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Background Before 2018, there was no standard of care for non-metastatic (M0) castration resistant prostate cancer nmCRPC. Androgen receptor antagonists (ARAs) were commonly used sequentially nmCRPC. Methods This was a multicenter, randomized clinical trial comparing the ARA flutamide+/−PROSTVAC, a pox viral vaccine targeting PSA that includes T-cell co-stimulatory molecules. Eligible men had negative CT and Tc99 bone scans, and rising PSA on ADT. Previous treatment with ARA was a stratification factor. Patients were also evaluated for antigen-specific immune responses using intracellular cytokine staining. Results Thirty-three patients randomized to flutamide and 31 to flutamide+vaccine. The median age was 71.8 and 69.8 years, respectively. The median time to treatment failure after a median potential follow-up of 46.7 months was, 4.5 months (range 2-70) for flutamide alone vs. 6.9 months (2.5-40; P = .38) with flutamide+vaccine. Seven patients in each arm had a >50% PSA response. Antigen-specific responses were similar in both arms (58% of patients in flutamide alone and 56% in flutamide+vaccine). The treatments were well tolerated. The most common side effect > grade 2 was injection site reaction seen in 29/31 vaccine patients which were self-limiting. Conclusion The combination of flutamide+PROSTVAC did not improve outcomes in men with nmCRPC compared with flutamide alone. (ClinicalTrials.gov Identifier: NCT00450463)

The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinomas as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown that a recombinant Saccharomyces cerevisiae (yeast) vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A phase I dose-escalation (3+3 design) trial enrolled 34 patients at 4 dose levels [3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)]. Expansion cohorts were enrolled at 40- and 80-YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events was observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising carcinoembryonic antigen (CEA), remains on study for greater than 1 year with stable disease, evidence of decreased tumor density, and decreased serum CEA. This is the first-in-human study to demonstrate the safety and immunogenicity of this therapeutic cancer vaccine and provides the rationale for exploration in phase II studies. A randomized phase II chordoma study is now enrolling patients. Cancer Immunol Res; 3(11); 1248–56. ©2015 AACR.

Yeast-brachyury progression-free survival; chordoma patients only.

Purpose: PANVAC is a recombinant poxviral vaccine that contains transgenes for MUC-1, CEA, and 3 T-cell costimulatory molecules. This study was conducted to obtain preliminary evidence of clinical response in metastatic breast and ovarian cancer patients.Experimental design: Twenty-six patients were enrolled and given monthly vaccinations. Clinical and immune outcomes were evaluated.Results: These patients were heavily pretreated, with 21 of 26 patients having 3 or more prior chemotherapy regimens. Side effects were largely limited to mild injection-site reactions. For the 12 breast cancer patients enrolled, median time to progression was 2.5 months (1–37+) and median overall survival was 13.7 months. Four patients had stable disease. One patient had a complete response by RECIST and remained on study for 37 months or more, with a significant drop in serum interleukin (IL)-6 and IL-8 by day 71. Another patient with metastatic disease confined to the mediastinum had a 17% reduction in mediastinal mass and was on study for 10 months. Patients with stable or responding disease had fewer prior therapies and lower tumor marker levels than patients with no evidence of response. For the ovarian cancer patients (n = 14), the median time to progression was 2 months (1–6) and median overall survival was 15.0 months. Updated data are presented here for one patient treated with this vaccine in a previous trial, with a time to progression of 38 months.Conclusions: Some patients who had limited tumor burden with minimal prior chemotherapy seemed to benefit from the vaccine. Further studies to confirm these results are warranted. Clin Cancer Res; 17(22); 7164–73. ©2011 AACR.

