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Patients receiving CD19 CAR T-cell therapy for relapsed/refractory lymphoma experience prolonged and profound B-cell aplasia and hypogammaglobulinemia, placing them at a higher risk for severe COVID-19. Independently, Oh et al and Atanackovic et al demonstrate that despite attenuated humoral response to mRNA-based vaccines, patients demonstrate normal or heightened functional T-cell responses, including antiviral T-cell activity against SARS-CoV-2 variants including Omicron. Collectively, these data reinforce the importance of COVID-19 vaccination following CD19 CAR T-cell therapy, despite long-term B-cell aplasia.

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

BackgroundSolid organ transplant recipients (SOTR), who typically receive post-transplant immunosuppression, show increased COVID-19-related mortality. It is unclear whether an additional dose of COVID-19 vaccines in SOTR can overcome the reduced immune responsiveness against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants.MethodsWe performed a prospective cohort study of 53 SOTR receiving SARS-CoV-2 vaccination into a prospective cohort study performing detailed immunoprofiling of humoral immune responses against SARS-CoV-2 and its variants.ResultsPrior to the additional vaccine dose, 60.3% of SOTR showed no measurable neutralization and only 18.9% demonstrated neutralizing activity of >90% following two vaccine doses. More intensive immunosuppression, antimetabolites in particular, negatively impacted antiviral immunity. While absolute IgG levels were lower in SOTR than controls, antibody titers against microbial recall antigens were in fact higher. In contrast, SOTR showed reduced vaccine-induced IgG/IgA antibody titers against SARS-CoV-2 and its delta variants. Vaccinated SOTR showed a markedly fewer linear B cell epitopes, indicating reduced B cell diversity. Importantly, a third vaccine dose led to an increase in anti-SARS-CoV-2 antibody titers and neutralizing activity across alpha, beta and delta variants. However, we observed a significant decrease in anti-spike antibody titers with the omicron variant.ConclusionsOnly a small subgroup of SOTR generated functionally relevant antibodies after completing the initial vaccine series based on dysfunctional priming of immune responses against novel antigens. An additional dose of the vaccine results in dramatically improved antibody responses against all SARS-CoV-2 variants except omicron.

PURPOSE/OBJECTIVE(S): Management of localized high-risk prostate cancer remains challenging. At our institution we performed a prospective Phase II study of 2 years of androgen deprivation therapy (ADT), pelvic radiation, Cesium (Cs)-131 brachytherapy boost, and adjuvant docetaxel in high risk, localized prostate cancer with a primary endpoint of 3-year disease-free survival. MATERIALS/METHODS: Acute/chronic hematologic, gastrointestinal (GI) and genitourinary (GU) toxicities were scored based on the CTCAE v3.0/RTOG-EORTC criteria, respectively. Actuarial biochemical recurrence free survival (bRFS), bRFSdisease free survival (DFS) and overall survival (OS) were calculated. Patients had a median age of 62 years (range 45–82), median Gleason score 8 (74% Gleason 8–10), median PSA of 11.2 (range 2.8–96), and 47% cT2-T3a stage disease. Androgen deprivation was given for two years, 45 Gy whole-pelvis IMRT was followed by an 85 Gy Cs-131 boost to the prostate gland, and adjuvant docetaxel was given for 4 cycles. RESULTS: Thirty eight patients enrolled from 2006–2014, with 82% completing protocol specified treatment, and 84.2% completing 4 cycles of docetaxel. Median follow-up for the entire and alive cohorts were 44 months and 58 months (range 3.4–118), respectively. Acute grade ≥ 2 GI and GU toxicity rates were 18.4% and 23.7%, respectively. Chronic grade ≥ 2 GI and GU toxicity rates were 2.6% and 2.6%, respectively. Twelve patients (31.6%) developed grade 4 hematologic toxicity, with no grade 5 toxicity. The 5-year DFS, bRFS and OS rates were 74.1%, 86.0% and 80.0%, respectively. CONCLUSION: This aggressive pilot multi-modal approach appears to be safe and well-tolerated, providing disease control in a significant proportion of patients with particularly high risk prostate cancer.

