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Supplemental figure S1: Representative immunochemistry staining of MHC-1 from tumor biopsied samples of partial response (top), stable disease (middle), and progressive disease (bottom), respectively. Scale bar: 20 X.

Purpose:The effectiveness of immune checkpoint inhibitors (ICI) is limited in pancreatic ductal adenocarcinoma (PDAC). We conducted a phase I study to evaluate the safety of ICI with stereotactic body radiation therapy (SBRT) in patients with metastatic PDAC.Patients and Methods:Patients enrolled must have received at least one line of prior systemic chemotherapy for metastatic disease. Cohorts A1 and A2 received durvalumab every 2 weeks plus either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day −3 to +1. Cohorts B1 and B2 received durvalumab plus tremelimumab every 4 weeks and either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day −3 to +1. ICIs were continued until unacceptable toxicity or disease progression. The primary objective was the safety and feasibility of treatment. Objective response was assessed in lesions not subjected to SBRT.Results:Fifty-nine patients were enrolled and 39 were evaluable for efficacy. No dose-limiting toxicities were seen. The most common adverse event was lymphopenia. Two patients achieved a partial response (one confirmed and the other unconfirmed). The overall response rate was 5.1%. Median PFS and OS was 1.7 months [95% confidence intervals (CI), 0.8–2.0 months] and 3.3 months (95% CI, 1.2–6.6 months) in cohort A1; 2.5 months (95% CI, 0.1–3.7 months) and 9.0 months (95% CI, 0.5–18.4 months) in A2; 0.9 months (95% CI, 0.7–2.1 months) and 2.1 months (95% CI, 1.1–4.3 months) in B1; and 2.3 months (95% CI, 1.9–3.4 months) and 4.2 months (95% CI, 2.9–9.3 months) in B2.Conclusions:The combination of ICI and SBRT has an acceptable safety profile and demonstrates a modest treatment benefit in patients with metastatic PDAC.

Supplemental table S1 and S2

PURPOSE: The effectiveness of immune checkpoint inhibitors (ICIs) is limited in pancreatic ductal adenocarcinoma (PDAC). We conducted a phase I study to evaluate the safety of ICI with stereotactic body radiation therapy (SBRT) in patients with metastatic PDAC. PATIENTS AND METHODS: Patients enrolled must have received at least one line of prior systemic chemotherapy for metastatic disease. Cohort A1 and A2 received durvalumab every 2 weeks plus either 8Gy in one fraction of SBRT on day 1 or 25Gy in 5 fractions on day −3 to +1. Cohort B1 and B2 received durvalumab plus tremelimumab every 4 weeks and either 8Gy in one fraction of SBRT on day 1 or 25Gy in 5 fractions on day −3 to +1. ICIs were continued until unacceptable toxicity or disease progression. The primary objective was the safety and feasibility of treatment. Objective response was assessed in lesions not subjected to SBRT. RESULTS: Fifty-nine patients were enrolled and 39 were evaluable for efficacy. No dose limiting toxicities were seen. The most common adverse event was lymphopenia. Two patients achieved a partial response (one confirmed and the other unconfirmed). The overall response rate was 5.1%. Median PFS and OS was 1.7 months (95% CI 0.8–2.0 months) and 3.3 months (95% CI 1.2–6.6 months) in cohort A1; 2.5 months (95% CI 0.1–3.7 months) and 9.0 months (95% CI 0.5–18.4 months) in A2; 0.9 months (95% CI 0.7–2.1 months) and 2.1 months (95% CI 1.1–4.3 months) in B1; and 2.3 months (95% CI 1.9–3.4 months) and 4.2 months (95% CI 2.9–9.3 months) in B2. CONCLUSION: The combination of ICI and SBRT has an acceptable safety profile and demonstrates a modest treatment benefit in patients with metastatic PDAC.

Purpose: The effectiveness of immune checkpoint inhibitors (ICI) is limited in pancreatic ductal adenocarcinoma (PDAC). We conducted a phase I study to evaluate the safety of ICI with stereotactic body radiation therapy (SBRT) in patients with metastatic PDAC. Patients and Methods: Patients enrolled must have received at least one line of prior systemic chemotherapy for metastatic disease. Cohorts A1 and A2 received durvalumab every 2 weeks plus either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day −3 to +1. Cohorts B1 and B2 received durvalumab plus tremelimumab every 4 weeks and either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day −3 to +1. ICIs were continued until unacceptable toxicity or disease progression. The primary objective was the safety and feasibility of treatment. Objective response was assessed in lesions not subjected to SBRT. Results: Fifty-nine patients were enrolled and 39 were evaluable for efficacy. No dose-limiting toxicities were seen. The most common adverse event was lymphopenia. Two patients achieved a partial response (one confirmed and the other unconfirmed). The overall response rate was 5.1%. Median PFS and OS was 1.7 months [95% confidence intervals (CI), 0.8–2.0 months] and 3.3 months (95% CI, 1.2–6.6 months) in cohort A1; 2.5 months (95% CI, 0.1–3.7 months) and 9.0 months (95% CI, 0.5–18.4 months) in A2; 0.9 months (95% CI, 0.7–2.1 months) and 2.1 months (95% CI, 1.1–4.3 months) in B1; and 2.3 months (95% CI, 1.9–3.4 months) and 4.2 months (95% CI, 2.9–9.3 months) in B2. Conclusions: The combination of ICI and SBRT has an acceptable safety profile and demonstrates a modest treatment benefit in patients with metastatic PDAC.

Background The prognosis of metastatic colorectal cancer (mCRC) is poor. We assessed the feasibility, safety, and efficacy of the anti-programmed cell death 1 fusion protein AMP-224 in combination with low-dose cyclophosphamide and stereotactic body radiation (SBRT) treatment in patients with mCRC refractory to standard chemotherapy. Patients and Methods Fifteen patients were enrolled. Six received SBRT 8 Gy on day 0 (dose level 1), whereas 9 received 8 Gy on days −2 to day 0. All received cyclophosphamide 200 mg/m2 intravenously (I.V.) on day 0. On day 1, both groups received AMP-224 10 mg/kg I.V., repeated every 2 weeks for a total of 6 doses. Primary end points were feasibility and safety. Results Ten (67%) patients completed 6 doses of AMP-224; 5 patients (33%) discontinued treatment because of disease progression. No dose-limiting toxicity was observed; 9 patients (60%) experienced treatment-related adverse events, all Grade 1 or 2. No objective response was noted; 3 patients (20%) had stable disease. Median progression-free survival and overall survival were 2.8 months (95% confidence interval [CI], 1.2-2.8 months) and 6.0 months (95% CI, 2.8-9.6 months), respectively. M2 macrophage polarization was present in the pretreatment tumor biopsy samples, but not post-treatment samples. Conclusion AMP-224 in combination with SBRT and low-dose cyclophosphamide was well tolerated, however, no significant clinical benefit was observed in patients with mCRC.

