bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraprostatic vaccine administration in patients with locally recurrent prostate cancer.
Authors: Heery C. , Pinto P. A. , Schlom J. , Tsang K. Y. , Madan R. A. , Poole D. , Vergati M. , Walter Rodriguez B. , Merino M. , Gulley J. L.
Published: February 2017

141

Background: PSA-TRICOM is a cancer vaccine consisting of recombinant poxviruses with transgenes for PSA and 3 T cell costimulatory molecules (TRICOM). A multicenter randomized vector controlled phase II study showed an 8.5 month improvement in median survival in men with metastatic CRPC. Preclinical studies showed intratumoral administration of TRICOM vaccines may improve anti-tumor outcomes. This study was intended to show safety of intraprostatic (i.p.) vaccine administration. 2° goals included immunologic and tumor response.

Methods: 21 pts were enrolled with locally recurrent prostate cancer after radiation into 5 cohorts and received initial vaccination with s.c. recombinant vaccinia (rV)-PSA-TRICOM and booster i.p. recombinant fowlpox (rF)-PSA-TRICOM. Cohorts 3-5 also received i.p. rF-GM-CSF. Cohort 5 received concurrent s.c. and i.p. boosters. Priming was given on day 1, and boosters were given on days 29, 57, and 85. Pts had pre- and post-treatment prostate biopsies. Tumor infiltrate was evaluated when adequate tissue was available. PBMCs were analyzed by ELISPOT for response to PSA and 3-color flow cytometry to characterize regulatory T cells (Treg) or effector T cells. Treg suppression function was assayed by suppression of the CD4+ effector T cell proliferation.

Results: Only 1 grade 3 toxicity occurred, a transient fever. Most common grade 2 adverse events for all doses were fever (14.5%) and injection-site reactions (21%). 15 of 21 pts had stable or improved PSA on study, and 16 of 21 pts had stable or improved PSA doubling time. Post-vaccination, 4 of 8 evaluable pts had immunological response by ELISPOT assay and 11 of 15 pts had decreased (n=8) or stable (n=3) Treg function. A paired t-test of 13 biopsies pre- and post- vaccination showed significant increases in immune infiltrates within tumors after vaccination. CD4+ cells increased from 1.3 → 13.1/high power field (hpf). CD8+ cells rose from 6.4 → 14/hpf.

Conclusions: I.p. administration of PSA-TRICOM is safe, feasible and can generate a substantial immunologic response. Improved PSA kinetics and intense post-vaccination immune infiltrates were seen in the majority of pts. Trials of i.p. PSA-TRICOM examining clinical endpoints are warranted.

No significant financial relationships to disclose.
Neoadjuvant trial of sunitinib malate and androgen ablation (ADT) in patients with localized prostate cancer (PCa) at high risk for recurrence.
Authors: Zurita A. J. , Ward J. F. , Araujo J. C. , Pettaway C. A. , Dieringer P. , Wang X. , Troncoso P. , Logothetis C.
Published: February 2017

143

Background: Presurgical ADT does not improve long-term outcomes in patients (pts) with high-risk localized PCa. Since the VEGF and PDGF signaling pathways have been implicated in PCa progression, and ADT results in endothelial cell apoptosis in the prostate by a VEGF-mediated mechanism, we hypothesized that combined treatment with sunitinib malate (SU), an oral inhibitor of the tyrosine kinases of VEGFR and PDGFR, might improve the efficacy of ADT in this pt population.

Methods: Pts with no radiological evidence of metastases and either PCa ≥ clinical (c)T3 disease or Gleason grade 8-10 or serum prostate-specific antigen (PSA) ≥ 20 ng/mL or cT2b-c and Gleason 7 and PSA ≥10 ng/mL (AJCC, 1992), received i.m. leuprolide and oral SU for three 30-day cycles followed by surgery. SU was administered continuously at 37.5 mg daily (25 mg daily in the initial 6 pts). The primary endpoint of this phase II trial was rate of pathologic complete response (pCR). Secondary endpoints included safety and time to progression (TTP). Unresectable pelvic nodal disease, confirmed post-operative PSA ≥ 0.2 ng/mL, or administration of post-operative radiation or ADT, defined treatment failure.

Results: Forty-four pts completed accrual, with a median age of 58 years (range 47-72); 34 Caucasian, 5 African-American, 4 Hispanic, and 1 Indian. High-risk criteria included cT3 (24/44), Gleason 8-10 (30/44), PSA ≥ 20 ng/mL (16/44). Two men were ineligible/declined therapy and one postponed surgery. No grade 4 toxicities or related discontinuations were observed. Thirty-five pts completed 3 months on 37.5 mg daily SU plus ADT and surgery with no unexpected complications. Of these, 2 pts experienced a pCR. Twenty (57%) pts have failed treatment or died, with a median TTP 27 months (95% CI: 12 – not estimable). The median follow-up of the remaining event-free pts is 35 months (range 23-41).