Patients after autologous (autoSCT) and allogeneic stem cell transplantation (alloSCT) are at an increased risk of COVID-19-related morbidity and mortality, compounded by an immune system weakened by the underlying malignancy and prior treatments. Allogeneic transplantation, including stem cell and solid organ transplants, requires intensive immunosuppressive prophylaxis, which may further undermine the development of a protective vaccine-induced anti-viral immunity. Herein, we report on short- and long-term antiviral immune responses in two peri-stem cell transplant recipients and a third patient who received a COVID-19 vaccination after kidney transplantation. Our data indicate that: (1) patients post-alloSCT may be able to mount an anti-COVID-19 immune response; however, a sufficient time interval between transplant and exposure may be of critical importance; (2) alloSCT recipients with preexisting anti-SARS-CoV-2 immunity are at risk for losing protective humoral immunity following transplantation, particularly if the stem-cell donor lacks antiviral immunity, e.g., vaccine-derived immunity; and (3) some post-transplant patients are completely unable to build an immune response to a COVID-19 vaccine, perhaps based on the prophylactic suppression of T cell immunity.

Key Points A severely immunocompromised patient with MM and COVID19 who received a convalescent plasma product showed SARS-CoV-2 clearance. The convalescent plasma showed humoral immunity against all structural SARS-CoV-2 proteins, which was successfully transferred to the patient.

This overview discusses several important developments in testicular germ cell tumors (TGCTs) over the past year.Genomic studies continue to investigate gene expression as possible markers for disease relapse and metastatic potential. Optimal treatment strategies for early-stage seminomas continue to evolve toward surveillance versus chemotherapy, although developing radiation delivery modalities may ultimately provide a safe alternative. The role of retroperitoneal lymph node dissection in postorchiectomy early-stage nonseminoma germ cell tumors remains a topic of debate.Treatment paradigms continue to be refined for TGCTs as research in these areas continues.

Lessons Learned The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC). The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. Background Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC). Methods This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events. Results The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm). Conclusion Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.

To discuss several important developments in the diagnosis, management, and risk stratification of testicular germ cell tumors (TGCTs) in the past year.Germ cell function and tumorigenesis may be influenced by exposure to a variety of agents, including metals and cannabinoids. Genome-wide association studies have identified variants in several genes that may produce susceptibility to the development of testicular malignancies, and expression of certain proteins predicts a poorer prognosis and may, thus, play a role in neoplastic progression. Retroperitoneal lymph node dissection continues to play a crucial role in definitive treatment of patients with nonseminoma germ cell tumor, whereas radiotherapy, as a standard treatment for early-stage seminoma, has been declining due both to the efficacy of platinum-based chemotherapy and to the increased risk of radiation-related secondary malignancies. Advanced and platinum-refractory disease states continue to be challenging entities in terms of optimizing therapy and outcome.Preclinical and clinical studies continue to enhance our insights into the complex biology of TGCTs, and are helping to further refine risk stratification and optimize treatment of patients with TGCTs.

Purpose of review To discuss several important developments in the diagnosis, management, and risk stratification of testicular germ cell tumors (TGCTs) in the past year. Recent findings Germ cell function and tumorigenesis may be influenced by exposure to a variety of agents, including metals and cannabinoids. Genome-wide association studies have identified variants in several genes that may produce susceptibility to the development of testicular malignancies, and expression of certain proteins predicts a poorer prognosis and may, thus, play a role in neoplastic progression. Retroperitoneal lymph node dissection continues to play a crucial role in definitive treatment of patients with nonseminoma germ cell tumor, whereas radiotherapy, as a standard treatment for early-stage seminoma, has been declining due both to the efficacy of platinum-based chemotherapy and to the increased risk of radiation-related secondary malignancies. Advanced and platinum-refractory disease states continue to be challenging entities in terms of optimizing therapy and outcome. Summary Preclinical and clinical studies continue to enhance our insights into the complex biology of TGCTs, and are helping to further refine risk stratification and optimize treatment of patients with TGCTs.