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Summary Background Avelumab (MSB0010718C) is a human IgG1 monoclonal antibody that binds to PD-L1, inhibiting its binding to PD-1, which inactivates T cells. We aimed to establish the safety and pharmacokinetics of avelumab in patients with solid tumours while assessing biological correlatives for future development. Methods This open-label, single-centre, phase 1a, dose-escalation trial (part of the JAVELIN Solid Tumor trial) assessed four doses of avelumab (1 mg/kg, 3 mg/kg, 10 mg/kg, and 20 mg/kg), with dose-level cohort expansions to provide additional safety, pharmacokinetics, and target occupancy data. This study used a standard 3 + 3 cohort design and assigned patients sequentially at trial entry according to the 3 + 3 dose-escalation algorithm and depending on the number of dose-limiting toxicities during the first 3-week assessment period (the primary endpoint). Patient eligibility criteria included age 18 years or older, Eastern Cooperative Oncology Group performance status 0–1, metastatic or locally advanced previously treated solid tumours, and adequate end-organ function. Avelumab was given as a 1-h intravenous infusion every 2 weeks. Patients in the dose-limiting toxicity analysis set were assessed for the primary endpoint of dose-limiting toxicity, and all patients enrolled in the dose-escalation part were assessed for the secondary endpoints of safety (treatment-emergent and treatment-related adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0), pharmacokinetic and pharmacodynamic profiles (immunological effects), best overall response by Response Evaluation Criteria, and antidrug antibody formation. The population for the pharmacokinetic analysis included a subset of patients with rich pharmacokinetic samples from two selected disease-specific expansion cohorts at the same study site who had serum samples obtained at multiple early timepoints. This trial is registered with ClinicalTrials.gov, number NCT01772004. Patient recruitment to the dose-escalation part reported here is closed. Findings Between Jan 31, 2013, and Oct 8, 2014, 53 patients were enrolled (four patients at 1 mg/kg, 13 at 3 mg/kg, 15 at 10 mg/kg, and 21 at 20 mg/kg). 18 patients were analysed in the dose-limiting toxicity analysis set: three at dose level 1 (1 mg/kg), three at dose level 2 (3 mg/kg), six at dose level 3 (10 mg/kg), and six at dose level 4 (20 mg/kg). Only one dose-limiting toxicity occurred, at the 20 mg/kg dose, and thus the maximum tolerated dose was not reached. In all 53 enrolled patients (the safety analysis set), common treatment-related adverse events (occurring in >10% of patients) included fatigue (21 patients [40%]), influenza-like symptoms (11 [21%]), fever (8 [15%]), and chills (6 [11%]). Grade 3–4 treatment-related adverse events occurred in nine (17%) of 53 patients, with autoimmune disorder (n=3), increased blood creatine phosphokinase (n=2), and increased aspartate aminotransferase (n=2) each occurring in more than one patient (autoimmune disorder in two patients at 10 mg/kg and one patient at 20 mg/kg, increased blood creatine phosphokinase in two patients at 20 mg/kg, and increased aspartate aminotransferase in one patient at 1 mg/kg, and one patient at 10 mg/kg). Six (11%) of 53 patients had a serious treatment-related adverse event: autoimmune disorder (two [13%]), lower abdominal pain (one [7%]), fatigue (one [7%]), and influenza-like illness (one [7%]) in three patients treated at 10 mg/kg dose level, and autoimmune disorder (one [5%]), increased amylase (one [5%]), myositis (one [5%]), and dysphonia (one [5%]) in three patients who received the 20 mg/kg dose. We recorded some evidence of clinical activity in various solid tumours, with partial confirmed or unconfirmed responses in four (8%) of 53 patients; 30 (57%) additional patients had stable disease. Pharmacokinetic analysis (n=86) showed a dose-proportional exposure between doses of 3 mg/kg and 20 mg/kg and a half-life of 95–99 h (3·9–4·1 days) at the 10 mg/kg and 20 mg/kg doses. Target occupancy was greater than 90% at doses of 3 mg/kg and 10 mg/kg. Antidrug antibodies were detected in two (4%) of 53 patients. No substantial differences were found in absolute lymphocyte count or multiple immune cell subsets, including those expressing PD-L1, after treatment with avelumab. 31 (58%) of 53 patients in the overall safety population died; no deaths were related to treatment on study. Interpretation Avelumab has an acceptable toxicity profile up to 20 mg/kg and the maximum tolerated dose was not reached. Based on pharmacokinetics, target occupancy, and immunological analysis, we chose 10 mg/kg every 2 weeks as the dose for further development and phase 3 trials are ongoing. Funding National Cancer Institute and Merck KGaA.

Summary Background Therapeutic cancer vaccines have shown activity in metastatic castration-resistant prostate cancer (mCRPC), and methods are being assessed to enhance their efficacy. Ipilimumab is an antagonistic monoclonal antibody that binds cytotoxic T-lymphocyte-associated protein 4, an immunomodulatory molecule expressed by activated T cells, and to CD80 on antigen-presenting cells. We aimed to assess the safety and tolerability of ipilimumab in combination with a poxviral-based vaccine targeting prostate-specific antigen (PSA) and containing transgenes for T-cell co-stimulatory molecule expression, including CD80. Methods We did a phase 1 dose-escalation trial, with a subsequent expansion phase, to assess the safety and tolerability of escalating doses of ipilimumab in combination with a fixed dose of the PSA-Tricom vaccine. Patients with mCRPC received 2×10 8 plaque-forming units of recombinant vaccinia PSA-Tricom subcutaneously on day 1 of cycle 1, with subsequent monthly boosts of 1×10 9 plaque-forming units, starting on day 15. Intravenous ipilimumab was given monthly starting at day 15, in doses of 1, 3, 5, and 10 mg/kg. Our primary goal was to assess the safety of the combination. This study is registered with ClinicalTrials.gov, number NCT00113984. Findings We completed enrolment with 30 patients (24 of whom had not been previously treated with chemotherapy) and we did not identify any dose-limiting toxic effects. Grade 1 and 2 vaccination-site reactions were the most common toxic effects: three of 30 patients had grade 1 reactions and 26 had grade 2 reactions. 21 patients had grade 2 or greater immune-related adverse events. Grade 3 or 4 immune-related adverse events included diarrhoea or colitis in four patients and grade 3 rash (two patients), grade 3 raised aminotransferases (two patients), grade 3 endocrine immune-related adverse events (two patients), and grade 4 neutropenia (one patient). Only one of the six patients previously treated with chemotherapy had a PSA decline from baseline. Of the 24 patients who were chemotherapy-naive, 14 (58%) had PSA declines from baseline, of which six were greater than 50%. Interpretation The use of a vaccine targeting PSA that also enhances co-stimulation of the immune system did not seem to exacerbate the immune-related adverse events associated with ipilimumab. Randomised trials are needed to further assess clinical outcomes of the combination of ipilimumab and vaccine in mCRPC. Funding US National Institutes of Health.

