Citations

TPS10099 Background: PDGFRα is a receptor commonly overexpressed in STS. Olaratumab is a fully human IgG1 MAb which specifically binds to human PDGFRα and blocks PDGFR-mediated signaling pathways. Olaratumab demonstrated significant tumor inhibition as a monotherapy and in combination with standard chemotherapy in preclinical human sarcoma xenograft models. A Phase 1b/2 clinical trial for patients with advanced or metastatic STS is currently enrolling patients in 9 sites across the United States; approximately 45 patients have been randomized. Methods: In Phase 1b, patients received olaratumab (15 mg/kg) via intravenous infusion on Days 1 and 8 of each 21-day cycle and D (75 mg/m²) 1 hour after olaratumab on Day 1. Phase 1b was completed without encountering dose-limiting toxicities; enrollment into Phase 2 has begun. The primary endpoint of the Phase 2 portion is to compare progression-free survival in patients with advanced STS when treated with D plus olaratumab versus D alone. Planned enrollment goal for Phase 2 is 130 patients. Patients are required to be ≥ 18 years old with ECOG 0-2, have appropriate organ function and histologically confirmed, measurable, and advanced STS. There is no restriction on the number of prior therapies. Patients are randomized 1:1 to either D plus olaratumab (Arm A) at same dose/schedule as in Phase 1b or D alone (Arm B). All patients can receive dexrazoxane. Upon completion of 8 cycles, patients in Arm A continue with olaratumab monotherapy. Patients in Arm B who develop disease progression during or after treatment can subsequently receive olaratumab monotherapy. Patients are stratified to treatment arms according to PDGFRα expression (positive vs. negative), number of previous lines of treatment, sarcoma subtype, and ECOG performance status. Response assessment occurs every 6 weeks. Exploratory analyses include biomarkers of olaratumab pharmacodynamic activity including PDGF ligands, PDGFR downstream molecules, VEGF, and changes in vascularity of tumor specimens.

e14555 Background: This study was done to assess the toxicity and efficacy of IMRT for anal cancer in a multi-institutional setting. Methods: Records of 152 total patients (pts) were reviewed retrospectively. Data on disease control and toxicity were collected as well as pt and treatment characteristics. Acute (<6 months) and late (>6 months) severe toxicity (grade >3) were recorded at each institution. Four were excluded for either presence of metastatic disease (2) or stage TX (2). There was data for late toxicity on 120 pts. Results: T stage was T1 in 28, T2 in 79, T3 in 29 and T4 in 12 pts. N stage was N0 in 77, N1 in 40, N2 in 19 and N3 in 12 pts. The median age was 56 yrs and median follow-up was 26.8 months. Cumulative IMRT dose was 51.25 Gy (median) (range: 4.32-61.2 Gy) in a median of 28 fractions (2-34). Chemotherapy was given in all but 2 pts and the most common regimen was 5- fluorouracil plus mitomycin-C. The median total elapsed treatment time was 40 days. Local control at 3 yrs was 87% and was significantly worse for patients with T3-4 disease (79% vs 90% at 3 years; p=0.04). There was no correlation between dose and local control. Regional control, distant control and overall survival were 97%, 91%, and 87% at 3 yrs, respectively. Nodal status was associated with regional and distal control as well as overall survival (p<0.01 for each). The most common acute severe toxicity was hematologic (41%). Severe acute GI, skin or other toxicity was 11%, 20% and 1% respectively. There were two grade 5 toxicities (hematologic and GI). Severe late toxicity was limited to skin (1%) and GI (3%). Conclusions: IMRT resulted in excellent local control in this multi-institutional cohort of pts. Although T stage did predict for worse local control, most pts with T3-4 disease were controlled with IMRT. Nodal status predicts for regional and distal control as well as overall survival. Severe toxicity was acceptable with this technique.