Purpose Weekly paclitaxel, concurrent radiation, and androgen deprivation (ADT) were evaluated in patients with high-risk prostate cancer (PC) with or without prior prostatectomy (RP). Methods and Materials Eligible post-RP patients included: pathological T3 disease, or rising prostate-specific antigen (PSA) ≥0.5 ng/mL post-RP. Eligible locally advanced PC (LAPC) patients included: 1) cT2b-4N0N+, M0; 2) Gleason score (GS) 8–10; 3) GS 7 + PSA 10–20 ng/mL; or 4) PSA 20–150 ng/mL. Treatment included ADT (4 or 24 months), weekly paclitaxel (40, 50, or 60 mg/m 2 /wk), and pelvic radiation therapy (total dose: RP=64.8 Gy; LAPC=70.2 Gy). Results Fifty-nine patients were enrolled (LAPC, n = 29; RP, n = 30; ADT 4 months, n = 29; 24 months, n = 30; whites n = 29, African Americans [AA], n = 28). Baseline characteristics (median [range]) were: age 67 (45–86 years), PSA 5.9 (0.1–92.1 ng/mL), GS 8 (6–9). At escalating doses of paclitaxel, 99%, 98%, and 95% of doses were given with radiation and ADT, respectively, with dose modifications required primarily in RP patients. No acute Grade 4 toxicities occurred. Grade 3 toxicities were diarrhea 15%, urinary urgency/incontinence 10%, tenesmus 5%, and leukopenia 3%. Median follow-up was 75.3 months (95% CI: 66.8–82.3). Biochemical progression occurred in 24 (41%) patients and clinical progression in 11 (19%) patients. The 5- and 7-year OS rates were 83% and 67%. There were no differences in OS between RP and LAPC, 4- and 24-month ADT, white and AA patient categories. Conclusions In addition to LAPC, to our knowledge, this is the first study to evaluate concurrent chemoradiation with ADT in high-risk RP patients. With a median follow-up of 75.3 months, this trial also represents the longest follow-up of patients treated with taxane-based chemotherapy with EBRT in high-risk prostate cancer. Concurrent ADT, radiation, and weekly paclitaxel at 40 mg/m 2 /week in RP patients and 60 mg/m 2 /week in LAPC patients is feasible and well-tolerated.

Excluding basal and squamous cell cancers of the skin, prostate cancer is the most common malignancy diagnosed in the United States. With increasing awareness and routine prostate-specific antigen testing, a remarkable migration in the clinical presentation of the disease has occurred in the past 20 years. An increasingly greater proportion of men are diagnosed with clinically organ-confined disease. In parallel, the incidence of men presenting with clinically bulky locoregional or metastatic disease has decreased. Despite the stage migration, when clinical and pathologic parameters are taken into account, a significant number of men with clinically localized prostate cancer do not have truly organ-confined disease. Such men might not to be cured with single modality, locally directed therapies. Thus, prostate cancer represents a disease spectrum with a number of biologic and clinical factors determining disease extent. An overview of some of these aspects of the disease is presented.

5079 Background: We report the long-term results of a prospective, Phase II study of 2 years androgen deprivation therapy (ADT), 45 Gy bone marrow sparing pelvic radiation (BMS-PR), Cs-131 brachytherapy boost (85 Gy), and 4 cycles of adjuvant docetaxel (75 mg/m2 q21d + prednisone) in high risk, localized prostate cancer. Methods: From2006-2014,38 patients were enrolled. Acute hematologic as well as acute and chronic gastrointestinal (GI) and genitourinary (GU) toxicities were scored based on the CTCAE v3.0 criteria. Biochemical recurrence was defined as a nadir + 2 rise in PSA. Actuarial freedom from PSA failure (bNED) and overall survival (OS) were calculated using SPSS v24. Median Gleason score was 8 (74% Gleason 8-10). Median PSA was 11.2 (range 2.8-96). Results: A total of 38 patients were enrolled on the trial. Median age was 62 years (range 45-82). 82% of patients completed all protocol specified treatments, while 84% completed all 4 cycles of docetaxel. After a median follow up of 44 mo (range 3.4-118), the 5-year bNED rate was 86% while 5-year OS was 80%. Acute grade ≥ 2 GI and GU toxicity rates were 12.5% and 21.9%, respectively. Chronic grade ≥ 2 GI and GU toxicity rates were 3.1% and 3.1%, respectively. 25.6% (n = 10) patients receiving docetaxel developed grade 4 hematologic toxicity. There were no grade 5 toxicities. Conclusions: We found this aggressive multi-modal approach to be feasible, safe, well-tolerated, and effective. It does not appear that BMS-PR decreases hematologic toxicity. Cs-131, with its 9.7 day half-life, does not appear to increase acute or late toxicity. These data build upon the ASCENDE-RT and RTOG 0521 trials that demonstrate the added benefits of brachytherapy boost and adjuvant docetaxel, respectively, in high-risk prostate cancer.

