Citations

Abstract Background Metformin has been associated with lower breast cancer (BC) risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones. We evaluated the effect of metformin on sex hormones in MA.32, a phase III trial of nondiabetic BC subjects who were randomly assigned to metformin or placebo. Methods We studied the subgroup of postmenopausal hormone receptor-negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after being randomly assigned. Sex hormone-binding globulin, bioavailable testosterone, and estradiol levels were assayed using electrochemiluminescence immunoassay. Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models. Results 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2-negative BC and had received (neo)adjuvant chemotherapy. Mean age was 58.1 (SD=6.9) vs 57.5 (SD=7.9) years, mean body mass index (BMI) was 27.3 (SD=5.5) vs 28.9 (SD=6.4) kg/m2 for metformin vs placebo, respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (−5.7 vs 0 pmol/L; P < .001) in univariable analysis and after controlling for baseline BMI and BMI change (P < .001). There was no change in sex hormone-binding globulin or bioavailable testosterone. Conclusion Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers.

Purpose: Multiple myeloma (MM) treatment has changed tremendously, with significant improvement in patient out-comes. One group with a suboptimal benefit is patients with high-risk cytogenetics, as tested by conventional karyotyping or fluorescence in situ hybridization (FISH). Methodology for these tests has been published, but not necessarily standardized. Methods: We address variability in the testing and reporting methodology for MM cytogenetics in the United States using the ongoing African American Multiple Myeloma Study (AAMMS). We evaluated clinical and cytogenetic data from 1,221 patients (1,161 with conventional karyotyping and 976 with FISH) tested between 1998 and 2016 across 58 laboratories nationwide. Results: Interlab and intralab variability was noted for the number of cells analyzed for karyotyping, with a significantly higher number of cells analyzed in patients in whom cytogenetics were normal (P 5.0025). For FISH testing, CD138-positive cell enrichment was used in 29.7% of patients and no enrichment in 50% of patients, whereas the remainder had unknown status. A significantly smaller number of cells was analyzed for patients in which CD138 cell enrichment was used compared with those without such enrichment (median, 50 v 200; P, .0001). A median of 7 loci probes (range, 1-16) were used for FISH testing across all laboratories, with variability in the loci probed even within a given laboratory. Chromosome 13–related abnormalities were the most frequently tested abnormality (n5956; 97.9%), and t(14;16) was the least frequently tested abnormality (n 5 119; 12.2%). Conclusions: We report significant variability in cytogenetic testing across the United States for MM, potentially leading to variability in risk stratification, with possible clinical implications and personalized treatment approaches.

Abstract Introduction Pediatric positive airway pressure (PAP) therapy can be challenging for children and their parent/guardian (PG). These challenges are complicated by the need to facilitate behavioral competency in the management of both device equipment and therapy. Methods As part of a larger quality management project aimed to improve PG and patient satisfaction we developed a targeted education visit provided by registered nurses prior to PAP trial initiation. Principle aims were to measure satisfaction with education and increase PG confidence in ability to manage therapy. The nurse session included: education on Obstructive Sleep Apnea (OSA) and PAP therapy, development of plan for first month of therapy, concepts of desensitization, regular practice, discussion and identification of concerns (assessment of barriers to implementation). A survey was administered pre-intervention to assess PG confidence in ability to manage therapy. Post-intervention, PG rated the interventions impact on baseline confidence, as well as an assessment of satisfaction with the education and content. Descriptive statistics were utilized to summarize the Likert survey questions. Results A total of 21of 25 (84%) participants completed surveys. 100% of PG that responded was either extremely satisfied or very satisfied with the educational intervention. Prior to the intervention, 19% (N4) indicated little to no confidence, 19% (N4) indicated some confidence and 62% (N13) indicated being very confident. 62% (N13) of PG’s indicated the information covered was new to them, while 24% (N5) indicated some information was new and 14% (N3) indicated none of the information was new. Regardless of baseline confidence, 100% (N21) responded that the intervention further improved confidence to a great degree. Conclusion The nurse visit resulted in high satisfaction with care and education and impacted PG confidence in ability to implement treatment. Future studies are needed to determine the impact on patient compliance. Support

