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This phase Ib study enumerated whole blood circulating tumor cells (CTC) and evaluated biomarkers in patients with potentially resectable soft-tissue sarcoma (STS) treated with olaratumab monotherapy (20 mg/kg) for one cycle followed by up to six cycles of olaratumab (20 mg/kg, cycles 1–2; 15 mg/kg, cycles 3–7) plus doxorubicin (75 mg/m2 on day 1). CTCs, platelet-derived growth factor receptors (PDGFR), and PDGF ligand expression in tumor tissue pre- and post-olaratumab monotherapy were evaluated. Antitumor activity, safety, pharmacokinetics, and PET/biomarker association with clinical outcome were assessed. Of 51 treated patients, 35, 43, and 37 were evaluable for CTC enumeration, PDGFRs, and PDGF ligand expression, respectively. An increase in CTCs at cycle 1 day 8 was observed, followed by a significant reduction by cycle 3 day 1 or 30-day follow-up. Decrease in CTC counts after olaratumab monotherapy was higher in patients with disease control than without disease control (57.9% vs. 31.2%). Baseline IHC expression was positive in most patients for PDGFRα [n = 31 (72.1%)] and PDGFRβ [n = 36 (83.7%)]. Similar rates were observed post-olaratumab monotherapy [PDGFRα, n = 30 (69.8%); PDGFRβ, n = 33 (76.7%)]. Eleven patients (29.7%) showed a 30% reduction by RT-PCR in PDGFRα at cycle 2. PDGFR expression and PET response showed no correlation with clinical outcome. Safety and pharmacokinetic profiles were consistent with previous reports. This study, the first to use a validated method for CTC detection, confirms that CTC enumeration in STS is feasible. However, no correlation was observed between PDGFRα expression and clinical outcome., This work was supported by Eli Lilly and Company.

TPS11578 Background: Conventional chondrosarcoma (cCS) accounts for ̃25% of primary bone cancers and is the second most common primary bone tumor after osteosarcoma. Surgical resection is the primary treatment for localized disease. No FDA approved therapy exists for advanced disease and chemotherapy has marginal efficacy with ORR < 12%. IDH1/2 mutation is seen in 50% of cases. Epigenetic dysregulation is central to oncogenesis in both IDH1/2 mutant and wild-type CS. Pre-clinical studies from our group show that combination treatment with HDAC and DNMT inhibitors is significantly more effective at suppressing the growth of CS models in vitro and in vivo compared to either therapy alone. The combination regimen mediates anti-tumor effects on CS by induction of apoptosis, induction of tumor suppressor genes (eg. E-cadherin), the induction of interferon responsive genes (eg. IRF7, OASL, ISG15, DDX58) and reversal of global hypomethylated state. Based on these findings we have designed a phase 2 clinical trial with an HDAC inhibitor (belinostat) and a DNMT inhibitor (guadecitabine) in patients with advanced cCS. Methods: NCI # 10330 is a single-arm, multi-center, Simon 2-stage, phase 2 clinical trial evaluating belinostat and guadecitabine in patients with advanced cCS. Eligible patients will have biopsy proven cCS which is measurable by RECIST v1.1 and amenable to biopsy, ECOG PS ≤ 2, any number of prior treatments (including none). Patients will receive guadecitabine 45 mg/m2 SC followed by belinostat 1000 mg/m2 IV once daily on days 1-5 of a 28-day cycle. A safety lead-in and continuous toxicity monitoring rule will be applied. The primary endpoint will be ORR. Since chemotherapy is associated with an ORR of 8-12% and targeted agents have shown an ORR of 0% in cCS, we will consider an ORR of 8% as inactive while an ORR of 28% will suggest promising activity. A Simon 2-stage design is employed. The design calls for 26 patients. If ≥ 2 responses are observed among 13 patients in stage I, the study will proceed to full accrual. If ≥ 5 responses are seen among 26 patients, the study treatment is considered promising. This design has 85% power with α of 0.054 to test for a response rate of 8% vs 28%. Secondary objectives include safety, tolerability and PFS. All patients will undergo pre-treatment and on-treatment tumor biopsies. Paired tissue will be used for correlative analysis including: 1) whole exome sequencing/RNAseq to evaluate changes in gene expression in response to treatment, 2) multiplex IHC to interrogate the effect of combination therapy on tumor immune microenvironment and 3) a global DNA methylation assay to better understand the changes in epigenetic landscape in response to treatment. This study is open throughout the ETCTN (NCT04340843). Six of the planned 26 patients in the safety lead-in have been enrolled without DLT. Further accrual is on hold pending completion of the safety lead-in. Clinical trial information: 04340843.