Treatment options for patients with advanced biliary tract cancer are limited. Dysregulation of the immune system plays an important role in the pathogenesis of biliary tract cancer (BTC). This study aimed to investigate whether tremelimumab, an anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, could be combined safely with microwave ablation to enhance the effect of anti-CTLA4 treatment in patients with advanced BTC. Patients were enrolled to receive monthly tremelimumab (10 mg/kg, intravenously) for six doses, followed by infusions every 3 months until off-treatment criteria were met. Thirty-six days after the first tremelimumab dose, patients underwent subtotal microwave ablation. Interval imaging studies were performed every 8 weeks. Adverse events (AEs) were noted and managed. Tumor and peripheral blood samples were collected to perform immune monitoring and whole-exome sequencing (WES). Twenty patients with refractory BTC were enrolled (median age, 56.5 years). No dose-limiting toxicities were encountered. The common treatment-related AEs included lymphopenia, diarrhea, and elevated transaminases. Among 16 patients evaluable for efficacy analysis, 2 (12.5%) patients achieved a confirmed partial response (lasting for 8.0 and 18.1 months, respectively) and 5 patients (31.3%) achieved stable disease. Median progression free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval [CI], 2.5-5.2) and 6.0 months (95% CI, 3.8-8.8), respectively. Peripheral blood immune cell subset profiling showed increased circulating activated human leukocyte antigen, DR isotype ([HLA-DR] positive) CD8+ T cells. T-cell receptor (TCR)β screening showed tremelimumab expanded TCR repertoire, but not reaching statistical significance (P = 0.057). Conclusion: Tremelimumab in combination with tumor ablation is a potential treatment strategy for patients with advanced BTC. Increased circulating activated CD8+ T cells and TCR repertoire expansion induced by tremelimumab may contribute to treatment benefit.

Background KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC. Methods A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC. Results 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg PO BID and cetuximab 250 mg/m2 weekly following a 400 mg/m2 load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease. Conclusions The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes.

Despite significant advances in the treatment of Hodgkin's lymphoma (HL), a significant proportion of patients will not respond or will subsequently relapse. We identified CD25, the IL-2 receptor alpha subunit, as a favorable target for systemic radioimmunotherapy of HL. The scientific basis for the clinical trial was that, although most normal cells with exception of Treg cells do not express CD25, it is expressed by a minority of Reed-Sternberg cells and by most polyclonal T cells rosetting around Reed-Sternberg cells. Forty-six patients with refractory and relapsed HL were evaluated with up to seven i.v. infusions of the radiolabeled anti-CD25 antibody (90)Y-daclizumab. (90)Y provides strong β emissions that kill tumor cells at a distance by a crossfire effect. In 46 evaluable HL patients treated with (90)Y-daclizumab there were 14 complete responses and nine partial responses; 14 patients had stable disease, and nine progressed. Responses were observed both in patients whose Reed-Sternberg cells expressed CD25 and in those whose neoplastic cells were CD25(-) provided that associated rosetting T cells expressed CD25. As assessed using phosphorylated H2AX (γ-H2AX) as a bioindicator of the effects of radiation exposure, predominantly nonmalignant cells in the tumor microenvironment manifested DNA damage, as reflected by increased expression of γ-H2AX. Toxicities were transient bone-marrow suppression and myelodysplastic syndrome in six patients who had not been evaluated with bone-marrow karyotype analyses before therapy. In conclusion, repeated (90)Y-daclizumab infusions directed predominantly toward nonmalignant T cells rosetting around Reed-Sternberg cells provided meaningful therapy for select HL patients.

The eukaryotic translation initiation factor 4E (eIF4E) is a potent oncogene that is found to be dysregulated in 30% of human cancer, including colorectal carcinogenesis (CRC). ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the eIF4E protein. In preclinical studies we found that EIF4e ASOs reduced expression of EIF4e mRNA and inhibited proliferation of colorectal carcinoma cells. An additive antiproliferative effect was observed in combination with irinotecan. We then performed a clinical trial evaluating this combination in patients with refractory cancer. No dose-limiting toxicities were seen but based on pharmacokinetic data and tolerability the dose of irinotecan was reduced to 160 mg/m(2) biweekly. Efficacy was evaluated in 15 patients with irinotecan-refractory colorectal cancer. The median time of disease control was 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13 of 19 patients. Matched pre- and posttreatment tumor biopsies showed decreased eIF4E mRNA levels in five of nine patients. In tumor tissue, the intracellular and stromal presence of ISIS 183750 was detected by IHC in all biopsied patients. Although there were no objective responses stable disease was seen in seven of 15 (47%) patients who were progressing before study entry, six of whom were stable at the time of the week 16 CT scan. We were also able to confirm through mandatory pre- and posttherapy tumor biopsies penetration of the ASO into the site of metastasis.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that negatively regulate the immune response during tumour progression, inflammation and infection. Only limited data are available on human MDSC because of the lack of specific markers. We have identified members of the S100 protein family-S100A8, S100A9 and S100A12 - specifically expressed in CD14(+) HLA-DR(-/low) MDSC. S100A9 staining in combination with anti-CD14 could be used to identify MDSC in whole blood from patients with colon cancer. An increase in the population of CD14(+) S100A9(high) MDSC was observed in the peripheral blood from colon cancer patients in comparison with healthy controls. Finally, nitric oxide synthase expression, a hallmark of MDSC, was induced in CD14(+) S100A9(high) upon lipopolysaccharide/interferon-γ stimulation. We propose S100 proteins as useful markers for the analysis and further characterization of human MDSC.