Purpose: PANVAC is a recombinant poxviral vaccine that contains transgenes for MUC-1, CEA, and 3 T-cell costimulatory molecules. This study was conducted to obtain preliminary evidence of clinical response in metastatic breast and ovarian cancer patients. Experimental design: Twenty-six patients were enrolled and given monthly vaccinations. Clinical and immune outcomes were evaluated. Results: These patients were heavily pretreated, with 21 of 26 patients having 3 or more prior chemotherapy regimens. Side effects were largely limited to mild injection-site reactions. For the 12 breast cancer patients enrolled, median time to progression was 2.5 months (1–37+) and median overall survival was 13.7 months. Four patients had stable disease. One patient had a complete response by RECIST and remained on study for 37 months or more, with a significant drop in serum interleukin (IL)-6 and IL-8 by day 71. Another patient with metastatic disease confined to the mediastinum had a 17% reduction in mediastinal mass and was on study for 10 months. Patients with stable or responding disease had fewer prior therapies and lower tumor marker levels than patients with no evidence of response. For the ovarian cancer patients (n = 14), the median time to progression was 2 months (1–6) and median overall survival was 15.0 months. Updated data are presented here for one patient treated with this vaccine in a previous trial, with a time to progression of 38 months. Conclusions: Some patients who had limited tumor burden with minimal prior chemotherapy seemed to benefit from the vaccine. Further studies to confirm these results are warranted. Clin Cancer Res; 17(22); 7164–73. ©2011 AACR.

5084Background: Immune checkpoint inhibitors (ICIs) have yet to demonstrated efficacy as monotherapy in non-MSI-HI prostate cancer. Vaccines may increase immune cells in the tumor microenvironment,...

215 Background: Annually about 30-50,000 men are diagnosed with biochemically recurrent prostate cancer (BCRpc), defined by a rising PSA after radical prostatectomy (RP) or definitive radiation therapy (RT) with negative conventional imaging (CT and bone scan). Standard treatments include salvage therapies, androgen deprivation or surveillance. The role of immunotherapy in BCRpc is undefined. Methods: This study evaluates PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA, in BCRpc. Key eligibility criteria include PSA > 0.8 after RP or > 2.0 after RT with a maximum PSA of 30, PSA doubling time (DT): 5-15 months; testosterone > 100, negative CT and bone scan. Patients (pts) are randomized to vaccine for 6 months or 6 months surveillance followed by 6 months of vaccine. In a post hoc analysis delayed PSA declines were characterized as a confirmed PSA decline after an intra-study apex PSA (ISAP) defined by a peak PSA affirmed by a contiguous PSA within 10% (to exclude lab variations). 80 pts will be enrolled at NCI, Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Results: Of the 26 pts enrolled thus far, 22 have been followed for > 9 months after vaccine and are evaluable. On-study median values were age 66.8 years (54-78), PSA 2.67 ng/ml (0.83-28.5), PSA DT 7.5 months (5.1-14.9). 8 pts (38%) had delayed PSA declines after ISAP (-12% to -99%). Of 13 pts on surveillance for 6 months, only one pt had a similar decline lasting only 56 days. Conclusions: Preliminary data from this study suggests that PROSTVAC may be associated with delayed, but sustained PSA declines in BCRpc which are rarely seen in surveillance alone. Additional data will be acquired from this study, but this provides rationale to develop immunotherapy combinations in BCRpc. Clinical trial information: NCT02649439. [Table: see text]

The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinomas as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown that a recombinant Saccharomyces cerevisiae (yeast) vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A phase I dose-escalation (3+3 design) trial enrolled 34 patients at 4 dose levels [3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)]. Expansion cohorts were enrolled at 40- and 80-YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events was observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising carcinoembryonic antigen (CEA), remains on study for greater than 1 year with stable disease, evidence of decreased tumor density, and decreased serum CEA. This is the first-in-human study to demonstrate the safety and immunogenicity of this therapeutic cancer vaccine and provides the rationale for exploration in phase II studies. A randomized phase II chordoma study is now enrolling patients. Cancer Immunol Res; 3(11); 1248–56. ©2015 AACR.

203 Background: Recently there has been growing evidence that 18F-Fluoride PET/CT has increased sensitivity relative to technetium-99m diphosphonate (Tc-99m MDP) bone scan for evaluating metastatic bone disease. This analysis studied changes in 18F-Fluoride PET/CT and evaluated associations with PSA changes for mCRPC patients (pts) on enzalutamide (enz). Methods: As part of a randomized phase II study evaluating enz with or without vaccine therapy, men with mCRPC electively underwent 18F-Fluoride PET/CT at 3 month (mos) intervals [NCT01867333]. At these points serum PSA was collected. Data was taken on max SUV and volume of presumed cancerous lesions and a variable, ΣSUV*Volume, was calculated which was defined as the sum of the products of SUV max and volume of cancerous lesions. Results: At the time of our analysis, 19 pts had PSA and PET/CT data for at least 2 time points within 1 year of initiating therapy. The median baseline PSA was 19.6 ng/ml (0.76-587). All pts had predominantly bone disease with 10 having small volume lymphadenopathy. Only 1/19 pts progressed by PSA Working Group criteria. An analysis found that 18/19 pts (95%) had an association between changes in PSA and ΣSUV*Volume. Of these 18 pts, 13 had a major ( > 50%) and 1 had a minor ( > 30%) PSA response and all 14 had an accompanying decrease in ΣSUV*Volume. For 11/14 pts with PSA responses, the change in ΣSUV*Volume paralleled the change in PSA at all time points, while for 3 pts an associated change between ΣSUV*Volume and PSA was delayed by 3 mos. 4/14 pts had short term responses lasting only 3 mos followed by PSA increases. For these 4 pts the changes in ΣSUV*Volume paralleled PSA changes, decreasing at 3 mos and increasing thereafter. Finally 4/18 patients had no PSA response to therapy. All 4 pts had increases in ΣSUV*Volume which paralleled rising PSA values. Conclusions: Preliminary data from a small cohort suggests that findings on 18F-Fluoride PET/CT are associated with PSA changes. This represents a substantial difference from standard Tc-99m MDP and further suggests that 18F-Fluoride PET/CT may provide a more sensitive analysis of bone disease. Additional data from this and other studies are required.

