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433 Background: Single agent checkpoint inhibition is effective in a small proportion of platinum-refractory UC patients but improvements are needed. UC is highly inflammatory, and low-dose chemotherapy may enhance the response to immunotherapy. We evaluated whether combination therapy with low-dose paclitaxel and pembrolizumab is more efficacious than single-agent pembrolizumab which had an objective response rate (ORR) of 21% in a similar patient population in the KEYNOTE-045 study. We also incorporated multiple novel biomarker studies to explore immune regulatory mechanisms in UC. Methods: This is a prospective, single-arm phase II trial (NCT02581982) of pembrolizumab combined with low-dose paclitaxel in patients with platinum-refractory metastatic UC. Key inclusion criteria included measurable progression of disease within 12 months of platinum therapy and ECOG ≤1. Patients received pembrolizumab 200mg day 1 and paclitaxel 80 mg/m2 days 1 and 8 of a 21 day cycle for up to 8 cycles unless clinical or radiographic disease progression or unacceptable adverse events (AEs) were observed. Responding patients could remain on pembrolizumab maintenance for up to 2 years. The primary endpoint was ORR; key secondary endpoints included overall survival (OS), 6-month progression free survival (PFS), and safety. Results: Twenty-seven patients were treated between 4/2016 - 6/2020, with a median follow up of 9.9 months. At baseline, the median age was 68 years (range 49-80), with 81% men and 78% non-Hispanic white. The majority (59%) were ECOG 1. Twenty-one of 27 (78%) received prior definitive therapy: chemoradiation in 24% and surgery in 76%. The majority (78%) of patients received prior cisplatin. 70% progressed on a cisplatin-based regimen while 30% progressed on carboplatin-based regimen within 12 months of study entry. The ORR by intention to treat was 9 of 27 patients (33%) and in patients evaluable for response by imaging was 9 of 25 (36%), including 3 with complete response. Disease control rate in evaluable patients was 72%. Six-month PFS was 46.8% (95% CI: 27.2%, 64.2%) and median OS was 11.7 months (95% CI: 8.7 mo, NR). Common ≥ grade 2 AEs were anemia (44%), lymphopenia (37%), hyperglycemia (33%), and fatigue (33%). Possible treatment-related at least grade 3 or 4 AEs occurred in 56% of subjects, including 2 immune-mediated AEs (pneumonitis and nephritis) resulting in therapy cessation but a durable partial response. There were no grade 5 events. Conclusions: This study illustrates that the addition of low-dose paclitaxel to pembrolizumab improves outcomes in patients with platinum-refractory UC, relative to single-agent pembrolizumab. No unanticipated safety signals emerged. Exploratory analyses including PDL1 status, tumor mutational burden, and change in circulating microRNAs and in immune cell populations are ongoing. Clinical trial information: NCT02581982.

e14000Background: The spatial distribution of brain metastasis has historically been assumed to be uniform; however, emerging evidence suggests that certain tumor characteristics may be associated ...

3055Background: Casitas-B-lineage lymphoma protein – b (cbl-b), an E3 ubiquitin ligase is an important intracellular checkpoint limiting activation of lymphocytes and NK cells. Silencing of cbl-b e...

e14541Background: Casitas-B-lineage lymphoma protein-b (Cbl-b), an E3 ubiquitin ligase, is a major intracellular checkpoint limiting lymphocyte activation. Silencing Cbl-b enhances T cell and natur...

PURPOSE Interleukin-1 (IL-1) and IL-2 have synergistic antitumor and myelostimulatory activities. We investigated the clinical and biologic effects of IL-1/IL-2 therapy. PATIENTS AND METHODS Twenty patients with metastatic cancer, divided into five cohorts, were treated with escalating doses of IL-1 beta (0.005 to 0.2 micrograms/kg/d) administered as a 30-minute intravenous (IV) infusion on days 1 to 4, combined with a fixed dose of IL-2 (0.1 mg/m2/d) administered by continuous IV infusion on days 1 to 4. The 4-day cycles were repeated weekly for up to 8 weeks in the absence of toxicity and/or progressive disease. RESULTS Patients tolerated up to 0.2 microgram/kg/d of IL-1 beta in combination with IL-2 without severe adverse effects. Peripheral-blood CD4-to-CD8 ratios and lymphokine-activated killer (LAK) activity were higher at the lower doses (0.005 to 0.05 microgram/kg/d) of IL-1 beta and higher than that of a cohort of patients treated with IL-2 alone. WBC counts, primarily neutrophils, increased significantly with higher doses of IL-1 beta (0.1 to 0.2 microgram/kg/d). Platelet counts were not significantly altered. Increases in serum IL-6, interferon gamma (IFN-gamma), and soluble IL-2 receptor levels were observed, but did not vary with IL-1 beta dose. Tumor regressions were observed in patients with colorectal cancer, melanoma, and renal cell carcinoma. CONCLUSION IL-1 beta cancer be administered in combination with IL-2 with acceptable toxicity. Our results suggest that the addition of even low-dose IL-1 beta to IL-2 may be associated with potentially beneficial biologic activity; higher doses of IL-1 beta (0.1 to 0.2 microgram/kg/d) may add potentially beneficial hematologic activity.