192 Background: Chemotherapy in aPDAC has resulted in only modest improvements in outcome. The effectiveness of ICI monotherapy is also limited in PDAC, suggesting an immunogenic inert tumor microenvironment. SBRT is safe and effective in locally advanced PDAC and exhibits enhanced antitumor immunity. We hypothesize that ICI plus SBRT will improves immunomodulatory effects of ICI in patients with aPDAC resulting in a greater clinical benefit. Methods: Eligible patients with aPDAC were enrolled to four different treatment cohorts. Cohort 1: Durvalumab (Durva) 1500 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 2: SBRT 5 fractions x 5Gy followed by Durva. Cohort 3: Durva + Tremelimumab (Treme) 75 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 4: SBRT 5 fractions x 5Gy followed by Durva + Treme. This was continued until unacceptable toxicity or progression of disease. A biopsy was performed at baseline and pre-cycle 2 of treatment for exploratory correlative analysis. The primary objective was to evaluate the safety and feasibility of combining ICI and SBRT to enhance the efficacy of ICI. Results: 51 patients with aPDAC were enrolled and 31 patients were evaluable for the efficacy. The most commonly TRAEs were lymphopenia. Grade 3-4 AEs were lymphopenia and anemia. No dose limiting toxicities were seen. Out of total 31 evaluable patients, 1 patient achieved a confirmed partial response seen in Cohort 1 and 2 patients in Cohort 4, and 7 stable disease across the 4 treatment arms. Median PFS and OS was 1.7 months (95% CI 0.7-2.8 months) and 3.4 months (95% CI 0.9-11.4 months) in cohort 1; 2.6 months (95% CI 2.1-4.7 months) and 9.1 months (95% CI 3.4-18.7 months)in cohort 2; 1.6 months (95% CI 0.5-4.0 months) and 3.0 months (95% CI 0.7-6.6 months) in cohort 3; and 3.2 months (95% CI 1.5-16.5months) and 6.4 months (95% CI 1.5-17.6 months) in cohort 4. Conclusions: The combination of ICI and SBRT is safe and well tolerated in patients with aPDAC. The overall response rate of 9.6% including 2 patients who achieved a durable partial response lasting over 12 months, suggests meaningful clinical activity. This signifies that ICI and SBRT is a potential new treatment for aPDAC. Clinical trial information: NCT02311361.

646 Background: The efficacy of immune checkpoint inhibitor has been limited to small portion of colorectal cancer (CRC) patients whose tumors with mismatch repair (MMR) gene abnormalities. There is an urgent need for patients with MMR proficient (pMMR) tumors. Oncolytic immunotherapy represents a novel therapeutic platform for the treatment of cancer with unique activity compared to conventional chemotherapy. The trial is to evaluate if the combination of Pexa-Vec oncolytic virus (PV) with immune checkpoint inhibition enhance antitumor immunity. Methods: Patients with microsatellite-stable and MSI-H mCRC refractory to PD-1 monotherapy were enrolled. Patients received either Arm A treated with PV + Durvalumab or Arm B with PV + Durvalumab and Tremelimumab. Each arm had two dose levels (DL) of PV, 3 x 108 pfu in DL1 and at 109 pfu in DL2, every 2 weeks for total 4 doses. The first dose of PV was administered on Day -12, followed by three more dose administration on Days 2, 16 and 30 in combination with the immune checkpoint inhibition. The primary endpoint is response rate, safety, tolerability and feasibility of these combination therapy in refractory metastatic CRC. Results: Here we report the safety data of Arm A.A total of 9 patients was enrolled so far. The longest follow-up time is 8 months. Four patients received DL1 PV and subsequent five patients received DL2 PV. No DLT was observed at the time of this abstract. No grade 4-5 adverse event (AE) were observed. All patients experienced lymphopenia. All patients with DL2 developed fever, hypotension and papulopastular rashes and were successfully managed with antipyretics, fluid support and skin protection, respectively. The most frequent treatment-related AEs were lymphopenia (8 [100%], fever (7 [87.5%]), chills (6 [75.0%]), hypotension (5 [62.5%]), papulopastular rashes (5 [62.5%], flu-like symptoms (2 [12.5%]), Nausea/vomiting (2 [12.5%]). Conclusions: Pexa-Vec in combination with Durvalumab showed a favorable safety profile. Clinical trial information: NCT03206073.

336 Background: Prognosis in advanced HCC and BTC is unfavorable, and 5-year overall survival (OS) rate is less than 20% and 10%, respectively. Single agent ICI in HCC has response rates (RR) of 20%, while early data in BTC reported 17.4% RR. Dual ICI has increased RR in other malignancies. The purpose of this study was to explore the efficacy of the combination of anti-CTLA4 (tremelimumab) with anti-PD-L1 (durvalumab) in advanced HCC and BTC. Methods: Eligible patients with advanced HCC or BTC who had received (or refused) at least one prior therapy, received monthly tremelimumab 75 mg in combination with durvalumab 1500 mg for 4 doses followed by monthly durvalumab 1500 mg monotherapy until progression of disease or unacceptable toxicity. Response was assessed with CT scan every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint is 6-month progression free survival (PFS). Results: Twenty-two patients were enrolled, 10 with advanced HCC and 12 with advanced BTC. Male to female ratio was 14:8, with median age of 62.5 years (range 19-80). Grade 3/4 treatment-related AEs included lymphocytopenia, hyponatremia, bullous dermatitis, maculopapular rash, mucositis, hypophosphatemia, anaphylaxis, dyspnea, pleural effusion, and pain. Twenty patients were evaluable for response analysis. Two patients (2/10, 20%) achieved a confirmed partial response (both with HCC, lasting 6.9 and 17.6 months), while 9 patients (4 [40%] with HCC and 5 [41.7%] with BTC) had stable disease, with the longest duration of 9.3 months (in an HCC patient). Disease control rate is 60% in HCC and 41.7% in BTC, respectively. In this small pilot cohort, median PFS was 3.1 months (95% CI 0.8 to 4.6 months) and median OS was 5.45 months (95% CI 4.60 to 8.3 months) among BTC patients, while HCC patients median PFS was 7.8 months (95% CI 2.6 to 10.6 months) and median OS was 15.9 (95% CI 7.1 to 16.3 months). Conclusions: Combined ICI with tremelimumab and durvalumab is well tolerated and demonstrates promising activity in patients with advanced HCC and BTC. Clinical trial information: NCT02821754.

Endoglin is an endothelial cell membrane receptor essential for angiogenesis and highly expressed on the vasculature of many tumor types, including hepatocellular carcinoma (HCC). TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis, and complements VEGF inhibitors.The aim of this phase II study was to evaluate the efficacy of anti-endoglin therapy with TRC105 in patients with advanced HCC, post-sorafenib.Patients with HCC and compensated liver function (Childs-Pugh A/B7), ECOG 0/1, were enrolled to a single-arm, phase II study of TRC105 15 mg/kg IV every two weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal two-stage design was employed with a 50% four-month PFS target for progression to the second stage. Correlative biomarkers evaluated included DCE-MRI as well as plasma levels of angiogenic biomarkers and soluble CD105.A total accrual of 27 patients was planned. However, because of lack of efficacy and in accordance with the Simon two-stage design, 11 patients were enrolled. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N = 3) and epistaxis (G1; N = 4). One patient had a confirmed partial response by standard RECIST criteria and biologic response on DCE-MRI but the four-month PFS was insufficient to proceed to the second stage of the study.TRC105 was well tolerated in this HCC population following sorafenib. Although there was evidence of clinical activity, this did not meet prespecified criteria to proceed to the second stage. TRC105 development in HCC continues as combination therapy with sorafenib.