172 Background: Results of recent clinical trials have intensified interest in immunotherapy in oncology. A number of cancer immunotherapies have been approved recently, while others are in late stage clinical development. The poxvirus-based active immunotherapy, PROSTVAC is generally well tolerated and is currently being evaluated in a global Phase 3 randomized, placebo-controlled trial. Ipilimumab, an approved immune checkpoint inhibitor in melanoma, is also being evaluated in a Phase 3 trial in chemo-naïve mCRPC. Methods: Results of two Phase 2 trials in men with mCRPC who were treated with PROSTVAC alone were compared with results from a Phase 1 combination study in mCRPC patients treated with PROSTVAC plus escalating doses of ipilimumab. Patients were enrolled in the Phase 1 combination study when docetaxel was the only FDA-approved mCRPC treatment that improved overall survival (OS). Results: In a multicenter Phase 2 trial, 125 men were randomized 2:1 to receive PROSTVAC or placebo. Patients treated with PROSTVAC had improved OS compared to placebo (25.1 vs 16.6 months; HR 0.56; 95% CI 0.37-0.85).Similar data was seen in a second phase 2 trial of PROSTVAC, where 32 patients with mCRPC had a median OS of 26.6 months (predicted median OS by the Halabi nomogram was 17.4 months). In a Phase 1 combination study of 30 mCRPC patients with similar baseline characteristics (predicted median OS of 18.5 months), patients were treated with PROSTVAC plus escalating doses of ipilimumab. The observed median OS was 31.3 months for all dose cohorts and 37.2 months for patients treated at 10 mg/kg based on updated overall survival data. Furthermore, there appears to be a tail on the curve with approximately 20% of patients at 10 mg/kg alive at 80 months. Conclusions: The comparison of data from three independent trials of PROSTVAC active immunotherapy in three similar patient populations provides hypothesis-generating data that the addition of an immune checkpoint inhibitor may have a positive effect on overall survival through a potential synergy in mechanism of action. The updated long term survival data is further evidence of improved OS with PROSTVAC. Future randomized trials are being planned to prospectively evaluate this hypothesis. Clinical trial information: NCT00113984.

In 2006, an estimated 212,920 American women will be diagnosed with breast cancer, and 40,970 will die from this disease.1 Breast cancer is the most common cancer in women in the United States, the second most common cause of cancer-related death in women, and the main cause of death in women aged 45-55 years. Patients with metastatic breast cancer (MBC) are unlikely to be cured of their disease by any means. A complete remission from chemotherapy, which is a prerequisite for a cure, is uncommon, and only a fraction of patients who experience a complete remission remain progression free for a prolonged period. In light of the fact that current therapeutic strategies have had very limited success in the metastatic disease setting, vaccine strategies represent an alternative approach to therapeutic intervention. This immunotherapeutic approach to the treatment of cancer is based on the observation that human tumor cells express a variety of tumor-associated antigens (TAAs) that are not expressed or are minimally expressed in normal tissues. These antigens, which include viral tumor antigens, cellular oncogene proteins, and tissue-specific differentiation antigens, can serve as targets for the host immune system and elicit responses that result in tumor destruction. Because tumors have developed a variety of mechanisms to evade immune detection and activation, the development of effective therapeutic vaccines for cancer will hinge on the ability to activate cellular immune responses. Antigen-specific active immunotherapy is designed to generate immune responses, particularly cellmediated responses, against specific TAAs using vaccines that express 1 of these antigens. The identification and isolation of genes encoding TAAs have allowed the development of recombinant antitumor vaccines designed to elicit immune responses to 1 antigen known to be expressed by a particular tumor type.

