Suman, V.

5544 Background: Pazopanib, an orally bioavailable multitargeted inhibitor of kinases including VEGF-R, demonstrated impressive activity in metastatic differentiated thyroid cancer (49% durable RECIST PRs) and promising preclinical activity in anaplastic thyroid cancer (ATC) models, prompting its evaluation also as a candidate therapeutic in advanced ATC. Methods: A multicenter single arm phase II trial of 800 mg pazopanib daily was undertaken with the primary endpoint of RECIST response rate. The trial was designed such that there would be a 90% chance of detecting a response rate of >20% at the 0.10 significance level when the true tumor response rate is >5%. A pre-specified stopping rule designated that enrollment would cease unless 1 or more RECIST PRs+CRs were observed in the first 14 of 33 potential patients. Eligibility required informed consent, >18 years of age, performance status ECOG 0-2, systolic blood pressure (BP) <140 mm Hg and diastolic BP <90 mm Hg at entry, QTc interval <480 msecs, and measurable disease by RECIST criteria. Anatomical imaging and toxicity evaluations were required every 4 weeks. Results: Sixteen patients were enrolled. One patient withdrew prior to therapy, leaving 15 evaluable patients – 33.3% were male, with a median age of 66 years (range 45-77); 11 of 15 patients had progressed through prior systemic therapy. Four patients required 1-2 dose reductions, with the most common severe toxicities (CTC-AE version 3.0 grades 3-5) hypertension (13%) and pharyngolaryngeal pain (13%). Reasons for treatment discontinuation included: disease progression (12 pts), death on study due to a vascular event possibly related to treatment (1 pt.), and intolerability (radiation recall tracheitis – 1 pt, and uncontrolled hypertension – 1 pt). Although transient disease regression was observed in several patients, there were no confirmed RECIST tumor responses, triggering study closure at time of interim analysis. Two patients are alive with disease 9.9 months and 2.9 years post-registration; the remaining 13 died of disease. The median time to progression was 62 days and the median survival time was 111 days. Conclusions: Pazopanib has poor single agent activity in advanced anaplastic thyroid cancer.

534 Background: mTOR plays a critical role in promoting tumor cell growth. In preclinical studies, the anti-tumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated by IGF-1R. We designed a phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT) and pharmacodynamic effects of the IGF-1R antibody IMC-A12 in combination with temsirolimus (tem) in patients (pts) with metastatic breast cancer (MBC) where mTOR is frequently activated. Methods: A 3+3 phase I design was chosen. Tem and IMC-A12 were administered IV days (d) 1, 8, 15, and 22 of a 4-week cycle in pts with MBC refractory to standard therapies. Tumor response was evaluated by RECIST. Adverse events (AE) were reported using CTC v3.0. Serum IGF 1 and C-peptide levels on d2 (24h post infusion) and d8 prior to drug infusion were compared to baseline (BL) using paired t-test. Results: Of 26 pts enrolled, 4 did not complete cycle 1 due to progression (3) or co-morbid condition (1). MTD was determined from remaining 22 pts aged 34-72 (median 48) years with ECOG PS 0 (55%) or 1 (45%). 86% had ER+ cancer. Median number of regimens for MBC was 4. Two DLTs at the starting DL (DL 1) necessitated dose de-escalation of tem to 20mg (DL-1), then to 15 mg (DL-2) which was tolerable (Table). Subsequent dose escalation of IMC-A12 led to DLTs in 0 of 6 in DL-2A and 2 of 3 pts in DL-2B. The MTD was defined as DL-2A. Other AEs included gr 1/2 fatigue, neutropenia, anemia, and hyperglycemia. No CR or PR, but 4 SD lasting ≥ 4 months were observed. At DL-2, -2A and -2B, serum IGF 1 levels were significantly elevated on d2 (p <0.002) and d8 compared to BL (p <0.001), but C-peptide levels were not found to differ from BL. Conclusions: The MTD for the combination of IMC-A12 and tem in pts with MBC is lower than that observed for single agents alone. A phase II study is ongoing in MBC. The study is supported in part by ASCO CDA, Komen Craft to CXM, N01-CM62205 and N01-CM-2011-00071. [Table: see text]

e21039 Background: Tumor-infiltrating neutrophils (TINs) and their myeloid precursors play an important role in cancer biology. While activated neutrophils have been shown to kill tumor cells, there is growing evidence that neutrophils may also support tumor progression by impairing T cell-dependent anti-tumor immunity. We hypothesized that low TINs would be associated with better responses to immunotherapy (IO). Methods: Pretreatment biopsies from 15 metastatic melanoma (MM) pts treated with anti-CTL4 and anti-PD-1 therapy from 2012-17 were collected and stained with myeloperoxidase (MPO). Slides were scanned at 40x magnification on the Aperio ScanScope AT Turbo brightfield instrument (Leica Biosystems) at a resolution of 0.25 microns per pixel. To indicate the region of analysis, the digital pen tool was used to trace a minimum 85% of tumor. Ten fixed-sized boxes were placed on the hottest staining region in a second annotation layer on the image. The boxes equaled 1mm2 in total area. If the tumor tracing had an area of 1mm2, or less, boxes were not placed on the image. The selected tissue was analyzed using an Aperio imaging quatification algorithm . The number of 3+ cells were considered positive for neutrophils and used in subsequent calculations. Quality control review was performed on a subset of cases by Anatomic Pathologists. Response to therapy was assessed using the Response Evaluation Criteria In Solid Tumors (RECIST). Overall survival (OS) was calculated using the Kaplan Meier method. Results: The median number of treatment lines before the biopsy was 1 (range 0-2). The treatment immediately following the biopsy consisted of ipilimumab (n = 10, 66.6%), pembrolizumab (n = 4, 26.6%), ipilimumab/nivolumab (n = 1, 6.6%). The median number of neutrophils in the biopsy hotspot was 92/mm2 (range 6-219) for the entire cohort. For patients achieving PR and CR after 4 cycles of therapy, the median neutrophils were 36/mm2 (IQ 14-78) while the median was 106/mm2 (IQ 60-138) for patients who had progressive disease,( p = 0.04). There was no correlation between the numbers of neutrophils in the biopsy with the absolute neutrophil count in the peripheral blood (R value: 0.012). Conclusions: Decreased TINs are significantly associated with better responses to IO in MM pts. Measurements of TINs may help to select patients who are likely to benefit from anti-CTL4 and anti-PD-1 therapy. Additionally, exploration of whether combining therapies that decrease neutrophils intratumorally should be explored.