Purpose: In preclinical studies, sequential exposure to irinotecan (CPT-11) then fluorouracil (5-FU) is superior to concurrent exposure or the reverse sequence; a 24-hour infusion of CPT-11 may be better tolerated than shorter infusions. Experimental Design: CPT-11 was first given at four levels (70-140 mg/m2/24 hours), followed by leucovorin 500 mg/m2/0.5 hours and 5-FU 2,000 mg/m2/48 hours on days 1 and 15 of a 4-week cycle. 5-FU was then increased in three cohorts up to 3,900 mg/m2/48 hours. Results: Two patients had dose-limiting toxicity during cycle 1 at 140/3,900 of CPT-11/5-FU (2-week delay for neutrophil recovery; grade 3 nausea despite antiemetics); one of six patients at 140/3,120 had dose-limiting toxicity (grade 3 diarrhea, grade 4 neutropenia). Four of 22 patients with colorectal cancer had partial responses, two of which had prior bolus CPT-11/5-FU. The mean 5-FU plasma concentration was 5.1 μmol/L at 3,900 mg/m2/48 hours. The end of infusion CPT-11 plasma concentration averaged 519 nmol/L at 140 mg/m2/24 hours. Patients with UDP-glucuronosyltransferase (UGT1A1; TA)6/6 promoter genotype had a lower ratio of free to glucuronide form of SN-38 than in patients with ≥1 (TA)7 allele. Thymidylate synthase genotypes for the 28-base promoter repeat were 2/2 (13%), 2/3 (74%), 3/3 (13%); all four responders had a 2/3 genotype. Conclusions: Doses (mg/m2) of CPT-11 140/24 hours, leucovorin 500/0.5 hours and 5-FU 3,120/48 hours were well tolerated.

365 Background: Treatment option for patients with advanced BTC is limited and prognosis is poor with a median survival of less than 1 year in the locally advanced or metastatic setting. It has been shown deregulation of the immune system plays an important role in the pathogenesis of BTC. This study aimed to investigate whether tremelimumab (Treme), anti-CTLA4, could be combined safely and feasibly with microwave ablation therapy to enhance the effect of anti-CTLA4 treatment in patients with advanced BTC. Methods: Patients with refractory BTC were enrolled in a study of monthly Treme (10mg/kg, IV, 6 doses), followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal microwave ablation. Staging image was performed every 8 weeks. Adverse events (AEs) were collected and managed. Tumor samples and peripheral blood samples were collected to perform immune monitoring. Results: Twenty patients with refractory BTC were enrolled. Male: female ratio was 10:10 with median age 56.5 years (range 37-67). Six patients had extrahepatic cholangiocarcinoma (ECC), two patients had gallbladder cancer, whereas the remaining 12 patients had intrahepatic cholangiocarcinoma (ICC). No dose-limiting toxicities were encountered. The common AEs included lymphocytopenia, colitis, adrenal insufficiency, anemia, and elevated transaminases. The most common clinical toxicity was diarrhea. Sixteen patients were evaluable for response analysis, one (6%) patient achieved a confirmed partial response (lasting for 8 months), 6 (37.5%) achieved stable disease with the longest lasting for 9.2 months. Among all 20 patients, median progression free survival, time to progression, and overall survival were 3.4 months (95% CI 2.5-5.2 months), 3.3 months (95% CI: 2.5-4.6 months) and 6.0 months (95% CI 3.8-8.8 months) respectively in this small pilot cohort. T cell receptor (TCR) b screening showed Treme expanded TCR repertoire though non-significantly. RNA seq is ongoing and will be presented. Conclusions: Treme in combination with tumor ablation is a potential new treatment for patients with advanced BTC. TCR repertoire expansion induced by Treme may contribute to treatment benefit. Clinical trial information: NCT01853618.

88 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Radiofrequency ablation (RFA) has been shown to induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment. Methods: Patients with refractory BTC were enrolled in a study of monthly Tremelimumab (10mg/kg, 6 doses) combined with RFA (to one lesion) performed on week 6. Tumor biopsies were performed at time of RFA with regular PBMC collection for intensive immunemontoring. Results: 17 pts enrolled. Characteristics: M:F 8:9; Median age 57(range 36-67); BTC subtype - intrahepatic/exrahepatic: 12/5. 13/17 had metastatic disease. All pts were chemorefractory with 12/17 having received at least 2 regimens. While on study, 6 pts had early PD within 6 weeks; 11 were able to undergo RFA. No DLT encountered. Most common toxicity was pruritus. There were no objective responses. Of evaluable pts N = 6 (55%) had stable disease as a best response. Conclusions: Tremelimumab in combination with subtotal RFA in patients with advanced BTC is safe and feasible. No objective responses have so far been seen in this predominantly primary intrahepatic BTC population. Full efficacy and immune monitoring data will be presented. Clinical trial information: NCT01853618.

Myeloid-derived suppressor cells (MDSC) are a heterogenous population of cells comprising myeloid progenitor cells and immature myeloid cells, which have the ability to suppress the effector immune response. In humans, MDSC have not been well characterized owing to the lack of specific markers, although it is possible to broadly classify the MDSC phenotypes described in the literature as being predominantly granulocytic (expressing markers such as CD15, CD66, CD33) or monocytic (expressing CD14). In this study, we set out to perform a direct comparative analysis across both granulocytic and monocytic MDSC subsets in terms of their frequency, absolute number, and function in the peripheral blood of patients with advanced GI cancer. We also set out to determine the optimal method of sample processing given that this is an additional source of heterogeneity. Our findings demonstrate consistent changes across sample processing methods for monocytic MDSC, suggesting that reliance upon cryopreserved PBMC is acceptable. Although we did not see an increase in the population of granulocytic MDSC, these cells were found to be more suppressive than their monocytic counterparts.