e22020 Background: The combination of nab-paclitaxel (NP) and bevacizumab (BEV) in patients with MM has shown promising clinical activity. AB160 is a 160 nm nano-immunoconjugate of NP nanoparticles non-covalently coated with BEV for targeted delivery into high VEGF expressing tissues. Preclinical data showed that AB160 improved tumor targeting/ tumor inhibition more than NP followed by BEV. Methods: A 3+3 phase I trial was conducted in patients (pts) with MM who had prior systemic treatment for metastatic disease to determine the maximum tolerated dose of AB160 administered intravenously on days 1, 8 and 15 of a 28-day cycle. Dose level 1 (DL1) was 125 mg/m2 NP /50 mg/m2 BEV. Dose limiting toxicities (DLT) included grade (G) 4 neutropenia or anemia, PLT < 25,000, serum creatinine ≥ 2 times baseline, G2-4 neurologic toxicity or G3-4 non-hematologic toxicities. Tumor evaluations (RECIST) were conducted every 8 weeks. Treatment continued until progression or intolerability. Results: 21 pts (11 ♀) aged 36-78 years old were enrolled. One of the first 3 pts on DL1 developed a G2 colonic perforation; this was considered a DLT. One of the next 3 pts on DL1 had a DLT: G4 neutropenia. Of the 3 pts on DL-1 (100 mg/m2 NP/40 mg/m2 BEV), 2 had no DLTs and 1 died of sepsis after C1D1 dose. Enrollment was suspended until an amendment modifying the eligibility criteria was approved by the IRB. The trial reopened. One of the 4 pts on DL-1 and 1 of the 5 pts on DL1 had a DLT: G3 pain and G3 fatigue, respectively. Enrollment ended after 2 of the 3 pts on DL2 (150 mg/m2 NP/ 60 mg/m2 BEV) developed G4 neutropenia. Thus, MTD is DL1. A median of 3 cycles was administered. Treatment ended due to progression (9), intolerability (9), refusal (2) and death (1). There were no objective tumor responses. Common G3-4 toxicities were: neutropenia (33%) and thromboembolic events (19%). Conclusions: AB160 was found to have insufficient clinical benefit in patients with previously treated MM to justify further development. However, parallel phase I testing in gynecologic cancers suggests clinical benefit (abstract #300225). Clinical trial information: NCT02020707.

10520 Background: Outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are superior with pediatric-inspired therapy. CALGB 10403, the first US adult cooperative group prospective trial using a pediatric-inspired augmented BFM (ABFM)-based regimen, demonstrated feasibility and improved survival. We examined differences in drug delivery and targeted toxicities in AYAs who received the same therapy on C10403 vs the Children’s Oncology Group (COG) study AALL1131. Methods: The proportion of AYAs receiving full dose (within 10% of protocol- specified) vincristine (VCR) and pegaspargase (PEG) during induction (IND), consolidation (CON), and delayed intensification (DI); the likelihood of selected grade ≥3 adverse events (AEs); and the impact of patient characteristics were compared in AYAs 16-30 years. Targeted AEs with analogous reporting requirements in both studies included hyperbilirubinemia, pancreatitis, sensory neuropathy, and GI/intracranial hemorrhage. Thrombosis, transaminitis and hyperglycemia were not comparably captured. Fisher’s Exact test and logistic regression models were used for analyses. Results: After excluding AYAs removed from study after induction, 87 AALL1131 AYAs (accrued 2012-2016) and 188 C10403 AYAs (accrued 2007-2012) were analyzed with median ages of 17 (16-26) vs 22 (17-30) years, p < 0.001. There was no difference in the intensity of VCR delivery during IND, but in CON and DI, AALL1131 AYAs were more likely to receive all specified VCR (93.1% vs 81.9%, p = 0.02; 92.7% vs 72.1%, p = 0.01). Women were less likely to receive all specified VCR (OR 0.57, 95% CI 0.34-0.94, p = 0.03), and overweight/obese AYAs were somewhat less likely to receive all VCR compared to those considered normal weight (OR 0.88 and 0.59, p = 0.09). More C10403 AYAs were obese/overweight compared to AALL1131 AYAs (p = 0.04). There were no significant differences in dosing of PEG during IND/CON, but in DI AALL1131 AYAs were more likely to receive both doses (75.6% vs 57.1%, p = 0.03). No patient variables impacted delivery of PEG. There was no significant difference in grade ≥3 toxicities captured similarly on both studies. Conclusions: AYAs enrolled on AALL1131 were more likely to receive all protocol-specified VCR and PEG compared to those on C10403. Selected AE rates were comparable, suggesting that older AYAs do not tolerate doses of VCR and PEG for reasons other than toxicity, with body habitus as one potential variable. Further analyses to compare dose density, toxicities, and outcomes experienced by younger AYAs versus older are ongoing.