e13501 Background: Loss of estrogen receptor alpha gene expression has been associated with insensitivity to endocrine therapy in human breast cancer patients. Histone deacetylase (HDAC) inhibitors have recently been found to restore sensitivity to the estrogen receptor by modulation of the estrogen and progesterone receptors. This had been shown with both aromatase and tamoxifen refractory and in triple negative cell lines . We performed a Phase I study of the combination of LBH589 (panobinostat) and letrozole to evaluate safety and tolerability in patients with metastatic breast cancer prior to the performance of a phase II trial. Methods: We enrolled postmenopausal women with metastatic breast cancer, ECOG PS 0 or 1, ANC>1500/mm3, platelets>100,000/mm3, normal total bilirubin, and ALT/AST adequate laboratory tests were eligible. Letrozole dose was 2.5 mg/day orally. Dose of LBH589: Level 1, 20 mg orally three times weekly; Level 2, 30 mg orally three times a week. Results: 12 patients (dose level 1:6 patients, dose level 2: 6 patients) have been enrolled. 43 cycles of treatment have been given to these12 patients. Initial cohort of 3 patients at the 20 mg dose level had no dose limiting toxicity (DLT). At the 30 mg dose level 3/6 patients had DLT (thrombocytopenia grade 1: 2 pts; grade 3:1 pt; grade 4: 1 pt; and diarrhea grade 3: 1 pt. One pt at the 30 mg dose level has a confirmed partial response and remains on study after 6 cycles of treatment. Subsequent cohort of 3 patients had 1 dose DLT with doubling of the creatinine. The main DLT was thrombocytopenia in 3/6 pts at the 30 mg dose level. Conclusions: The recommended dose for phase II testing of LBH589 is 20 mg orally 3 times per week in combination with standard dose letrozole.

AbstractObjectivesIn the TOURMALINE‐MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib‐lenalidomide‐dexamethasone (IRd) showed different magnitudes of progression‐free survival (PFS) benefit vs placebo‐Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT).MethodsRNA sequencing data were used to investigate the basis of these differences.ResultsThe PFS benefit of IRd vs placebo‐Rd was greater in patients with tumors expressing high c‐MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c‐MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c‐MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81.ConclusionsPFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c‐MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE‐MM1 study. This trial was registered at www.clinicaltrials.gov as: NCT01564537

8530 Background: RAD-001 (Everolimus) is an oral inhibitor of mammalian target of rapamycin (mTOR). Interim analysis results from a phase II study of RAD-001 in patients with metastatic melanoma (MM) were presented at ASCO 2005. This study was re-opened using a higher dose based on an improvement in the 16 week progression free survival (PFS) rate and good tolerability. Methods: A two- stage, phase II multi-institutional trial was conducted in patients with MM to assess that 16 weeks PFS rate was at least 50%. Inclusion criteria: measurable disease, ECOG performance score of 0–2. Exclusion criteria: presence of intracranial metastases, concurrent use of inducers of cytochrome 3A4 and abnormal organ function. The dose of RAD-001 in the second cohort was increased to 10 mg daily (increased from 30 mg weekly) based on evidence of safety of the higher dose. Results: Twenty-nine patients were enrolled; baseline information is available on 27. Median age was 63 yrs; 15 (56%) had >2 sites of metastatic disease. Most (48%) had stage M1c disease. PS was 0, 1 and 2 in 58%, 38% and 4%. All but 4 (15%) had received prior therapy. Grade 3 adverse events included stomatitis and fatigue (2 each), leukopenia, neutropenia, diarrhea, anorexia, dehydration, dyspnea, hyperglycemia, and hypersensitivity (1 each). Planned interim analysis was done after 20 patients were enrolled. 14 (70%) had progressed 16 weeks, failing to meet the decision rule needed (PFS >30%) to restart accrual. The median PFS for all 29 patients was 56 days. The median overall survival (OS) has not been reached. For the entire cohort of 53 pts treated on this study (at both dose levels), the median PFS, median OS were 59 and 286 days respectively. Conclusion: Interim analysis after enrollment of 20 patients at a higher dose of RAD-001 demonstrated significantly more toxicity and no added clinical efficacy. The 16 week PFS rate target was not reached, and accrual was suspended. No significant financial relationships to disclose.