TPS470 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and causes inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. MEDI4736 is a human monoclonal antibody directed against PD-L1. Blockage of ligation between PD-L1 and PD1 induces local immune activation and prevents anergy and exhaustion of effector T-cells. Several studies have documented an increase in peripheral antitumor immunity following radiation. This effect is evidently too weak to be clinically relevant, but has the potential to be boosted by immune modulation. The underlying hypothesis of this study is that the effect of immune checkpoint inhibition (accomplished via tremelimumab and/or MEDI4736) treatment can be enhanced by radiation in patients with advanced pancreatic carcinoma. Whilst radiation treatment in pancreas cancer is commonly employed in limited or early stage disease, if radiation can enhance the effect of immune checkpoint inhibition to produce systemic anti-tumor effects the combination could become an effective treatment modality for patients with advanced disease. Methods: Patients with histologically confirmed metastatic pancreatic cancer with primary in-situ (or locally-recurrent) disease are being enrolled to this pilot study. The primary objectives are to determine the safety, tolerability and feasibility of immune checkpoint inhibition [comprising either MEDI4736 alone (Cohort A), Tremelimumab (Cohort B) or combined MEDI4736 and Tremelimumab (Cohort C)] in combination with stereotactic body radiation therapy (SBRT) in patients with unresectable pancreatic cancer. Select eligibility criteria are as follows: at least 1 measurable metastatic lesion by RECIST 1.1 criteria and accessible for biopsy. No prior radiation therapy to the pancreas allowed. There is no limit to the number of prior chemotherapy regimens received; ECOG ≤ 1; Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. No active or prior documented autoimmune or inflammatory disorders. Clinical trial information: NCT02311361.

270 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA) and cryoablation (CA) have been shown to induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced HCC. Methods: Patients with HCC [Childs Pugh A/B7; BCLC B/C; ECOG 0/1; post-sorafenib (BCLC stage C only)] or refractory BTC were enrolled in a study of Tremelimumab combined with subtotal TACE, RFA or CA performed on week 6. All BTC patients received RFA as the immune-stimulant in combination with tremelimumab. Tumor biopsies were performed at baseline and at time of RF/TACE. Results: 34 pts enrolled (28 HCC, 6 BTC). Characteristics: M:F 26:8; Median age 54(range 42-76); In HCC pts cirrhosis present in 17pts, BCLC Stage B/C: 9/19; Hepatitis B/C/neg: 4/15/9. 13 pts received TACE, 16 underwent RFA (inc 6 BTC pts), 3 CA during week 6 of tremelimumab therapy. 2 pts did not receive an ablative procedure. No DLT encountered. Most common toxicity was pruritus. One patient developed pulmonitis and was taken off study but remained disease-free at 16m. Of N = 17 pts evaluable for response outside of TACE/RFA-treated lesion 4 (23.5%) achieved confirmed partial responses. 8 of 9 pts with quantifiable HCV experienced a marked reduction in viral load. 6-week tumor biopsies showed immune cell infiltration on all evaluable patients. Median PFS for the evaluable HCC population (N = 25) was 5.7m. Conclusions: Tremelimumab in combination with subtotal TACE, RFA or CA in patients with advanced HCC and BTC is safe and feasible. Obtaining tumor biopsies at baseline and at the time of RFA/TACE is safe. Evidence of immune cell infiltration was seen on evaluable patients. Encouraging clinical activity seen with objective confirmed responses, PFS 5.7m and possibly surrogate reductions in HCV viral load. Clinical trial information: NCT01853618.

Background New chemotherapy regimens for patients with colorectal cancer have improved survival, but at the cost of clinical toxicity. Oxaliplatin, an agent used in first-line therapy for metastatic colorectal cancer, causes acute and chronic neurotoxicity. This study was performed to carefully assess the incidence, type and duration of oxaliplatin neurotoxicity. Methods A detailed questionnaire was completed after each chemotherapy cycle for patients with metastatic colorectal cancer enrolled in a phase I trial of oxaliplatin and capecitabine. An oxaliplatin specific neurotoxicity scale was used to grade toxicity. Results Eighty-six adult patients with colorectal cancer were evaluated. Acute neuropathy symptoms included voice changes, visual alterations, pharyngo-laryngeal dysesthesia (lack of awareness of breathing); peri-oral or oral numbness, pain and symptoms due to muscle contraction (spasm, cramps, tremors). When the worst neurotoxicity per patient was considered, grade 1/2/3/4 dysesthesias and paresthesias were seen in 71/12/5/0 and 66/20/7/1 percent of patients. By cycles 3, 6, 9, and 12, oxaliplatin dose reduction or discontinuation was needed in 2.7%, 20%, 37.5% and 62.5% of patients. Conclusion Oxaliplatin-associated acute neuropathy causes a variety of distressing, but transient, symptoms due to peripheral sensory and motor nerve hyperexcitability. Chronic neuropathy may be debilitating and often necessitates dose reductions or discontinuation of oxaliplatin. Patients should be warned of the possible spectrum of symptoms and re-assured about the transient nature of acute neurotoxicity. Ongoing studies are addressing the treatment and prophylaxis of oxaliplatin neurotoxicity.

639 Background: ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of eukaryotic translation initiation factor 4E (eIF4E), a potent oncogene. In preclinical models, ISIS demonstrated enhanced activity in combination with irinotecan (Iri). The purpose of this study was to determine maximum tolerated dose (MTD) and explore efficacy in an irinotecan-refractory colorectal cancer (CRC) population. Methods: Phase (Ph) I: Patients (pts) with advanced carcinoma (ECOG 0-2) received ISIS 183750 at 800 or 1,000 mg IV q-weekly in combination with Iri 180 mg/m2 q-2weekly. Ph II: Pts with irinotecan-refractory colorectal cancer were treated with ISIS 183750 1,000mg IV q-weekly in combination with Iri 160 mg/m2. Peripheral blood was analyzed for eIF4E mRNA. Tumor biopsies were obtained at baseline and C1D15 for ISIS 183750 IHC and eIF4E mRNA quantification. Response was assessed q8weeks by RESIST criteria. Results: 24 pts (14M/10F, median age 63 (range 43-79), ECOG PS 0/1/2: 5/18/1, prior chemotherapy regiments 3 (1-7)) were treated with ISIS 183750 + Iri. Ph 1: N=14 (colorectal (9), pancreas (3), endometrial (1), small bowel (1)). Ph 2: N=10 (colorectal). Median time on treatment was 56 days (2-232). The most common grade 3-4 adverse events were neutropenia 8/24 pts (33%) and hypoalbuminemia 6/24(25%). No dose limiting toxicities were seen. Efficacy data were evaluated in 15 irinotecan-refractory CRC pts. There were no objective responses. Stable disease was seen in 7/15 (47%) patients, median time of disease control was 22.1 wks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13/19 pts. Matched pre- and post-treatment tumor biopsies showed decreased eIF4E mRNA levels in 5/9 pts. In tumor tissue, intracellular presence of ISIS 183750 was detected by IHC in all biopsied patients. Conclusions: ISIS 183750 at the maximum dose tested of 1,000 mg in combination with irinotecan was feasible and relatively well tolerated. Even though intracellular penetration of ISIS was observed, it did not result in objective tumor response. Consequently, further exploration of resistance mechanisms is needed. Clinical trial information: NCT01675128.