TPS5104 Background: There is a strong rationale to combine therapeutic cancer vaccines with hormonal abrogation in prostate cancer. Androgen abrogation augments T-cell trafficking to prostate, decreases immune tolerance, increases production of naïve thymic T-cells, enhances cytotoxic T-cell repertoire. PSA TRICOM (PROSTVAC) is a therapeutic, viral-vector based, off-the-shelf, cancer vaccine of PSA & 3 co-stimulatory molecules in phase III testing. This was developed at the NCI in collaboration with Bavarian Nordic Immunotherapeutics. It has demonstrated safety and survival benefit in a randomized phase 2 trial of metastatic castrate resistant prostate cancer (mCRPC). Enzalutamide is a modern androgen receptor inhibitor (ARI) approved for the treatment of mCRPC. Data from the clinical trials with these therapies suggest good individual tolerability without any overlapping toxicities. Analysis of previous trials suggests that vaccines may enhance clinical outcomes with ARI. These data form the scientific basis for a combination approach of a cancer vaccine with ARI to control tumor progression in mCRPC. Methods: A randomized, phase 2, open-label clinical trial at the NCI will enroll 72 chemo-naïve, minimally symptomatic patients with mCRPC. They will be randomized (1:1) to enzalutamide (160 mg daily) alone, or enzalutamide with PSA TRICOM for treatment until radiographic progression. PSA-TRICOM will be administered in a core phase (with day 1, 15 and 29 then 4 additional monthly boosts) followed by continued boosts every 3 months. The primary end point will evaluate time to progression in each arm with secondary endpoints including overall survival and systemic immune responses (lymphocyte subsets, regulatory T-cells, regulatory T-cell function, cytokines, naïve thymic emigrants). If a therapeutic cancer vaccine can enhance the clinical efficacy of a hormonal agent such as enzalutamide, it may help define a new role for vaccines as an adjuvant to standard therapies. We will also evaluate this combination in a second trial in non-metastatic, castration-sensitive patients where this combination may yield its greatest clinical impact.

TPS3127 Background: Saccharomyces cerevisiae has been genetically modified to express CEA protein and developed under a CRADA with GlobeImmune/NCI as a heat-killed immune-stimulating, therapeutic cancer vaccine (GI-6207). A phase I study with GI-6207 demonstrated safety, biomarker stabilization and enhanced immune response in some patients. CEA is over-expressed in multiple malignancies, including medullary thyroid cancer (MTC). Two therapies recently approved by the FDA for metastatic MTC (vandetanib, cabozantinib) come with toxicity and should be reserved for symptomatic/progressive disease. However, a large population of asymptomatic MTC patients has small tumor burden and/or disease that is more indolent. The standard management of these patients is observation. Preliminary data suggest that tumor growth measured by the rate of CEA and calcitonin increase can be quantified in a 3-6 months. Retrospective data from prostate cancer studies suggest vaccines can alter growth rates within 3-4 months. We hypothesize that GI-6207 can alter tumor growth rates in MTC and impact long-term outcome. Methods: A phase II study will evaluate the effect of GI-6207 onthe rates ofincrease in calcitonin in metastatic MTC. 34 patients with minimally symptomatic, radiographically evaluable, metastatic MTC will be randomized 1:1. Arm A will receive vaccine for a year from the time of enrollment. Arm B will receive vaccine after 6 months of surveillance. GI-6207 will be administered subcutaneously at 4 sites (10 yeast units/site), every 2 weeks for 3 months, then monthly up to 1 year. The primary endpoint will compare the effect of GI-6207 on calcitonin kinetics between the vaccine and surveillance arms in the first 6 months. Secondary endpoints include immunologic responses (including antigen-specific T cell responses), objective responses, time to progression, and changes in CEA kinetics. If this trial can prospectively demonstrate that vaccines can alter tumor growth rates, and if such changes are associated with clinical outcomes, then changes in tumor growth rates may become a clinical metric to evaluate vaccine efficacy in MTC and other populations.

e16036 Background: Recombinant (rec) poxviruses have been developed as therapeutic cancer vaccines. A multi-institutional, randomized phase II trial of poxviral vaccine, PROSTVAC-V/F, suggested an improvement in median overall survival in men with metastatic castration resistant prostate cancer. A phase III trial in this same population is accruing. Accumulating data suggest a favorable safety profile of the poxviral vaccines (vacs). Methods: We reviewed all vaccine injections (inj) from 297 patients (pts) in 9 clinical trials involving poxviral vaccines. Vacs consisted of rec vaccinia and rec fowlpox encoded with 3 human costimulatory molecules (TRICOM), and a) prostate specific antigen, or b) carcinoembryonic antigen +/-mucin-1. Vacs were administered at doses between 1.2x108 to 2x109 pfu, subcutaneously, in all pts. 21 pts were also vaccinated intra-tumorally. 84 pts received concurrent treatments, such as radiation, celecoxib, ipilimumab, samarium-153, or flutamide in 4 of these trials. All 9 trials involved granulocyte-macrophage colony-stimulating factor (GM-CSF), or rec fowlpox encoding GM-CSF as an immune adjuvant. We report the grade >=2 adverse events (AEs) at least possibly attributed to vaccine. Results: A total of 1,793 poxviral inj were given. 33% (593) of all inj were associated with grade >=2 vaccination emergent AEs. Of those, 25.3 % (454) were local inj site reactions; none serious. There was no contact transmission or inadvertent inoculation. One patient experienced grade 4 myocardial infarction and thrombotic thrombocytopenic purpura (TTP) reported as possibly related to vaccine. Below is the summary of AEs. Conclusions: Recombinant poxviral TRICOM vaccines appear safe and well tolerated at a broad range of doses, routes of administration and in combination with other treatments. Clinical trial information: NCT00081848, NCT00088413, NCT00060528, NCT00060528, NCT00078585, NCT00096551, NCT00113984. [Table: see text]

