalation follows a standard 3+3 design. Results: There have been 23 patients enrolled into groups and cohorts as shown in Table 1. Median age was 73 (range 49–89) and 13 (57%) were women. ISS stage was advanced in all patients, 0 in stage 1, 4 (18%) in stage 2 and 19 (82%) in stage 3. The regimen was well tolerated. Indeed, the MTD has not been reached in any of the groups, as no DLTs have occurred to date. The most commonly reported clinical adverse events (all grades, independent of attribution) across all patients included infections, hyperglycemia, constipation, dizziness, hyponatremia, hypocalcemia and tremor. Hematological toxicities (grade 3–4) occurred in 13 out of 21 pts (62%), mostly neutropenia and thrombocytopenia. Grade 3–4 events at least possibly related to the regimen occurred in 70% and included pneumonia (26%) and otitis media (9%). Response was seen in 14 patients, resulting in an overall response rate of 61%. CR was seen in 1 patient (4%), VGPR in 2 patients (9%), PR in 11 patients (43%), and SD for 9 patients. With median follow-up of 15.5 months, median progression-free survival is 9.8 months and median overall survival is 22 months. Conclusion: Lenalidomide and dexamethasone is a safe and effective regimen in patients with multiple myeloma and renal insufficiency. It is also very well tolerated, although cytopenias are common but manageable. MTD has yet to be reached in each group, allowing for higher doses to be given than previously thought, including 25mg daily (for 21/28 days) in patients with CrCl 30–60 mL/min, 25 mg every other day (for 21/28 days) in patients with CrCl < 30 mL/min not on dialysis, and 10mg daily (for 21/28 days) in patients with CrCl < 30 mL/min on dialysis. These results will provide needed, clinically relevant dosing for lenalidomide in MM patients with renal insufficiency. Disclosures: Kaufman: Millenium: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Novartis: Consultancy.

Abstract Abstract 464 Myeloid-derived suppressor cells (MDSC) are important, albeit incompletely characterized, immune regulatory cells which suppress host anti-tumor immunity in malignancies like melanoma. We sought to address 3 outstanding questions in the present study: i) does tumor burden drive the expansion of MDSC; ii) do MDSC express immunosuppressive B7-H family members,;iii) are MDSC depleted following chemotherapy administration. As MDSC expand in response to tumor-derived factors, including those elevated in melanoma patients, we hypothesized that the frequency of MDSC present in the peripheral blood of melanoma patients may be dependent on tumor stage. Therefore, PBMC were obtained from both normal donors and melanoma patients with all stages of disease (stage I, n=10; stage II, n=10; stage III, n=10; stage IV, n=47). A discreet population of CD14+HLA-DR-/lo MDSC was appreciated in samples obtained from melanoma patients, but was largely absent in normal donors. Approximately 0.5% of PBMC were CD14+HLA-DR-/lo in normal donors. In contrast, the frequency of these cells progressively increased with tumor stage in melanoma. While a two-fold increase in CD14+HLA-DR-/lo MDSC was observed in stage I patients, this difference did not reach statistical significance. In contrast, a significant increase in CD14+HLA-DR-/lo MDSC was observed in patients with stage II-IV disease (2.2% Stage II, p<.01; 3.4% stage III, p<.001; 13.2% stage IV, p<.001). While the observed range (range: 0.8-66.3%) in frequency of CD14+HLA-DR-/lo MDSC was broad in stage IV melanoma, these cells comprised more than 10% of total PBMC in the majority of patients. Various B7 homologues (e.g. B7-H1, B7-H2, B7-H3 and B7-H4) may inhibit T-cell activation, proliferation and cytokine production or promote the induction of T-cell apoptosis and unresponsiveness. Due to their immunosuppressive affects, and expression by tumor cells or immune regulatory cells (e.g. Treg, MDSC), these B7-H members are associated with adverse outcomes in multiple human malignancies. As the expression of these important immunoregulatory molecules on MDSC is unknown, we sought to determine whether CD14+HLA-DR-/lo MDSC in melanoma may express B7-H family members. Therefore, PBMC from patients with metastatic melanoma were stained with either an isotype control or antibodies against B7-H1, B7-H2, B7-H3 or B7-H4. In all cases, B7-H family members were more highly expressed on CD14+HLA-DR-/lo MDSC when compared with the expression observed on CD14+ cells from normal donors. While B7-H1 (p<.01), B7-H2 (p<.001) and B7-H4 (p<.01) were preferentially expressed on HLA-DR-/lo cells in melanoma patients, B7-H3 was more highly expressed on both HLA-DR+ (p<.05) and HLA-DR-/lo (p<.001) CD14+ cells. Serial blood samples, both at baseline and at least 12 weeks after therapy, were availabel for 10 patients with metastatic melanoma undergoing therapy wither either carboplatin and nanoparticle albumin bound paclitaxel (nab paclitaxel; n=6) or carboplatin, paclitaxel and bevacizumab (n=4). The frequency of both CD14+HLA-DR-/lo MDSC and conventional CD14+HLA-DR+ monocytes was determined both before and after chemotherapy. An approximately 50% reduction in the frequency of CD14+HLA-DR-/lo MDSC was observed following chemotherapy (p=.004), with no significant reduction in the frequency of conventional HLA-DR+ monocytes (p=.08). Collectively, the data presented implicates multiple B7-H family members in MDSC-mediated immune suppression and demonstrates that the expansion of B7-H+CD14+HLA-DR-/lo MDSC in melanoma is directly associated with the tumor burden, but may be abrogated by the administration of taxane-based chemotherapy. Disclosures: No relevant conflicts of interest to declare.