TPS788 Background: AMP-224, a B7-DC Fc fusion protein, binds to PD-1, an inhibitory receptor that is present on the cell surface of exhausted, activated, effector, and memory T cells. AMP-224 has a unique mechanism of action in that it binds specifically to PD-1HI T cells (chronically stimulated / exhausted T cells) but not to PD-1LOcells which represent the normal activated T cell population. Several preclinical studies have documented an increase in peripheral antitumor immunity following radiation, a phenomenon known as the “abscopal effect”. Tumor PD-L1 expression has also been shown to be induced by radiation, which can suppress the anti-tumor immune response. Inhibition of PD-1/PDL-1 axis has been shown to improve anti-tumor immunity by blocking the tumor-mediated suppression of cytotoxic T cells. The aim of the study is to evaluate whether the anti-tumor immunity of anti-PD1 therapy (with AMP-224) can be enhanced by radiation therapy. Methods: Patients with histologically confirmed metastatic colorectal cancer to liver are being enrolled to this pilot study. The objectives are to determine the safety, tolerability and feasibility of AMP-224 in combination with stereotactic body radiation therapy (SBRT) to metastatic hepatic metastasis in patients with advanced colorectal cancer. Select eligibility are as follows: at least 1 measurable metastatic hepatic lesion by RECIST 1.1 criteria and amenable to SBRT. Patient must have progressed on or been intolerant of at least one prior oxaliplatin- and/or irinotecan-containing regimen and have metastatic lesions that are not amenable to curative resection; ECOG ≤ 1; Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. No active or prior documented autoimmune or inflammatory disorders. Clinical trial information: awaited.

291 Background: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including HCC. CD105 is essential for angiogenesis and its expression is upregulated by hypoxia and VEGF inhibition. TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and causes ADCC and apoptosis of proliferating endothelium. Sorafenib is the only FDA-approved drug in HCC. Methods: Preclinical: Murine BNL HCC cells were grown subcutaneously in wildtype Balb/c mice and treated with antibody to murine CD105, (clone MJ7/18; 10-200ug) + sorafenib (10 mg/kg daily p.o.) or sorafenib alone with assessment for CD105 expression, tumor size. Clinical: Patients with HCC (Childs Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, 15mg/kg q 2wks plus sorafenib 400mg bid. Correlative biomarkers included DCE-MRI, color Doppler ultrasonography, circulating endothelial and endothelial progenitor cells, plasma levels of angiogenic factors, soluble CD105 and tumor IHC for CD105. Samples were also collected for immunogenicity and pharmacokinetics. Results: Preclinical studies: CD105 expression was increased in BNL HCC tumors by sorafenib. Anti-CD105 antibody + sorafenib reduced tumor volume compared to sorafenib alone. Clinical trial: 19 pts were enrolled; Hep B/C/NA: 2/10/7; M:F 13:6; Mean age of 60 (range 18-76); 1 DLT (increased AST) occurred at 10mg/kg. Three of 14 (21%) evaluable pts achieved PR by RECIST. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median time on study was 4 months (range 2 to 22 months). Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity was observed and the study is proceeding to the phase 2 stage. Full correlative and clinical data will be presented. Clinical trial information: NCT01306058.

Meeting abstracts Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated down regulation of T cell activation. Both transcatheter arterial chemoembolization (TACE) and radiofrequency

4081 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregul...

211 Background: Endoglin (CD105), is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including in HCC. CD105 is essential for angiogenesis and its expression is upregulated by hypoxia and VEGF inhibition. TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that acts by endothelial cell growth inhibition, ADCC and apoptosis. Methods: Preclinical: Murine BNL HCC cells were grown subcutaneously in wildtype Balb/c mice and treated with antibody to murine CD105, (clone MJ7/18; 10-200ug) ± sorafenib (10 mg/kg daily p.o.) or sorafenib alone. Clinical: Patients with HCC (Childs Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, 15mg/kg q 2wks plus sorafenib 400mg bid; or (if sorafenib-refractory) a phase II study of TRC105 at 10 or 15mg/kg q 2wks. Correlative biomarkers: DCE-MRI; FDG-PET; color Doppler ultrasonography; circulating endothelial and endothelial progenitor cells, plasma levels of angiogenic factors; soluble CD105 and tumor IHC for CD105. Results: Preclinical studies: CD105 expression was increased in BNL HCC tumors of mice treated with sorafenib. Anti-CD105 + sorafenib was more effective than sorafenib alone. Clinical trials (N=16): M:F 13:3; Median age = 55 (range 24-67); Phase I with sorafenib (N=8): 1 DLT (increased AST) occurred at 10mg/kg. The most frequent toxicity has been epistaxis. One patient with coronary stenosis developed a fatal MI and one patient with thrombocytopenia developed G3 cerebral tumor hemorrhage. Phase II (N=8): No grade 3/4 treatment-related toxicities . Most frequent toxicities headache (G2; N=3) and epistaxis (G1; N=4). No patient was progression free at 4 months. Median time on study: Phase I- 4 months; Phase II - 2 months. Preliminary evidence of biologic response seen on DCE-MRI in 1pt (of 3 evaluable) with a reduction in Ktrans and kep and 3pts (of 3 evaluable) with reduction in intra-tumoral color flow on Doppler. Conclusions: TRC105 is well tolerated both as single agent and combined with sorafenib. Evidence of biological activity was observed. Full preclinical, clinical and correlative data will be presented. Clinical trial information: NCT01306058, NCT01375569.