Interferon-beta-serine (IFN-beta-ser) is a muteine, recombinant IFN that is tolerated at a dose fivefold to 10-fold higher than IFN-alfa and interacts with the same cell membrane receptor as IFN-alfa. We hypothesized that at high doses IFN-beta-ser might induce a higher response rate than IFN-alfa in metastatic renal cell carcinoma. We undertook a phase II trial of IFN-beta-ser in patients with metastatic renal cell carcinoma. Patients were treated three times each week by a 2-hour intravenous infusion. Doses were escalated weekly (.25 to 5.5 mg, 1 mg = 180,000,000 U) until the maximum-tolerated treatment dose (MTTD) was determined. The MTTD is defined as one dose level less than that which caused grade 3 toxicity and was subsequently administered three times weekly for at least 4 weeks. Twenty-nine patients were entered, and 25 were assessable for response and toxicity. The performance status was 0-1 in all patients and only one patient received previous chemotherapy. The MTTD dose was 2.5 mg (range, 0.5 to 5.5 mg per treatment), although in 10 patients, doses were later deescalated because of cumulative toxicity. Initial dose-limiting toxicity and cumulative toxicity were fatigue, malaise, and fever in most patients. Hepatic transaminitis, neutropenia, and elevation of serum creatinine were also observed but were not dose-limiting. There was one complete response (CR) and four partial responses (PRs). All responses but one occurred in pulmonary metastases. The median time to response was 26 days (range, 17 to 102 days). These data demonstrate that IFN-beta-ser given in high doses exhibits significant antitumor activity in renal cell carcinoma; however, the objective response rate is 20%. This is no higher than previous IFN studies; therefore, we reject the hypothesis than IFN-beta-ser at high doses may induce a greater response rate than IFN-alfa. However, we did observe more responses than were seen in a similar trial undertaken with lower dose IFN-beta serine in renal cell carcinoma.

3070 Background: The E3 ubiquitin ligase cbl-b has been identified as an important gatekeeper limiting T cell activation. Concordantly, the immune system of cbl-b deficient mice can effectively fig...

e13521 Background: The vascular endothelial growth factor (VEGF) antibody bevacizumab (Bev) and the VEGF receptor (VEGFR) inhibitor sunitinib are efficacious agents in many malignancies. This combination has been previously evaluated in phase I studies of advanced solid tumors. In addition to renal cell carcinoma (RCC), objective responses in the previous phase I occurred in melanoma and adrenal carcinoma. An expansion phase of the phase I study was undertaken primarily to obtain further safety data in these tumor types. Methods: Patients (pts) with metastatic solid tumors with ECOG performance status 0-1 were enrolled on a phase I trial of sunitinib (37.5 mg daily weeks 1-4) and Bev (5 mg/kg iv on days 1, 15 and 29) of a 6 week cycle. Responses were assessed by CT scans performed at baseline and every 12 weeks based on RECIST criteria v1.0. Results: Twenty-two pts were enrolled (10 males, 12 females; median age 58 years) in the expansion cohort. Tumor types included melanoma (11), RCC (5), adrenal cancer (5) and angiosarcoma (1). Prior systemic treatment included chemotherapy (41%) and immunotherapy (27%). Common all grade toxicities included fatigue (77%), hypertension (73%), thrombocytopenia (68%), nausea (59%) and oral mucositis (55%). Grade 3 or higher toxicities occurred in 15 pts (68%); including hypertension (41%), thrombocytopenia (23%) and fatigue (14%). Seven pts developed hemorrhagic events, all grade 1 or 2. Two pts experienced grade 4 thrombocytopenia, 3 RCC pts developed grade 1 thrombotic microangiopathy (TMA); while 1 melanoma patient developed decreased haptoglobin (grade 1) with associated thrombocytopenia (grade 4) and schistocytes consistent with TMA. A median of 2 cycles were completed (range, 1-8). Best response in 19 evaluable pts included partial response 21% (4/19; melanoma (2), adrenal (1), and RCC(1)); stable disease 21% (4/19) and progressive disease 58% (11/19). Overall, 6 pts (31.5%) had measurable reduction in tumor burden. Conclusions: The safety profile of Bev plus sunitinib in melanoma and adrenal carcinoma pts is similar to the previously evaluated toxicities in RCC pts. Although reversible, combined VEGF and VEGFR inhibition may lead to microangiopathy even in non-RCC pts. Clinical trial information: NCT00357318.