e19214 Background: ARST1321(PAZNTIS): A Phase II/III Randomized Trial of Preoperative Chemoradiation or Preoperative Radiation Plus or Minus Pazopanib (NCT02180867) was the first National Clinical Trials Network (NCTN) study co-developed by pediatric (COG) and adult (NRG Oncology) consortia anticipating enrollment of adolescent and young adult (AYA) cancer patients. ARST1321 had two treatment cohorts, enrolling patients ≥ 2 years of age to either chemotherapy (C) (chemoradiation ± pazopanib) or non-chemotherapy (NC) (radiation ± pazopanib) arms. It was anticipated adults would contribute the majority of enrollments on the NC arm based on prior enrollment patterns. While the C arm accrued as anticipated (with high enrollment of adults and children), the NC arm had low enrollment leading to premature closure. We report on AYA accrual (defined as 15-39 years) to the NC arm and a survey aiming to identify barriers to enrolling AYA patients onto ARST1321. Methods: Our survey was emailed to 161 adult, surgical, and radiation oncologists at large sarcoma centers. A link was sent to an online questionnaire via SurveyMonkey Inc. and responses were reviewed on their platform. Results: 33 patients enrolled on the ARST1321 NC arm, of which 24% were AYA. 25% of AYA enrollments were from non-COG adult cooperative groups. This trial arm was closed in October 2017 after 3.25 years of accrual below anticipated rates. The survey response rate was 31% with a 70% completion rate. Almost half of respondents were medical oncologists with most seeing 50-200 new sarcoma cases/year at an academic institution and 30% in a pediatric environment (divided equally between radiation and surgical oncologists). 70% of respondents have a joint collaboration with their pediatric oncology team with 23% having a joint clinic. 70% of respondents’ sites opened ARST1321 and anticipated 1-5 patients would be eligible for the NC cohort. However, 42% of respondents’ sites had zero patients enrolled on that arm. The most common reasons for not opening the study and/or not enrolling patients on the NC arm included: lack of interest, disagreement with the therapy, lack of a site investigator, premature study closure, patient/family decision, competing trials, insufficient reimbursement, and regulatory delays. Conclusions: Our survey highlights multiple barriers to enrollment of AYA onto cross-NCTN consortia clinical trials spanning the age spectrum. The information obtained will help inform investigators aiming to effectively design, enroll, and conduct similar trial efforts for AYA in the future.

e18097 Background: AB160 is a 160 nm nano-immunoconjugate consisting of nab-paclitaxel (NP) nanoparticles non-covalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of vascular-endothelial growth factor (VEGF). Both taxanes (GOG-0129C, GOG-0126R, GOG-0127V) and BEV (GOG-0229E, AURELIA, GOG-0227C) have demonstrated clinical activity in previously treated metastatic endometrial cancer (EC), ovarian cancer (OC), and cervical cancer (CC), respectively. Methods: A 3+3 phase I trial was conducted in patients with EC, platinum-resistant OC and CC who had prior systemic treatment for metastatic disease to determine the maximum tolerated dose of AB160 administered intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose level (DL1) was NP at 125 mg/m2 with BEV at 50 mg/m2. There were 2 higher dose levels: DL2 (NP at 150 mg/m2 with BEV at 60 mg/m2) and DL3 (NP at 175 mg/m2 with BEV at 70 mg/m2). Dose limiting toxicities (DLT) included grade (G) 4 neutropenia or anemia, PLT < 25,000, serum creatinine ≥2 times baseline, G2-4 neurologic toxicity or G3-4 non-hematologic toxicities. Disease evaluations were conducted after every 2 treatment cycles using RECIST criteria. Patients were treated until disease progression or intolerability. Samples were collected for pharmacokinetic (PK) studies. Results: Nine women 41 – 74 years of age (median 57) have enrolled (5 with EC and 4 with OC); data are available for the first 8. No DLTs have been observed among the 3 women enrolled on DL1, 3 women on DL2, and 2 women on DL3. All 3 patients on DL3 continue on treatment. The other 6 patients have discontinued due to adverse reactions (3), progression (2), and patient choice (1). The median number of cycles administered is 6 (4-14). The most common severe (G3/4) toxicities include neutropenia (37.5%) and leukopenia (25%). There have been 5 partial responses (62.5%): 1 on DL1 and 2 each on DL2 and DL3. PK evaluation is pending. Conclusions: AB160 therapy is safe and demonstrates promising clinical activity in patients with previously treated metastatic gynecologic malignancies. Further clinical testing is being pursued in this patient population. Clinical trial information: NCT02020707.