Conclusions: The 3-months preoperative combination of SU and ADT is safe and well tolerated in pts with high-risk primary PCa. We observed 2 complete remissions in 35 patients. Ongoing characterization of molecular changes in the epithelial and stromal compartments will help understand the mechanisms of SU activity in PCa.

[Table: see text]
Phase II trial of combination therapy with intravenous bevacizumab (B), oral satraplatin (S), and prednisone (P) in docetaxel-pretreated (DP) metastatic castrate-resistant prostate cancer (CRPC).
Authors: Vaishampayan U. N. , Heilbrun L. K. , Dickow B. , Heath E. I. , Smith D. W. , Baranowski K. , Cher M. L. , Powell I. , Pontes J. E. , Fontana J. A.
Published: February 2017

152

Background: Satraplatin is an oral platinum that has demonstrated efficacy and tolerability in metastatic CRPC. Bevacizumab has revealed safety and efficacy in advanced prostate cancer, and synergy was noted between platinum based chemotherapy and B.

Methods: Primary endpoint was time to progression (TTP). Latter wasdefined per RECIST 1.0 or onset of a skeletal event, or > 2 new areas of bone metastases. DP metastatic CRPC patients were eligible. S 80mg/m2 orally on days 1-5, P 5 mg twice daily, and B 10mg/kg on day 1, and 15mg/kg on day 15 were administered in 35 day cycles.

Results: 31 patients enrolled (13 African American and 18 Caucasian) to complete accrual. Median age was 67 years (range 50-85 years) and 21 patients (68%) were > 65 years of age. Median pretherapy PSA was 180.7 ng/ml (range 4.7-1,433 ng/ml). 21 (68%) had bone pain, Gleason score was > 8 in 20 (65%) patients. Pretherapy 12 patients had measurable disease progression, 17 (55%) had bone scan progression, and 8 had PSA only progression. 176 cycles have been administered; median 4 cycles (range 0-12 cycles). Grade 4 toxicities noted were, pulmonary embolism in 2 patients and thrombocytopenia in 1 patient. Grade 3 toxicities observed were neutropenia and hypertension in 3, anemia in 7 and , thrombocytopenia and diarrhea in 2 patients each. No treatment related deaths. 29 patients are response evaluable to date; 10 (34%) had a ≥30% PSA decline and 3 (10%) had a > 90% PSA decline. Of 12 patients with MD, 2 had a response and 7 had stable disease. Median TTP was 7.4 months (90% CI 4.8-12.8 months) and median survival was 11.2 months (90% CI 9.1-18.3 months). 47% of patients were alive at 12 months. Genotype characterization for excision repair cross-complementation group 1 (ERCC1) polymorphism was performed in 17 patients with 9 having homozygous (CC), 3 with heterozygous, (CT) and 2 patients with absence of ERCC expression respectively.

Conclusions: The combination was tolerable and revealed promising efficacy in metastatic CRPC. ERCC1 testing will be correlated with outcome endpoints. Supported in part by Genentech Inc and GPC Biotech.

[Table: see text]
Encouraging activity of bicalutamide and everolimus in castration-resistant prostate cancer (CRPC): Early results from a phase II clinical trial.
Authors: Pan C. , Ghosh P. , Lara P. , Robles D. , Beckett L. , de Vere White R.
Published: February 2017

157

Background: Multiple signaling pathways are involved in the development of CRPC. We previously showed that the mTOR pathway is activated in CRPC cell lines while inhibition of this pathway results in upregulation of androgen receptor (AR) signaling (Wang et al, Oncogene. 2008). Simultaneous blockade of the mTOR and AR pathways synergize in inducing PCa cell death and delaying tumor formation in mouse models. We hypothesize that simultaneous blockade of the AR and mTOR pathways in CRPC patients with bicalutamide and everolimus will result in improved efficacy compared to bicalutamide alone.

Methods: A phase II clinical trial with a lead-in safety phase was designed to determine the efficacy and tolerability of the bicalutamide and everolimus combination in CRPC patients compared with bicalutamide alone. Patients must have histologically confirmed disease and demonstrated disease progression (either by PSA or radiographically) while on androgen deprivation therapy. At the lead-in phase, all patients receive both agents. At the phase II stage, patients are randomized to bicalutamide +/− everolimus. The primary endpoint is PSA response. The second endpoints include progression-free survival, time-to-treatment failure, overall survival and toxicity. Here, we report the results of the lead-in phase.

Results: Eight patients were recruited at the lead-in phase. The bicalutamide/everolimus combination was well tolerated with no unexpected toxicities. Six of 8 patients have had PSA response after at least 8 weeks of therapy and the remaining two patients had stable PSA response. The median time to disease progression was 6.8 months. Nine patients have been recruited at the phase II stage so far. This clinical trial is being subcontracting to the other sites of the California Cancer Consortium. Tumor and blood specimens are being collected for molecular correlative studies of mTOR pathway markers.