Introduction: Growing evidence demonstrates activity of neoadjuvant carboplatin in triple negative breast cancer (TNBC). Underlying germline and somatic Homologous Recombination (HR) repair deficiency may predict response to DNA damaging agents like platinum compounds in TNBC. Certain DNA repair machinery genes (Fanconi Anemia gene) are also involved in the maintenance of hematopoetic stem cell (HSC) function and impaired repair of DNA double strand breaks can lead to HSC and progenitor cell dysfunction. Thus, in presence of HR defects DNA damaging chemotherapy may lead to unique hematological toxicity. It is also possible that in presence of HR defects breast cancer response and hematological toxicity with DNA damaging agents will parallel each other. Aim: To evaluate the impact of hematological toxicity on response to neoadjuvant Carboplatin/Docetaxel chemotherapy in patients with sporadic and BRCA associated TNBC utilizing clinical and BRCA mutation data from a prospective TNBC registry. Methods: 288 patients with Stage I (T>1cm) II and III TNBC were enrolled on a multisite prospective registry between 3/2011 to 4/2014, out of which 49 patients received neoadjuvant Carboplatin AUC 6 + Docetaxel 75mg/m2 every 21 days (4-6 cycles) and have undergone breast surgery. Carboplatin was dosed using the modified Cockcroft-Gault formula. Hematologic toxicity was graded using the CTCAE version 4.03. All patients received prophylactic pegfilgrastim on day 2. Pathological complete response (pCR) was defined as absence of invasive disease in the breast and axilla. All patients underwent comprehensive BRACAnalysis®(Myriad). Results: For the 49 eligible patients median age was 50 years, median weight was 172 lbs, 18% were African American, and 37% had LN+ disease. 26% (13 /49) of patients carried deleterious BRCA mutation (9 BRCA1, 4 BRCA2). pCR of the cohort was 65%. Overall 61%, 96%, and 12 % patients demonstrated > Grade1 thrombocytopenia (Tp), anemia, or neutropenia, respectively; 4%, 6%, and 6% patients demonstrated grade 3/4 thrombocytopenia, anemia, or neutropenia, respectively. There was no association between pCR and anemia or neutropenia. Carboplatin dose reductions/delays/omission was more common in patients with Tp compared to patients without Tp (33% vs. 5%; p=0.02). Patients with Tp were more likely to achieve a pCR compared to patients without Tp (85% vs. 47%; p=0.013). 77% of BRCA carriers and 64% of BRCA wild type TNBC demonstrated Tp (NS). pCR rates in BRCA wild type patients with and without Tp were 82% and 47%, respectively (p=0.041). pCR rates in BRCA mutation carriers with and without Tp were 89% and 50%, respectively (p=0.20). On multivariable platelet count was independently associated with pCR (p=0.001)Conclusions: Tp was associated with decreased dose delivery of carboplatin but an improved pCR in BRCA wild type TNBC. Comprehensive assessment of HR defects beyond germline BRCA mutation status may be required to elucidate the biological process that explains this observation. Tp may be a harbinger of underlying HR deficiency and further correlative studies exploring this association of Tp with pathological response to carboplatin in TNBC are warranted. Citation Format: Priyanka Sharma, Benjamin C Powers, Bruce F Kimler, Claire Ward, Jennifer R Klemp, Carol S Connor, Marilee K McGinness, Joshua MV Mammen, Jamie L Wagner, Qamar J Khan, Roy A Jensen, Andrew K Godwin, Carol J Fabian. Thrombocytopenia is associated with pathological complete response to neoadjuvant carboplatin/docetaxel chemotherapy in BRCA wild type triple negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-16.