102 Background: A prior randomized, placebo-controlled, multi-center phase 2 trial of PSA-TRICOM demonstrated survival benefit. Sm-153 is a radiopharmaceutical that targets osteoblastic lesions. Preclinical data indicated that Sm-153 could alter tumor phenotype, causing upregulation of Fas, MHC Class I, and tumor-associated antigens, making tumor cells more amenable to immune-mediated killing. This trial was intended to examine the safety and efficacy of the Sm-153 with PSA-TRICOM vs. Sm-153 alone. Methods: This phase 2 multi-center trial was designed to randomize 68 pts to Sm-153 with or without PSA-TRICOM. Eligibility included mCRPC, bone metastases, no visceral disease, prior docetaxel, ECOG ≤2, and normal organ function. Sm-153 was given at 1mCi/kg IV on day 8 and then every 12 weeks. PSA-TRICOM was given on days 1, 15, 29, then every 4 weeks. The 1° endpoint was comparison of progression-free survival at 4 months (mo) utilizing PCCWG, but not PSA criteria. A Fisher’s exact test, assuming a one-tailed alpha = 0.10, was used to compare these fractions. 2° endpoints were OS, ORR, PSA changes, immunologic, and toxicity. Results: 44 pts were enrolled, 5 were not evaluable for the 1° endpoint due to withdrawal prior to 4 mos (4 on Arm A, 1 on Arm B). PFS and PSA findings are provided below. Hematologic toxicities were most common, and were well matched. Conclusions: This final analysis suggests the combination of PSA-TRICOM and Sm-153 has a similar toxicity profile to Sm-153 alone. Despite early closure of this trial due to poor accrual, which may be related to recent approval of multiple agents for mCRPC, this analysis appears to demonstrate improvement in PFS with the combination. This may indicate synergy between PSA-TRICOM and bone-seeking radiopharmaceuticals. Based on the data presented here, we are exploring the potential to combine PSA-TRICOM with alpharadin (radium-223), a next generation bone-seeking radiopharmaceutical. Clinical trial information: NCT00450619. [Table: see text]

85 Background: Recombinant poxviruses have been developed as therapeutic cancer vaccines. Here, we report the safety data from NCI clinical trials with poxviral vaccines. Methods: We evaluated all vaccine injections from 215 patients in 8 clinical trials involving poxviral viral vaccines. The Office of Biotechnology Activities, National Cancer Institute (NCI) Institutional Review Board, and NCI Scientific Review Committee approved all of these trials. Vaccines were consisted of recombinant vaccinia and recombinant fowlpox encoded with 3 human costimulatory molecules (TRICOM), and prostate specific antigen (PSA), or carcinoembryonic antigen, and/or mucin-1. Vaccines were administered at doses between 1.2x108 to 2x109 pfu, subcutaneously, in all patients. Twenty-one patients were also vaccinated intra-tumorally. 84 patients also received other concurrent treatment modalities, such as radiation, celecoxib, ipilimumab, samarium-153, or flutamide on 4 of these trials. All 8 clinical trials involved granulocyte-macrophage colony-stimulating factor (GM-CSF) 100mcg, or recombinant fowlpox encoding GM-CSF at 1x 108pfu as an immune adjuvant. Here, we report here the grade 2 or higher adverse events given at least a possible attribution to vaccine. Results: A total of 1,348 poxviral injections were given in 215 patients. No contact transmission, inadvertent inoculation, or any serious adverse events (AEs) related to vaccinia was observed. Below is the summary of proportion of vaccine administrations associated with specific AEs. Conclusions: These data demonstrate a favorable safety profile of the poxviral vaccines at a broad range of doses, routes of administration, in combination with other treatments, and in various tumor types. Clinical trial information: NCT00060528, NCT00096551, NCT00088413, NCT00081848, NCT00113984, NCT00450619, NCT00450463. [Table: see text]

2526 Background: A prior randomized, placebo-controlled, multi-center phase 2 trial of PSA-TRICOM (PROSTVAC) demonstrated an overall survival benefit. Sm-153 is a radiopharmaceutical that targets osteoblastic bone lesions. Preclinical data indicated that Sm-153 could alter tumor phenotype, causing upregulation of Fas, MHC Class I, and tumor-associated antigens, making tumor cells more amenable to immune-mediated killing. Methods: This is a phase 2 multi-center trial design intended to randomize 68 patients (pts) to Sm-153 with or without PROSTVAC. Eligibility included castrate resistant prostate cancer bone metastases, no visceral disease, prior docetaxel, ECOG ≤2, and normal organ function. Sm-153 was given at 1mCi/kg IV on day 8 and then every 12 weeks. PROSTVAC was given on days 1, 15, 29, then every 4 weeks. The 1° endpoint is a comparison of progression-free survival at 4 months (mo) utilizing PCCWG, but not PSA criteria. 68 patients will provide 80% power to detect a difference of 15% vs. 40% without progression at 4 mo with a one-tailed alpha = 0.10 assuming Fisher’s exact test comparing these fractions as the primary method of analysis. 2° endpoints are OS, ORR, PSA changes, immunologic, toxicity, and palliation. Reported here is the result of a pre-specified interim analysis, which required ≥20% conditional power to detect 15% vs. 40% without progression at 4 months for the trial to continue. Results: Of 37 enrolled pts, 3 were not evaluable for PFS. PFS and PSA findings are found below. Hematologic toxicities (anemia, thrombocytopenia, neutropenia, or lymphocytopenia) are most common, with grade 3 or 4 thrombocytopenia occurring in 22% and 26% of treatment cycles on Arms A and B, respectively. The conditional power for the comparison of fractions without progression at 4 mo is 77%. Conclusions: This interim analysis suggests the combination of PROSTVAC and Sm-153 is well tolerated with similar toxicity profile to Sm-153 alone. The early indication of improved TTP warrants continued study accrual. [Table: see text]