e15177 Background: CD105, also known as endoglin, is an endothelial cell membrane receptor that is highly expressed on tumor vasculature, including HCC. CD105 is essential for angiogenesis and its expression is upregulated by hypoxia and VEGF inhibition. TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis. Methods: Patients with HCC and compensated liver function (Childs Pugh A/B7), ECOG 0/1, were enrolled to a single arm phase II study of TRC105 15mg/kg IV every 2 weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal 2-stage design was employed with a 50% 4-month PFS target for progression to the second stage. Correlative biomarkers evaluated included: DCE-MRI; FDG-PET; color Doppler ultrasonography; circulating endothelial progenitor cells, plasma levels of angiogenic factors; soluble CD105 and tumor IHC for CD105. Immunogenicity studies were also performed. Results: 8 pts have been treated so far; M:F 6:2; Median age = 58 (range 24-67); 7 pts had progressed following sorafenib (N=1 intolerant). N=1 pt had fibrolammellar HCC. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N=3) and epistaxis (G1; N=4). One patient with a history of ischemic heart disease developed acute cardiac syndrome during the first infusion and was replaced. No patient was progression free at 4 months by RECIST criteria. Median time on study was 8 weeks (range 4-16 weeks). Median no. of doses administered was 4 (range 2-7). Preliminary evidence of biologic response was seen on DCE-MRI in 1pt (of 3 evaluable) with a reduction in kTrans and kep and 3pts (of 3 evaluable) who demonstrated reduction in intra-tumoral color flow on color Doppler. Conclusions: TRC105 is well tolerated in this HCC population post-sorafenib. Although there was biological evidence of antiangiogenic activity it is unlikely that the study will proceed to the second stage. Full clinical and correlative data for the first stage of the study will be presented. Future role of TRC105 in HCC will most likely be as combination therapy with sorafenib or other anti-VEGF therapy. Clinical trial information: NCT01375569.

2532 Background: CS is characterized by germline PTEN mutations. Because tumors from CS patients show increased activation of the PI3K/Akt/mTOR pathway, mTOR inhibitor such as S might have activity in such patients. Methods: Eligibility: subjects with germline PTEN mutation who meet international diagnostic criteria for CS, age 18, ECOG PS 0-2, and adequate organ function. Subjects were treated with a 56-day course of daily oral S (2 mg). Objective: Inhibition of the mTOR pathway in benign skin/GI lesion, as assessed by IHC (P-AKT, Total S6, P-S6, P-4E-BP1, score 0-4), changes in benign or malignant tumor by CT/MRI/PET, digital dermoscopy/endoscopy, and changes in cerebellar testing by modified SARA (Neurology 2006). Protocol was amended to allow up to 20 subjects. Results: A total of 18 pts/16 families were enrolled. Median age 42 (range 19-69). Male/Female: 9/9. Involvement in skin, thyroid, GI polyps, breast, CNS, and all of the five organs was observed in 18, 15, 13, 8, 18, 5 subjects, respectively. 7 had h/o malignancies: 3 renal cell, 4 breast, 3 thyroid, 4 others. 3 cerebellar gangliocytomas and 2 others were measurable by CT or MRI. PTEN mutations: 6 families in Exon 1-2, 1 in Exon 4, 9 in Exon 5-8. All but one (D24H) were truncating mutations. 11 of 16 pts who completed a 56-day course reported subjective improvement in energy, mood, focus or skin lesion. Pts with Ex6-8 mutation (n=4) had a median SUV decrease of 29.4%. Regression of skin and GI lesions was observed by dermoscopy or endoscopy. Cerebellar evaluation showed a significant improvement in a total SARA score at 1 month (n=9, p=0.034). 3 pts were treated for only 28 days due to voluntary withdrawal. IHC analysis in skin and GI benign lesions showed a decrease in average P-S6K, P-S6, Total S6, P-S6/Total S6 in response to S. P-S6K/Total S6 ratios at d14 and d56 were significantly lower than at baseline (p=0.0026, 0.0391, respectively). The most common AEs (all grades >25%) were LFTs/Hb (39%), fatigue/hypercholesterolemia (28%). Grade 3 AEs: 1 pt hypophosphatemia/lymphopenia. Conclusions: A 56-day course of S was well tolerated in subjects with CS and was associated with improvement in symptoms, skin/GI lesions, cerebellar function and decreased mTOR signaling. Clinical trial information: NCT00971789.

Abstract 3706 Despite the success of treatment of patients with refractory and relapsed Hodgkin's lymphoma with combination chemotherapy, radiation and hematopoietic stem cell transplantation, a significant fraction of patients will not respond to treatment or will subsequently relapse and succumb to Hodgkin's lymphoma (HL). We have focused on CD25, the IL-2 receptor alpha subunit, as a target for systemic radioimmunotherapy of HL. The scientific basis for this choice is that with the exception of T regs, CD25 is not expressed by normal resting lymphoid cells whereas it is expressed on both a minority of Reed-Sternberg cells and also on regulatory T cells rosetting around the Reed-Sternberg cells. We have utilized the humanized monoclonal antibody, daclizumab that targets CD25 (IL-2R alpha) armed with yttrium-90 a radionuclide that provides strong beta emissions that kill tumor cells at a distance via a crossfire effect. Patients with histologically confirmed HL and expression of CD25 in at least 10% of the cells in the lymphomatous mass were eligible. Thirty consecutive patients with HL were entered. The patients had received a median of 4 prior chemotherapy regimens and were required to have had an autologous and/or allogeneic stem cell transplant or had refused a transplant. Patients were treated with an initial dose of 10 or 15 mCi of 90Y-daclizumab depending on transplant status. After the first cycle, patients could receive 90Y-daclizumab 15 mCi per cycle every 6 to 10 weeks to complete up to a maximum of 7 doses if tolerated. A total of 98 cycles of treatment were administered to 30 patients with a median aggregate radiation dose of 40 mCi. In 30 HL patients treated with 90Y-daclizumab there were 7 partial responses and 12 complete responses. Toxicities were limited to transient bone marrow suppression and the myelodysplastic syndrome (3 cases). Responses were seen among the 5 patients whose Reed-Sternberg cells expressed CD25 as well as in those whose neoplastic cells were CD25 negative provided that the associated rosetting T regs expressed CD25. The increased efficacy compared to alternative radioimmunotherapy strategies for HL appears to reflect the increase in the target antigen, CD25, in lymphomatous masses provided by the overexpression of CD25 by associated rosetting T cells, and the use of a high energy, beta-emitting radionuclide Yttrium-90 to arm the antibody that thereby does not have to come in contact with each tumor cell but can kill cells by crossfire at a distance. In conclusion, repeated 90Y-daclizumab infusions predominantly directed toward non-malignant T cells rosetting around Reed-Sternberg cells provided effective therapy for select HL patients. Disclosures: No relevant conflicts of interest to declare.