3038 Background: VB-111 is a tissue and condition specific vascular disrupting and anti-angiogenic agent based on a novel Vascular Targeting System (VTS) which contains the modified angiogenic spec...

5116 Background: Cyclooxygenase-2 (COX-2) has been correlated with RCC stage and grade, and overexpression can lead to dysregulation of dendritic cells (DC) and CD4+/CD25+/FOXP3+ regulatory T cells (Treg). A previous trial of celecoxib in combination with IFNα2b in RCC (Rini et al, Cancer. 2006) demonstrated an association between more intense COX-2 RCC tumor staining and clinical response. Methods: Pts with cytokine-naïve mRCC with at least 10% maximal COX-2 tumor staining received IFNα2b MU five times/week plus celecoxib 400 mg BID continuously. Baseline tumor tissue was stained for COX-2, CD4+ and CD8+ T cells, Treg and DC (s100 and CD208). Peripheral blood prostaglandin E2 (PGE2), DC and Treg number/function and intracellular T cell cytokine production were measured at baseline, at the end of cycles 2 and 4 and at end of treatment. Activation of DC was assessed by IL-12 and IL-10 mRNA and protein production by ELISA. The primary endpoint was objective response rate (ORR). Secondary endpoints were DC / Treg number and cytokine production changes with therapy. The trial tested a null hypothesis of ORR 40%; beta = 0.8 and alpha = 0.05 (n = 34). Immune parameters were analyzed using non-parametric methods. Results: Fourteen pts have been enrolled; 79% male, median age 62 (range, 43–74) and 64% ECOG performance status 0. All pts had prior nephrectomy and 36% had received prior tyrosine kinase inhibitors (TKI); MSKCC Risk Group was favorable 14%, intermediate 71%, and unfavorable 14%. The ORR was 21% and 69% of pts experienced tumor shrinkage. Median PFS is 4.4 months. Toxicity was as expected for IFN therapy. Baseline 3+ COX-2 staining was associated with elevated peripheral blood PGE2 levels (p = 0.02), reduced DC IL-12 expression (p = 0.04) and reduction in IFN gamma-producing CD3+CD4+ T-cells (p = 0.04) compared to a control group of RCC pts with [Table: see text]

5143 Background: Ketoconazole (Keto) is an active second-line hormonal maneuver that induces PSA responses in 20–30% of CPPCA patients (pts). In addition to the suppression of testicular and adrena...

5103 Background: Interleukin-2 and bevacizumab, a VEGF ligand-binding antibody, have each demonstrated antitumor activity in mRCC. Increased VEGF levels can lead to immunosuppression and resistance to immunotherapy through inhibition of dendritic cell (DC) differentiation and increase in immunosuppressive regulatory T cells (Tregs). To further evaluate the clinical and immunomodulatory effect of low-dose IL-2 and bevacizumab in mRCC, a phase II trial was conducted. Methods: Previously untreated good and intermediate risk mRCC pts received 8-week cycles of IL-2 (250,000 U/kg/d SC D1–5 during week 1 and 125,000 U/kg/d SC D1–5 during weeks 2–6, followed by a 2 week break). Bevacizumab 10mg/kg was administered IV every 2 weeks starting on day -14. Eligibility included RECIST-defined measurable disease, clear cell histology, normal organ function, and prior nephrectomy. A Simon 2 stage phase II design was employed to test the hypothesis of a 40% improvement in the 3-month PFS vs. historical IL-2-treated controls. Overall response rate (ORR) and toxicity were recorded. Exploratory endpoints included activation of circulating DC’s, Tregs and VEGF levels. Results: To date 16 of a planned 35 pts are enrolled. Median age is 59 years (range, 44–67); Eight patients have >1 site of metastasis; median treatment duration is 8 weeks (8–32+). Among 11 pts evaluable for response, 1 PR and 3 SD lasting >3 months have been observed. All pts with SD have demonstrated some degree of tumor shrinkage. Seven pts have discontinued therapy (5 PD, 2 withdrew consent). Most common treatment-related toxicity included fatigue, nausea, diarrhea, and fever. When comparing immune correlates at day 56 of therapy vs. baseline, all pts had an increase in the number of Tregs (median increase 1.65, range; 0.76–10.4; p= 0.008). Similarly, all pts had a decline in VEGF levels (median decline 164.38 pg/ml, range; 2.20–393.04 pg/ml; p= 0.008). No differences in DC activation have been observed. Conclusions: The combination of LD IL-2 and bevacizumab produces antitumor activity and moderate toxicity. Preliminary correlative data demonstrates inhibition of VEGF and increase in Tregs without effect on DC activation. No significant financial relationships to disclose.