Acute promyelocytic leukemia (APL) is classically characterized by chromosomal translocation (15;17), resulting in the PML-RARA fusion protein leading to disease. Here, we present a case of a 50-year-old man who presented with signs and symptoms of acute leukemia with concern for APL. Therapy was immediately initiated with all-transretinoic acid. The morphology of his leukemic blasts was consistent with the hypogranular variant of APL. Subsequent FISH and cytogenetic analysis revealed a unique translocation involving five chromosomal regions: 9q34, 17q21, 15q24, 12q13, and 15q26.1. Molecular testing demonstrated PML/RARA fusion transcripts. Treatment with conventional chemotherapy was added and he went into a complete remission. Given his elevated white blood cell count at presentation, intrathecal chemotherapy for central nervous system prophylaxis was also given. The patient remains on maintenance therapy and remains in remission. This is the first such report of a 5-way chromosomal translocation leading to APL. Similar to APL with chromosomal translocations other than classical t(15;17) which result in the typical PML-RARA fusion, our patient responded promptly to an ATRA-containing regimen and remains in complete remission.

Video abstract A video abstract by the authors of this paper is available. video-abstract5127.mov, The epidermal growth factor receptor (EGFR) plays an important role in the development of many cancers, including non-small cell lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are a class of novel biologically-targeted agents widely used in the management of recurrent non-small cell lung cancer. Erlotinib, one of the EGFR TKIs, is currently FDA approved in second and third line therapy. However, recent studies showed that erlotinib is also effective as maintenance therapy after initial chemotherapy, improving disease free survival and possibly overall survival. Our current understanding of erlotinib’s mechanism of action, with the discovery that EGFR mutation confers higher response rate, has propelled this agent into the first line setting. Advances in molecular testing and clinical research of this agent and other agents in this class will eventually change the way we utilize EGFR TKIs in the near future.

281 Background: Prostate cancer is the second most common cancer worldwide in males. The initial treatment in advanced cases is medical or surgical castration. The outlook declines when prostate cancer advances independently, despite the aforementioned castration. Within the last ten years, a handful of new agents have proven effective in this castration-resistant phase, but finding more effective, novel ways of treating advanced prostate cancer is warranted. MAGMAS (mitochondria-associated, granulocyte-macrophage colony stimulating factor (GM-CSF) signaling molecule) is a protein ubiquitously expressed in eukaryotic cells that plays a key role in embryonal development in a variety of species. Overexpression of MAGMAS has anti-apoptotic effects, as GM-CSF is a growth factor essential for survival, proliferation and differentiation of cells. MAGMAS and GM-CSF receptor levels have been shown to be overexpressed in prostate cancer, but do not correlate with pathological grade or clinical stage. The purpose of our study was to evaluate the efficacy of a MAGMAS inhibitor, synthesized by Dr Bhaskar Das, in androgen-dependent and androgen-independent prostate cancer cell lines, as well as in a normal prostate cell line as another control. Methods: The different cell lines were treated with MAGMAS inhibitor at various concentrations in vitro. For analysis, we used MTT Cell Proliferation assay at 24 and 48 hours, per manufacturer’s protocol. We tested MAGMAS inhibitor effect on apoptosis/necrosis, cell migration and microtubule destabilization as well. Results: After prostate cancer cell lines were treated with MAGMAS inhibitor in vitro, cell proliferation and migration decreased, apoptosis and necrosis were induced, and microtubules were destabilized, all showing more impressive results in the androgen-independent cells. MAGMAS inhibition did not affect cell proliferation in the normal prostate cells. Conclusions: In vitro studies show MAGMAS inhibition proves efficacious in both androgen-dependent and androgen-independent prostate cancer cell lines. This will be evaluated further in a xenograft mouse model.