8043 Background: ATL is an aggressive malignant lymphoproliferative disorder with a poor prognosis and no standard therapy. ATL can be classified into four subtypes: acute, lymphomatous, chronic and smoldering. Daclizumab is a humanized monoclonal antibody that prevents binding of interleukin-2 by recognizing the α-chain of the interleukin-2 receptor (CD25), which is over-expressed on ATL cells. Preclinical studies in the MET-1 mouse model of ATL showed daclizumab treatment improved survival. A phase I trial demonstrated that up to 8 mg/kg daclizumab was well tolerated with clinical evidence of antitumor activity in ATL. Based on this data, a phase II trial was initiated. Methods: A single institution open-label Phase II trial was conducted, with a primary endpoint of response rate. Eligibility: All ATL subtypes with ≥10% of tumor cells expressing CD25. Patients received intravenous daclizumab 8 mg/kg on days 1 and 15, and then every 3 weeks to complete 6 doses. Responding patients continued to receive da...

Conjugation of radionuclides to monoclonal antibodies provides a strategy to target radiation therapy directly to cells expressing the antigen of interest, also known as radio-immunotherapy (RIT). This modality has emerged as an effective targeted anti-neoplastic strategy in patients with B cell lymphoma. Certain hematologic malignancies express abnormally high levels of interleukin (IL)-2Rα (CD25, Tac) including cutaneous T cell lymphoma, peripheral T cell lymphoma, anaplastic large cell lymphoma, Hodgkin’s lymphoma (HL) and chronic lymphocytic leukemia. In this study 90Y-labeled daclizumab in CD25 positive malignancies, other than adult T cell leukemia, was investigated. We determined that 15 millicuries (mCi) was the maximum tolerated dose (MTD) in patients without a history of stem cell transplantation. As objective responses were only seen in HL, the phase II component of the study has focused on patients (pts) with relapsed and refractory HL. Eligibility criteria include: Karnofsky performance status (KPS) >50%, AGC >1,500/mm3, platelet >100,000/mm3, adequate hepatic/renal function and informed consent. As an added safety measure pts with a prior history of peripheral stem cell transplantation received an initial dose of 10mCi; in the absence of hematologic toxicity subsequent cycles were administered at 15mCi. All other pts received 15 mi 90Y-daclizumab every 6 weeks until disease progression, DLT or completion of 7 cycles. Ca-DTPA was used to reduce bone marrow exposure to free 90Y. 111In-labeled daclizumab was used for tumor imaging. Thirty pts with Hodgkin’s lymphoma have been treated, median age of 35 years (range, 20 to 67 years). The majority are heavily pre-treated, median of 4 prior chemotherapy regimens, range 1–8. Twenty pts had received a prior autologous transplantation; while 4 patients had received both autologous and allogeneic transplantation. One hundred cycles have been administered, median cycles per patient is 3 (range 1–7 cycles). Of 30 pts treated with 90Y-daclizumab, 12 achieved a complete response (CR), 7 had a partial response (PR), 5 had stable disease and 6 progressed. The response rate in pts who had undergone a transplant was 80%. Interestingly, many of the responses were seen in pts with CD25 negative malignant cells but with surrounding CD25 positive T cells within the tumor microenvironment. The median response duration was 129 days (range 28 to 720 days). The freedom from progression for the pts with a CR ranged from 28 to 788 days with a median of 222 days. There were no infusional reactions, however 5 pts developed non-symptomatic human anti-human antibody (HAHA) titers to daclizumab after one or more treatments. Seven pts failed to recover platelet count to the protocol mandated limit of 75,000, resulting in halting therapy, and 3 pts developed myelodysplastic syndrome (MDS) after 90Y-daclizumab, however one of those patients in retrospect had evidence of the same cytogenetic abnormalities predating therapy. 90Y-daclizumab produces objective responses in relapsed and refractory HL but as with other RIT strategies is not a curative approach. The role for 90Y-daclizumab in patients with relapsed HL with stem cell transplantation will be investigated.

4762 Background: BAY 43–9006 (Sorafenib) is a bis-aryl urea with potent anticancer properties. It is a potent inhibitor VEGFR-2, Raf kinase and BRAFV599E. Accumulating evidence suggests that the Ras-Raf-MAPK-ERK signaling pathway is dysregulated in the setting of AIPC. Furthermore, published studies have shown a role for anti-angiogenic therapy for AIPC. We have launched a phase II study to determine the clinical and biological activity of BAY 43–9006 in patients with AIPC. Methods: Patients are enrolled in an open-label, single arm phase II study. They must have good performance status and normal end-organ function. Patients with uncontrolled hypertension and those requiring therapeutic anticoagulation are excluded. All patients are treated with orally administered BAY 43–9006 at a dose of 400 mg bid given continuously on 28-day cycles. Clinical assessment occurs every 28 days with radiographic measurements of disease every 2 cycles. Treatment continues until progression. Tissue and bone marrow biopsies ...

3103 Background: KRAS mutations have been recognized as clinically important predictors of resistance to EGFR-directed therapies in CRC. Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor receptor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cet in KRAS mutant CRC. A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cet, with an expanded cohort in KRAS mutant CRC at the MTD dose to evaluate preliminary anti-tumor activity. Methods: In the dose escalation portion, patients (pts) with advanced solid tumors received fixed dose cet with escalating doses of selumetinib in cohorts of 3-6 pts. In the expansion cohort, 14 pts with KRAS mutant CRC were enrolled at the MTD level. Results: 15 pts (9 M, 6 F), average age of 60 (41-73) years were treated at 3 dose levels in the dose escalation cohort and 14 pts were treated in the expansion cohort. Pts had the following tumor types: CRC 73%, NSCLC 13%, and H&N 13%, and had received a median of 4 (1-8) prior lines of therapy. 33% (only CRC) had prior EGFR-directed therapies. ECOG PS 0 (40%), 1 (53%), 2 (7%). 13 of 15 pts were evaluable for tolerability and response. One DLT for grade 4 hypomagnesemia occurred, and no other grade 4 toxicities were seen. Grade 3 (20%) toxicities included; rash, hyponatremia, and headache. The most common cycle 1 grade 1 and 2 adverse events included acneiform rash (100%), fatigue (54%), nausea/vomiting, (54%), diarrhea (54%), dry skin (46%), fever (23%), and hypomagnesemia (15%). Most pts (60%) required no dose modifications. The MTD was established at selumetinib 75 mg PO BID and cet 250 mg/m2 weekly following a 400 mg/m2load. Best response included 2 PR in pts with CRC and SD in 4 pts (1 SCC of the tonsil, 1 NSCLC, and 2 CRC). Conclusions: The combination of selumetinib and cet is well tolerated, and preliminary anti-tumor activity was observed in multiple pts. Results of the KRAS mutant CRC expansion cohort will be presented.