Twitter use has increased among patients with cancer, advocates, and oncology professionals. Hashtags, a form of metadata, can be used to share content, organize health information, and create virtual communities of interest. Cancer-specific hashtags modeled on a breast cancer community, #bcsm, led to the development of a structured set of hashtags called the cancer tag ontology. In this article, we review how these hashtags have worked with the aim of describing our experience from 2011 to 2017. We discuss useful guidelines for the development and maintenance of health-oriented communities on Twitter, including possible challenges to community sustainability and opportunities for future improvement and research.

Reactive airway diseases are significant sources of pulmonary morbidity in neonatal and pediatric patients. Supplemental oxygen exposure in premature infants contributes to airway diseases such as asthma and promotes development of airway remodeling, characterized by increased airway smooth muscle (ASM) mass and extracellular matrix (ECM) deposition. Decreased plasma membrane caveolin-1 (CAV1) expression has been implicated in airway disease and may contribute to airway remodeling and hyperreactivity. Here, we investigated the impact of clinically relevant moderate hyperoxia (50% O2) on airway remodeling and caveolar protein expression in a neonatal mouse model. Within 12 h of birth, litters of B6129SF2J mice were randomized to room air (RA) or 50% hyperoxia exposure for 7 days with or without caveolin-1 scaffolding domain peptide (CSD; caveolin-1 mimic; 10 µl, 0.25 mM daily via intraperitoneal injection) followed by 14 days of recovery in normoxia. Moderate hyperoxia significantly increased airway reactivity and decreased pulmonary compliance at 3 wk. Histologic assessment demonstrated airway wall thickening and increased ASM mass following hyperoxia. RNA from isolated ASM demonstrated significant decreases in CAV1 and cavin-1 in hyperoxia-exposed animals while cavin-3 was increased. Supplementation with intraperitoneal CSD mitigated both the physiologic and histologic changes observed with hyperoxia. Overall, these data show that moderate hyperoxia is detrimental to developing airway and may predispose to airway reactivity and remodeling. Loss of CAV1 is one mechanism through which hyperoxia produces these deleterious effects. Supplementation of CAV1 using CSD or similar analogs may represent a new therapeutic avenue for blunting hyperoxia-induced pulmonary damage in neonates.

Abstract Despite unprecedented successes with immune checkpoint blockade in advanced cancers, these agents provide durable clinical benefit in only a subset of patients. In addition, the clinical management of patients receiving immune checkpoint blockade remains quite challenging due to the unpredictable and kinetically heterogeneous responses which can manifest as late responses, pseudoprogression, or hyperprogression in subsets of patients. The dynamics and heterogeneity of programmed cell death protein ligand 1 (PD-L1, aka B7-H1) expression confound its use as a predictive biomarker in cancer immunotherapy, but blood-based biomarkers have the potential to predict responders and detect mechanisms of resistance to immunotherapy. We previously reported that Bim (BH3-only protein) is a downstream signaling molecule of the PD-1 pathway, and that Bim levels in circulating tumor-reactive T-cells reflected patient responses to anti-PD-1 therapy in melanoma. We also discovered the existence of soluble PD-L1 (sPD-L1) in the plasma of cancer patients and showed a correlation of sPD-L1 with cancer stages in renal cell carcinoma and with prognosis in metastatic melanoma. Here we evaluated the frequency of tumor-reactive T cells with Bim expression along with effector memory profile and sPD-L1 as biomarkers of response in a new cohort of patients with metastatic melanoma and lung cancer undergoing anti-PD-1 therapy. We recruited 100 cancer patients treated with anti-PD-1 therapy who had peripheral blood collected at baseline and at each subsequent radiographic tumor evaluation. Frequencies of Bim+ and effector memory CD8+ T cells were measured by flow cytometry in gated tumor-reactive CD11a high PD1+ CD8+ T cells. We also measured levels of sPD-L1 in plasma at baseline and serially during treatment with ELISA. Baseline T cell markers and sPD-L1 levels and their percent changes in patients who had a radiographic response were compared to those who had progressive disease (PD). We found that patients with objective response after 4 cycles of anti-PD-1 therapy had higher frequency of Bim+ CD8+ T cells at baseline compared to patients with PD (mean 43% vs. 30%, P=0.0484). The frequencies of Bim+ T cells decreased significantly after the first 3 months of treatment in responders compared with progressors (mean -16% vs. + 40% P=0.0111). The frequency of effector memory CD8+ T cells also dramatically increased in responders in 3-6 months after anti-PD-1 therapy (mean 89% vs. 9.56%, p=0.002). High baseline sPD-L1 was associated with progression on anti-PD-1 therapy (mean 2.8 ng/mL vs. 0.7 ng/mL, p=0.07) or development of immune-related toxicities and the levels increased by 12 weeks in patients progressing on therapy. Conclusion: Measurements of T cell biomarkers (Bim and effector memory) and sPD-L1 levels provide a new noninvasive way to predict and monitor patient responses to anti-PD-1 monotherapy in melanoma and lung cancers. Note: This abstract was not presented at the conference. Citation Format: Roxana S. Dronca, Aaron Mansfield, Xin Liu, Susan Harrington, Elizabeth Enninga, Svetomir Markovic, Lisa Kottschade, Rob Mcwilliams, Matthew Block, Wendy Nevala, Michael Thompson, Haidong Dong. Blood-based T cell biomarkers and soluble PD-L1 predict responses and immune-related toxicity to PD-1 blockade in melanoma and lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A38.