TPS4701 Background: In high-risk prostate cancer, radiation therapy (RT) + androgen deprivation therapy (ADT) improve survival. Nonetheless, 10-year disease specific mortality is about 25%. L-BLP25 is a cancer vaccine containing the BLP25 lipopeptide that targets MUC1 tumor antigen. It may enhance immune targeting of cells that express MUC1 (e.g. prostate cancer). In murine models, RT synergizes with vaccine-induced anti-cancer immunity (augments T-cell mediated cancer cytolysis, up-regulates cellular Fas and co-stimulatory/adhesion molecules). ADT augments T-cell trafficking to prostate. Immune response to combining the three (L-BLP25 + RT + ADT) is not known. The current trial intends to study this immune response to L-BLP25 + RT + ADT and compare it to RT+ADT alone. Using ELISPOT, endo-rectal MRI and serial prostate biopsies, this trial was designed to correlate systemic immune response with changes in tumor imaging and/or tumor microenvironment after treatment with L-BLP25. This trial may provide insight into immune response biomarkers that are most appropriate in this setting. Methods: A randomized (1:1), open-label, phase II trial of 42 pts is planned. Eligibility: Adult males with newly diagnosed high-risk prostate cancer (T3 or Gleason ≥ 8 or seminal vesicle involvement or N1 or PSA>20) and HLA-A2/A3 positivity (to allow for ELISPOT analysis). The vaccine arm will receive RT + 2-year ADT + L-BLP25. Standard arm will receive RT + 2-year ADT. L-BLP25 vaccine schedule: biweekly X 5 starting with neo-adjuvant ADT, then 6 weekly X 4 starting with RT. A single 300mg/m2 cyclophosphamide infusion (decreases suppressor T-cells) will be given 3 days before L-BLP25 to enhance immune response in the vaccine arm. The impact of L-BLP25 + RT+ADT on MUC-1-specific systemic immune response will be determined using interval peripheral blood ELISPOT assays. Endo-rectal coil MRI will be done before and after treatment to study prostate signal changes for correlative and predictive analysis. MRI-UltraSound guided lesion-targeted serial prostate biopsies will be obtained to assess immune response in tumor microenvironment. Two pts have been enrolled.

458 Background: Saccharomyces cerevisiae (yeast) has been genetically modified to express CEA protein and employed as a heat-killed immune-stimulating, vector-based vaccine. Preclinical studies have shown that yeast CEA vaccine can induce a strong CEA-specific T-cell immune response (IR) and anti-tumor activity. Methods: Patients (Pts) were enrolled in this phase I trial at 3 dose levels: 4, 16, and 40 yeast units (each unit =107 yeast particles). The vaccine was administered equally at 4 sites subcutaneously in bilateral inguinal and anterior chest wall regions. Vaccine was administered at 2 week intervals for 3 months, then monthly. Eligible pts were required to have a serum CEA > 5 ng/ml or > 20% CEA+ positive tumor block and no autoimmune history. An expansion cohort of 10 pts was enrolled to focus on IR. Pts had re-staging scans at 3 months, then bimonthly. Peripheral blood was collected for analysis of IR including the Effector/Regulatory T-cell ratio, ELISPOT assay, changes in the myeloid-derived suppressor cells (MDSC) and natural killer cells (NK). Results: 25 pts with progressive metastatic CEA-expressing carcinoma were enrolled; 22 had colorectal adenocarcinoma. Vaccine was well tolerated with no dose limiting toxicities. The most common adverse event was grade 1/2 injection site reaction. Overall, 7 patients had stabilization or declines in serum CEA after treatment. Of them, 5 pts (3 with colorectal cancer) had stable disease beyond 3 months and 1 is still on-going (14 +, 8, 8, 4.5 and 4 months). No anti-CEA antibodies were detected. Post vs. pre-vaccination: a) five out of 9 evaluable pts showed evidence by ELISPOT of CEA-specific T-cell IRs b) 8/16 pts had increased and 8/16 pts had decreased CD4 Effector/Treg ratio and c) 6/13 pts had increased and 2/13pts had decreased NK frequency. Conclusions: Saccharomyces cerevisiae-CEA demonstrated an acceptable safety profile. Although this is an advanced disease population of pts which is not ideal for immune-based therapy, CEA serum stabilizations and CEA-specific IRs were seen in some pts. Randomized studies are required to determine the clinical benefit of this vaccine in a more appropriate patient population for vaccine therapy.