This overview discusses several important developments in testicular germ cell tumors in the past year.Genomic studies are examining gene expression as possible markers for disease relapse and chemotherapy resistance. Optimal posttreatment surveillance strategies continue to evolve. Retroperitoneal lymph node dissection remains a prominent treatment modality, although the sequencing and extent of surgical intervention is controversial. Platinum-based chemotherapy remains the gold standard for treatment of systemic disease. Poor risk, platinum-refractory and late relapse disease states continue to be challenging entities in terms of optimizing therapy and outcome.Significant challenges remain for treatment of certain categories of testicular germ cell tumors. Treatment and surveillance paradigms continue to be defined and refined as research in these areas continues.

Locally advanced prostate cancer encompasses several disease states that vary in the risk for progression and recurrence after Initials treatment. Further, the optimal treatment strategies for locally advanced prostate cancer are continuing to evolve, reflecting the complex nature of this disease state. For many patients, clinical experience demonstrates that a combined approach of locally directed therapy and systemic therapy is likely to provide better long-term outcome than singlemodality therapy. Randomized studies have established hormone ablation with external-beam radiation as an important form of treatment for this group of patients. However, additional progress needs to be made, particularly in the subgroup of patients with very high-risk disease features. As the optimal integration of local and systemic treatments becomes more clearly defined, the long-term prognosis for patients with high-risk locally advanced prostate cancer will improve.

Introduction: Thrombotic microangiopathy (TMA) is clinical syndrome characterized by microvascular thrombosis, consumptive thrombocytopenia and microangiopathic hemolytic anemia (MAHA). It is a feature of a number of clinical conditions, most prominently thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) and rarely an initial manifestation of systemic malignancy. Case: A previously healthy 31-year-old black woman presented to the emergency department with a 2 week history of lower back pain and hematuria and 1 week history of dyspnea on exertion and dizziness. She denied diarrhea, hematochezia, fever, or abdominal pain. Physical findings were unremarkable with normal blood pressure. Initial laboratory results revealed a white blood cell count of 4.4 x103/µL, hemoglobin of 4.4 g/dL, hematocrit 12.9%, platelets 43 x103/µL, absolute reticulocyte count 259.8 x103/µL, reticulocyte percentage 23.1%, haptoglobin 50 red blood cells per high powered field on microscopic urinalysis. Coombs test results were negative, the coagulation profile was normal, and peripheral blood smear revealed evidence of thrombocytopenia and MAHA (figure 1a). Diagnosis of TTP was made and treatment with daily therapeutic plasma exchange (TPE) was initiated. On hospital day 4, ADAMTS13 level drawn at diagnosis before initiation of plasma exchange returned at 94%, prompting further investigation as to the cause of her TMA. Serologic tests for hepatitis B & C virus, human immunodeficiency virus, antinuclear antibody (ANA), cardiolipin and beta-2 glycoprotein antibodies and computerized tomography (CT) scan of the abdomen and pelvis were all negative. Despite daily TPE for 6 days, she remained thrombocytopenic and continued to have ongoing hemolysis. Therefore, on hospital day 6, bone marrow aspiration and biopsy (figure 1b) was performed which showed a normocellular bone marrow for age (cellularity 70%) with full-spectrum trinlineage hematopoiesis, involved by metastatic signet-cell ring carcinoma. Immunostains were positive for CK7, CK20, CK 8/18, CDX2, pancytokeratin, and negative for PAX-8 and mammoglobin. TPE was discontinued and she was supported with packed red blood cell and platelet transfusions. Positron emission tomography–computed tomography (PET-CT) revealed a heterogeneously enhancing mass in the midline superior anterior wall of the bladder measuring 2.7 x 5.1 cm, but without abnormal uptake on PET. She underwent cystourethroscopy and a transurethral resection of bladder tumor which revealed a 6 cm solid sessile mass. Final pathology confirmed the diagnosis of moderate to poorly differentiated invasive urachal adenocarcinoma with mucinous and signet-ring cell features. Given the presence of metastatic disease, she was treated with a chemotherapy regimen consisting of cisplatin, fluorouracil, and leucovorin on days 1 through 5. Gemcitabine was held due to elevated liver transaminases. On day 1 of treatment, platelet count was 24 x103/µL and hemoglobin 8.1 g/dL. By treatment day 7, platelets had risen to 79 x103/µL. She last required a PRBC transfusion on treatment day 4. Discussion: TMA can occur in a variety of disorders, including TTP, HUS, malignant hypertension, scleroderma, antiphospholipid antibody syndrome, systemic lupus erythematosus, preeclampsia, HIV infection, and disseminated malignancy. Patients presenting with evidence of TMA and thrombocytopenia should elicit a high clinical suspicion for TTP and be urgently treated with plasma exchange. Deficiency of the von Willebrand factor-cleaving metalloproteinase ADAMTS13, or the presence of antibodies to ADAMTS13 plays a key role in the pathogenesis of primary TTP, although these findings are not necessary to make the diagnosis. However, patients with a high or normal ADAMTS13 level and without antibodies to ADAMTS13, especially those who do not improve with plasma exchange, should prompt an investigation for other causes of TMA. To our knowledge, we report the first case of metastatic urachal carcinoma presenting with features of MAHA and thrombocytopenia. Conclusion: TMA associated with malignancy is a rare, but potentially fatal condition. Recognition of this rare entity is critical to the initiation of appropriate treatment of underlying malignancy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