7029 Background: A leukocyte count of > 15 ×109/L has recently been associated with myocardial infarction in polycythemia vera (PV). In the current study, we examine the impact of such degree of leukocytosis on survival, leukemic transformation (LT), and thrombosis in a large cohort of PV patients from a single institution Methods: Data was abstracted from the medical records of a consecutive cohort of patients with PV defined by the World Health Organization criteria. Results: i. Patient characteristics The study cohort included 459 patients (median age, 60 years). Median follow-up was 64 months. ii. Survival In a multivariable analysis, advanced age, leukocyte count of = 15 × 109/L, and arterial thrombosis at diagnosis were significantly associated with inferior survival. A prognostic model based on age = 60 years and leukocyte count = 15 × 109/L separated low-risk, intermediate-risk, and high-risk patient groups with respective median survivals of 272, 162, and 108 months (p<0.0001). iii. Leukemic transformation In a multivariable analysis, only leukocyte count was significantly associated with LT; median leukemia-free survival for patients with leukocyte count = 15 × 109/L was 273 months vs. not reached for those with lower leukocyte count (p<0.0001). iv. Thrombosis at diagnosis In multivariable analysis, arterial thrombosis at diagnosis was significantly associated with previous history of arterial thrombosis, hypertension, and tobacco use; venous thrombosis at diagnosis was significantly associated with previous venous event and splenomegaly. v. Thrombosis during follow- up In multivariable analysis, arterial thrombosis during follow-up was significantly associated with previous arterial event, hypertension, and tobacco use; venous thrombosis during follow-up was significantly associated with previous venous event, diabetes mellitus, advanced age, and leukocyte count = 1,500 × 109/L. Conclusions: The current study for the first time identifies leukocytosis as a risk factor for inferior survival, LT risk, and venous thrombosis in PV. No significant financial relationships to disclose.

AbstractPrevious transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta‐analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case‐only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS‐significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast‐cancer gene in three of six regions harboring multiple TWAS‐significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

Abstract Background: Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) using Mendelian randomization (MR) analysis. Methods: Genome-wide association study data from the InterLymph Consortium were available for 2,661 DLBCLs, 2,179 CLLs, 2,142 FLs, 824 MZLs, and 6,221 controls. SNPs associated (P &lt; 5 × 10−8) with high-density lipoprotein (HDL, n = 164), low-density lipoprotein (LDL, n = 137), total cholesterol (TC, n = 161), and triglycerides (TG, n = 123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8%, and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance–weighted method, estimating odds ratios (OR) per standard deviation and 95% confidence intervals (CI). Results: HDL was positively associated with DLBCL (OR = 1.14; 95% CI, 1.00–1.30) and MZL (OR = 1.09; 95% CI, 1.01–1.18), while TG was inversely associated with MZL risk (OR = 0.90; 95% CI, 0.83–0.99), all at nominal significance (P &lt; 0.05). A positive trend was observed for HDL with FL risk (OR = 1.08; 95% CI, 0.99–1.19; P = 0.087). No associations were noteworthy after adjusting for multiple testing. Conclusions: We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes. Impact: Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.

Background: Invasive hemodynamic evaluation through right heart catheterization plays an essential role in the diagnosis, categorization, and risk stratification of patients with pulmonary hypertension. Methods: Subjects enrolled in the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) program undergo an extensive invasive hemodynamic evaluation that includes repeated measurements at rest and during several provocative physiological challenges. It is a National Institutes of Health/National Heart, Lung, and Blood Institute initiative to reclassify pulmonary hypertension groups based on clustered phenotypic and phenomic characteristics. At a subset of centers, participants also undergo an invasive cardiopulmonary exercise test to assess changes in hemodynamics and gas exchange during exercise. Conclusions: When coupled with other physiological testing and blood -omic analyses involved in the PVDOMICS study, the comprehensive right heart catheterization protocol described here holds promise to clarify the diagnosis and clustering of pulmonary hypertension patients into cohorts beyond the traditional 5 World Symposium on Pulmonary Hypertension groups. This article will describe the methods applied for invasive hemodynamic characterization in the PVDOMICS program. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02980887.