2604 Background: Saccharomyces cerevisiae (yeast) were engineered to express human CEA protein and administered as a heat killed, whole yeast therapeutic vaccine. Preclinical studies have shown that these modified yeast can induce a strong immune response to CEA as well as antitumor responses in a CEA-transgenic host. Methods: Patients (pts) were enrolled in this classic phase I design at 3 dose levels: 4, 16, and 40 yeast units (each unit =107 yeast particles). The vaccine was administered in equal doses at 4 sites subcutaneously in bilateral inguinal and anterior chest wall regions. Vaccine was administered at 2 week intervals for 3 months, then monthly. Eligible patients were required to have a serum CEA > 5 ng/ml or >20% CEA+ positive tumor block, ECOG PS 0-2, and no autoimmune history. An expansion cohort of 10 ECOG PS 0-1 pts was enrolled to focus primarily on immune response at the 40 yeast unit dose. Pts had re-staging scans at 3 months, then bimonthly. Peripheral blood was collected for analysis ...

163 Background: PSA-TRICOM is a vector-based, therapeutic cancer vaccine regimen consisting of recombinant poxviruses containing the transgenes for prostate-specific antigen (PSA) and 3 T-cell co-stimulatory molecules (TRICOM). A previous randomized, placebo-controlled phase II study demonstrated an 8.5-month improvement in median survival (25.1 months for PSA-TRICOM group vs. 16.6 months for control group) in men with metastatic CRPC. Methods: This study is currently enrolling patients with non-metastatic CRPC on testosterone suppression therapy who have a rising PSA. Patients are stratified by PSA doubling time and randomized to androgen receptor antagonist alone (flutamide) or flutamide plus PSA-TRICOM. Flutamide is given at the standard dose of 400 mg TID while PSA-TRICOM is given by monthly subcutaneous injections. The primary endpoint of the study is time to treatment failure (TTF) which is defined as biochemical recurrence (PSA rise) or development of metastatic lesions on scans. Results: The first 26 patients enrolled are evaluated in this analysis. For flutamide alone (n = 13), the median age at enrollment was 64.7 years and median Gleason Score was 8. For flutamide + PSA-TRICOM (n = 13), the median age at enrollment was 67.1 years and median Gleason score was 8. Median time to progression is 223 days for Fluatmide + PSA- TRICOM (range 70-638) vs. 85 days for Flutamide alone (56-372). Progression for 11/12 flutamide alone patients and 9/10 fluatmide + PSA-TRICOM patients has been by PSA rise only. Conclusions: Preliminary evidence suggests improvement in time to treatment failure using combination of hormonal therapy with flutamide + PSA-TRICOM vaccine compared to fluatmide alone in patients with non-metastatic CRPC. This trial will continue to accrue a total of 62 patients and also will evaluate immunological responses. No significant financial relationships to disclose.

5144 Background: There are few treatment options for mCRPC pts. Immunotherapy + adjuvant immunomodulators is a promising modality. PSA-TRICOM V is composed of poxviral vectors encoding PSA and 3 costimulatory molecules (ICAM-I, LFA-3, and B7.1) and has clinical activity in mCRPC. Ipi blocks CTLA-4, a T-cell downregulatory receptor, has clinical activity in mCRPC as monotherapy and has also been shown to enhance anti-tumor responses in combination with V in preclinical studies. Methods: Pts received V and GM-CSF q 4 weeks in 4 sequential cohorts of escalating doses of ipi at 1, 3, 5, and 10 mg/kg (DL1–4 respectively). After 6 courses of ipi, pts could receive a maintenance dose q 3 months (mo) until progression. Results: Study accrual is complete with 30 pts. There was no DLT and no > G2 adverse event (AE) attributed to V. There were 20 ≥ G2 immune-related AE (irAE): 0/3, 2/6, 5/6 and 13/15 pts on DL1–4, respectively. There was no evidence of clinical benefit in the 6 pts who had prior chemo on DL1 and 2, so subsequently we excluded pts with prior chemo. Median TTP for 9 chemo-naïve pts treated on DL2 and 3 was 6.1 mo (2.9–11.6 mo). Median PSA doubling time (DT) ↑ from 2.2 mo at baseline to 3.7 on study (p = 0.17). 5 of 9 had ≥ 50% ↓ in PSA from peak during study and 1 had a sustained ↓ PSA > 95% from baseline. 4 of these pts had stable disease (SD) for ≥ 6 mo and 2 had unconfirmed partial responses by RECIST. Of the 15 pts on DL4, to date 9 have had SD for ≥ 6 mo (2 ≥ 12 mo); 4 remain on trial. 1 had a sustained ↓ in PSA > 99% from baseline and is still on study after 12 mo. Median PSA DT ↑ > 3-fold from 2.6 mo at baseline to 8.2 on study (p = 0.01) in DL4. The 24 chemo-naïve pts had PSA DT ↑ from 2.5 to 6 mo (p = 0.003). 14 of 30 pts had a PSA ↓ from baseline or peak PSA on study. 2 of 14 had no irAE, 12 showed ≥ G2 irAE temporally associated with PSA ↓. 5 of 9 pts had > 2–5 fold ↑ in T-cell responses by ELISPOT assay and 4 of 13 had significant ↓ in their IL-6 levels. Immune responses appeared to correlate with clinical activity. Conclusions: This combination has clinical activity in pts with chemo-naïve mCRPC and seems to correlate with immune responses. It is associated with manageable side effects; however, further studies are required to see if the combination is more effective than either agent alone. No significant financial relationships to disclose.

3035 Background: PANVAC (V) is a recombinant pox viral vaccine that targets the TAAs (tumor associated antigens) MUC1 and CEA. V also contains three T-cell co-stimulatory molecules (B7.1, LFA-3, IC...