38 Background: Cediranib + Doc were shown in a phase I trial to be feasible, with early evidence for efficacy in mCRPC patients (pts). A multi-center randomized Phase II screening trial of Cediranib+Doc+Pred (Arm A) vs. Doc+Pred (Arm B) was initiated in mCRPC pts. Methods: mCRPC pts with no prior chemotherapy were eligible. All received Doc at 75 mg/m2IV q 3 weeks and Pred 5 mg po bid. Cycle length was 21 days. Arm A pts also received Cediranib at 30 mg po daily. The primary endpoint was 6-month progression-free survival (PFS). We hypothesized 6-month PFS rates of 0.70 on Arm A and 0.50 on Arm B. Secondary endpoints included toxicity, PSA response, and RECIST response. Here we report the toxicity and PSA response data. Results: Of 58 pts enrolled, 57 were treated (29 Arm A, 28 Arm B). Median age = 68 years (range 51-84); 33% African-American, 63% Caucasian; median baseline PSA136 ng/mL (range 0.12 – 3,650); 57% had Gleason grade 8-10; and 40% had both bone/ visceral disease. Median nadir PSA was 10.5 ng/mL (range 0.10 – 1,484) in Arm A, and 25.9 ng/mL (range 0.00 – 2,076) in Arm B. Median number of cycles (range): Arm A = 9 (0 - 31); Arm B = 6.5 (1-39 ). 68% pts in Arm A required a dose reduction of at least one Cediranib dose level. Doc dose was reduced in 45% pts on Arm A and in 18% pts on Arm B. Primary grade 4 toxicity was neutropenia (11 [38%] pts A; 5 [18%] pts B), which prompted Cediranib dose reduction. Grade 3 toxicities included fatigue (9 (31%) A, 1 (4%) B); hypertension (8 (28%) A, 1 (4%) B); anemia (6 (21%) A, 2 (7%) B); neutropenia (4 (14%) A; 6 (21%) B); diarrhea (3 (10%) A, 1 (4%) B); deep vein thrombosis (2 (7%) A, 1 (4%) B); and pulmonary embolism (1 (3%) A). An amendment reduced Cediranib to 20 mg daily dose. PSA decrease ≥ 90% at nadir occurred for 13/29 = 45% on Arm A, and 6/28 = 21% on Arm B. PSA decrease ≥ 50% at nadir occurred for 19/29 = 66% on Arm A, and 17/28 = 61% on Arm B. Clinical partial response rates were 8/15 = 53% on Arm A and 3/9 = 33% on Arm B. Conclusions: The addition of Cediranib to Doc/Pred has increased toxicity but may be associated with higher rates of PSA response and clinical response in mCRPC patients. PFS results will be reported. Clinical trial information: NCT00527124.