3531 Background: ctDNA has emerged as a promising biomarker for noninvasive monitoring of treatment response and disease progression in many tumor types. However, the clinical use of ctDNA in patients with HCC has not been established. Here, we evaluated longitudinal and personalized detection of ctDNA for monitoring the treatment response to atezolizumab (atezo) + bevacizumab (bev) in patients with unresectable HCC not previously treated with systemic therapy. Methods: A subset (n = 48) of 104 patients with HCC who enrolled in Arm A of GO30140 (NCT02715531; Phase 1b) and received atezo + bev treatment were included in this study. These patients had 10 CR, 11 PR, 12 SD and 15 PD per IRF-assessed RECIST 1.1. Serial plasma samples were collected at baseline (Cycle [C]1 Day [D]1), during treatment (C2D1, C4D1) and at disease progression. Somatic mutations in individual tumors were identified via whole exome sequencing of archival tumor tissues or fresh biopsies collected before treatment. Personalized ctDNA assays (Signatera 16-plex multiplex PCR next-generation sequencing assay) specific to each patient’s tumor mutational signatures were successfully designed for 47 of 48 patients. Results: At C1D1, a median of 25.7 ng of cell-free DNA was extracted from 2-mL plasma samples. ctDNA was detected in 45 of 47 patients (96%), with a median of 70.6 mean tumor molecules/mL of plasma (MTM/mL) and a median of 1.8% mean variant allele frequency (mean VAF) in plasma. Higher ctDNA levels detected at C1D1 appeared to be associated with increased tumor burden ( P < 0.03). Dynamic changes in ctDNA levels post-treatment were associated with response at C4D1. ctDNA status changed from positive at baseline to negative in 7 of 10 CR (70%), 3 of 11 PR (27%), 1 of 11 SD (9%) and 0 of 11 PD (0%) patients. Longer PFS was observed in patients whose ctDNA became undetectable post-treatment. The median PFS in patients with ctDNA present vs cleared at C4D1 was 6.5 months and not reached, respectively (HR, 12 [1.7-93], log-rank P < 0.00029). Conclusions: Our study showed that Signatera, a personalized and tumor-informed ctDNA assay, could be used as a sensitive method for detecting ctDNA in patients with unresectable HCC. More importantly, our results illustrate the promise of ctDNA as an emerging biomarker that may potentially help to monitor treatment responses and disease progression in patients with HCC.

e15184 Background: Clinical responses to anti-PD1 immunotherapy in patients with metastatic melanoma (MM) remain challenging to predict. This clinical heterogeneity is also reflected in the tumor-immune microenvironment among patients and within a single tumor lesion. With the emergence of multiplex imaging platforms, defining complex phenotypes at single cell resolution has become possible. Here, we sought to objectively quantify paracrine tumor-immune interactions contributing to the variable clinical responses observed in patients receiving anti-PD1 therapy. Methods: Excisional lymph node (LN) biopsies were obtained from treatment-naïve patients with MM who underwent subsequent anti-PD1 therapy. A single 5µm section of LN tissue was used to assess a 42 analyte panel by multiplex immunofluorescence. From 30 LN samples, 418 fields of view (FOVs) were selected resulting in 14,360 high-resolution images of 4 anatomical subregions: tumor core, tumor-immune interface, tumor infiltrate and adjacent immune stroma. Following image processing, we developed an adaptive classification for tumor-centric cellular neighborhoods (TCCN) to identify and quantify critical paracrine interactions within the tumor-immune microenvironment. Results: Stratification based on responsiveness to anti-PD1 therapy resulted in 4 complete responders (CR) and 12 non-responders (NR) at 12-week follow-up. From 126 FOVs, we defined the cellular composition of 197,865 TCCN across patients based on clinical response and LN subregions. Overall, the percentage of TCCN devoid of any T cells, B cells or macrophages was significantly higher in NR compared to CR irrespective of subregion. However, other markers differentiated TCCN based on subregion. Specifically in CR, tumor core regions were enriched for CD8 T cells, while enrichment for B cells and endothelial cells was demonstrated at the tumor-immune interface. Strikingly, tumor infiltrate regions demonstrate robust immune reactivity with enrichment for M1 polarized macrophages, NK cells and B cells in CR compared to NR. Complete data from the 30 patient cohort across 418 FOVs will be presented. Conclusions: Taken together, this data suggests cellular composition of TCCN across subregions of the LN is dynamic within a single metastatic site. In this small cohort, we introduce a formalized stratification to quantify and classify critical paracrine interactions within the immune-tumor microenvironment with the potential to inform clinical responsiveness to therapy.