15515 Background: Administration of GM-CSF in combination with thalidomide induces PSA responses in 20–25% of pts with HRPC. When administered in the neoadjuvant setting, this combination induces T cell and dendritic cell (DC) infiltration in prostate tumor tissue. Lenalidomide is an immunomodulatory analogue of thalidomide. In an effort to evaluate the clinical and immune activity of GM-CSF plus lenalidomide, we conducted a phase I/II trial in pts with HRPC. Methods: Pts had progressive asymptomatic HRPC by Consensus Criteria. Prior immunotherapy or chemotherapy was not permitted. A phase I safety phase followed by a phase II trial was undertaken. All pts received GM-CSF at 250 μg administered SC three times weekly along with lenalidomide 25 mg/day orally on days 1–21 of a 28-day cycle. Primary endpoints were safety and objective and PSA responses. Exploratory endpoints included activation of circulating DC, regulatory T cells (Treg) and cytokine production. Results: To date 19 of 34 planned pts are enrolled (13 with evidence of metastases; 6 with PSA-only disease). Seventeen pts are eligible for response (2 pts too early) Median age is 71 (49–80), median PSA is 19.1 (2.1–153.1). Median cycles of therapy is 4 (range: 1–14+). Overall, 13 of 17 pts (76%) experienced a reduction in PSA (50% 4/17). Objective and PSA partial responses were observed in 2 and 4 of 17 pts respectively. Nine pts discontinued therapy (5 due to PD, 3 due to toxicity, and 1 withdrew consent). No pts on the phase I portion of the trial experienced a DLT. Grade (G) 1–2 toxicities for all 17 pts included neutropenia (20%), thrombocytopenia (13%), diarrhea (43%), dizziness, (25%), and fatigue (90%). Three pts developed G4 toxicities (PE, neutropenia, and emesis). The number of Treg cells decreased after 2 cycles of therapy. Similarly, Th1 cytokine and TNF-a production was increased after therapy. Although mean serum VEGF levels were decreased after therapy, changes in the mean serum levels of IL-8 and bFGF were not observed. Conclusions: The combination of GM-CSF and lenalidomide is relatively well tolerated with evidence of antitumor activity. Exploratory studies support the ability of this therapy to modulate immune cells. Accrual to this study is ongoing. [Table: see text]

2556 Background: Current therapeutic options for metastatic melanoma are limited. KW-2871 is an IgG1 kappa chimeric monoclonal antibody targeting ganglioside antigen GD3, expressed on neuroectodermal tumors including melanoma, glioma and neuroblastoma. GD3 expression is known to be upregulated with malignant transformation of melanoma and tumor progression. KW-2871 has mediated antibody-dependent cellular cytotoxicity (ADCC). Method: Seventeen patients with stage IV melanoma not amenable to surgical intervention with ECOG performance status of 0, 1 or 2 were enrolled in the study to evaluate the safety, tolerance and pharmokinetics of KW-2871. All patients received a test dose of 10 mg/m2 IV. Patients were stratified into 4 cohorts receiving 4 doses at 2 week interval of 20, 40, 80 and 120 mg/m2. No premedications were administered prior to infusion of KW-2871. Results: No dose limiting toxicities (DLT: grade ≥ 2 allergic reaction and/or Grade ≥ 3 toxicity) were observed in the 20 and 40 mg/m2 cohorts. Th...