5122 Background: EBRT with ADT (4 mos to 2–3 yrs) is standard treatment for high risk PC. In this trial, we evaluated weekly P given concurrently with EBRT and ADT in high risk PC. Methods: For pts undergoing RP, high risk was defined as: pT3 and/or pN+, M0, and/or rising PSA (> 0.5) post RP. For pts not undergoing RP (i.e. locally advanced PC [LAPC]) high risk included: cT2b-4N0, N+, M0; bGS 8–10; bGS ≥ 7 + PSA ≥ 10 but ≤ 150; and/or PSA ≥ 20 but ≤ 150. Treatment included ADT (4 or 24 mos, preplanned based on clinical presentation), P (40, 50, or 60 mg/m2/wk) x 7 with EBRT, and whole pelvis EBRT 45 Gy with 19.8 Gy boost (total 64.8 Gy) to prostate bed in RP pts and 25.2 Gy boost (total 70.2 Gy) to prostate in LAPC pts. Results: Between October 1999 and December 2006, 59 pts (29 W, 28 AA) were enrolled (n = 29 LAPC, n = 30 RP); median age 67 yrs, median PSA at trial entry 5.9 (27.5 LAPC, 1.6 RP), median GS 8. Pts were enrolled at different weekly doses of P: 40 mg/m2 n = 10 pts; 50 mg/m2 n = 31 pts; 60 mg/m2 n = 18 pts. ADT for 4 mos was given in 29 pts and for 24 mos in 30 pts. At 40 mg/m2 67/70 (96%), 50 mg/m2 202/217 (93%), and 60 mg/m2 98/126 (78%) planned doses of P were given. There were no acute grade 4 toxicities. Most common grade 3 toxicities were diarrhea 15%, urinary urgency or incontinence 10%, tenesmus 5%, and leukopenia 3%. Median duration of f/u was 75.3 mos, OS 78%, biochemical progression 24/59 (41%) pts, clinical progression 11/59 (19%) pts. Time to biochemical progression was similar between RP vs. LAPC (p = 0.17), between ADT 4 mos vs. 24 mos (p = 0.61), and between AA vs. W (p = 0.54). Conclusions: This trial establishes the feasibility of tri-modality therapy with ADT, EBRT and weekly paclitaxel in high risk PC, both in RP pts and in LAPC pts with intact prostate glands. The maximum tolerated dose of paclitaxel is 50 mg/m2 /wk when given weekly with concurrent radiation to the pelvis and hormone ablation. No significant financial relationships to disclose.

4665 Background: With the need to identify more active combination chemotherapy regimens in PC, and demonstrated pharmacokinetic synergism between Doxo and Doce, each of which has known single agen...

4765 Background: For PC pts with PSA failure after surgery (RP) and/or XRT no standard treatments are established. An approach being piloted by our group is to give chemotherapy first, then HA. We report phase I results of an ongoing phase I/II trial of weekly Doxo/Doce followed by HA in such pts. Methods: Pts with histologically documented PC with rising PSA post RP, XRT were eligible. PSA had to be > 4 ng/ml with serum testosterone (T) in non-castrate range at entry. Positive bone scans, CT scans were not an exclusion criteria. Treatment is: weekly Doxo/Doce x 4 cycles (each cycle: Doxo d1, 8, 15 IVP; Doce d1, 8, 15 IV over 30 min, q 28 d) followed by LHRH agonist + Bicalutamide 50 mg/d x 1 yr. Two dose levels of Doxo (cohort 1: 15 mg/m2 d1, 8, 15; cohort 2: 20 mg/m2 d1, 8, 15) with fixed dose Doce (30 mg/m2 d1, 8, 15) were used. Results: 16 pts have been enrolled. Baseline characteristics (medians): age 62.5 y, PSA 19.05 ng/ml, GS 7, serum T 409 ng/dl; Baseline imaging: + bone scans 4, + CT 2. 11 pts c...