Conclusions: The rational combination of bicalutamide and everolimus appears to have promising anti-tumor activity and an acceptable toxicity profile. The randomized phase of the clinical trial is currently ongoing and will be reported. Supported by Novartis.

[Table: see text]
The effect of PSA doubling time (PSADT) and Gleason score on the PSA at the time of initial metastasis in men with biochemical recurrence after prostatectomy.
Authors: Antonarakis E. S. , Keizman D. , Carducci M. A. , Eisenberger M. A.
Published: February 2017

16

Background: We previously reported on a cohort of men with biochemical recurrence after prostatectomy (n=430) who underwent observation until metastatic progression. Here, we describe the PSA at metastasis for those patients who developed metastatic disease.

Methods: PSA at metastasis was defined as the PSA value collected at the time of the first occurrence of metastasis as determined by CT or bone scan. We calculated the median PSA at metastasis and the interquartile range (IQR) for the entire cohort of men with metastatic progression, and also across different strata of PSADT (≤3 vs 3-9 vs 9-15 vs ≥15 mo) and Gleason score (≤7 vs 8-10). We used Pearson's correlation coefficient (r) to examine the relationship between PSADT or Gleason score and PSA at metastasis.

Results: With a median follow-up of 4 years after biochemical recurrence, 126/430 men (29.3%) had developed metastases. Sites of first metastasis included bone in 114 men (90.5%), extra-pelvic lymph nodes in 5 men (4.0%), lung in 3 men (2.4%), liver in 3 men (2.4%), and brain in 1 man (0.8%). The median PSA at the time of initial metastasis was 31.4 ng/mL (IQR, 8.8–87.5). Median PSA at metastasis across different PSADT strata is shown below (Table). There was a weak but statistically significant correlation between PSADT and 1/PSA at metastasis (r=0.20, P=0.02). There was no correlation between Gleason score and PSA at metastasis (r=0.01, P=0.83). Median PSA at metastasis was 30.3 ng/mL (IQR, 8.6–74.9) for men with Gleason ≤7 (n=69) and 34 ng/mL (IQR, 7.9–115) for men with Gleason 8-10 (n=57).

Conclusions: In patients with biochemical recurrence after prostatectomy, there is an inverse correlation between PSADT and PSA at metastasis, while Gleason sum has no effect on PSA at metastasis. These data may be used by clinicians to estimate at what PSA level metastases are likely to first develop across different strata of PSADT, helping to determine when/if to initiate therapy.

[Table: see text]

No significant financial relationships to disclose.
Phase II study of maintenance therapy with temsirolimus (TEM) after response to first-line docetaxel (TAX) chemotherapy in castration-resistant prostate cancer (CRPC).
Authors: Emmenegger U. , Berry S. R. , Booth C. , Sridhar S. S. , Winquist E. , Bandali N. , Chow A. , Kerbel R. S. , Ko Y.
Published: February 2017

160

Background: TAX is the standard first-line chemotherapy for CRPC. However, a number of questions remain regarding the optimal use of TAX following maximal response. Aside from intermittent TAX, maintenance therapy with well-tolerated agents such as the mTOR inhibitor TEM could be one strategy to prolong treatment response and the chemotherapy-free interval, without significantly compromising quality of life. In fact, the mTOR pathway is involved in many aspects of CRPC, and mTOR inhibitors have demonstrated significant anti-CRPC activity in preclinical testing.

Methods: CRPC pts eligible for this single-arm, multicenter phase II trial must have received between 6 to 8 cycles of first-line TAX (75 mg/m2 q3wks) with documented treatment response by PSA (>50% decline from baseline) or RECIST criteria. 30 pts will be enrolled and administered weekly TEM (25 mg iv × 4/cycle). The primary endpoint is time to treatment failure (TTF, by RECIST or symptomatic progression). Secondary endpoints include safety (NCI-CTCAE v3.0), quality of life (FACT-P, PPI), changes in PSA doubling time and time to PSA progression, objective tumor response rate (RECIST), and overall survival. We will also study correlative endpoints using plasma and peripheral blood mononuclear cells (i.e., markers of mTOR inhibition, of antiangiogenic TEM effects and of intratumoral hypoxia/acidosis, the latter as potential predictive markers).

Results: 10 pts have been enrolled to date: mean age 68 (range 52-80), prior definitive local therapy (7)—radiation (6), prostatectomy (1), mean PSA at entry 99.28 (2.3- 380.7), ECOG 0 (4) or 1 (6), prior cycles of TAX 6 (6) or 8 (4), sites of metastasis—bone (8), lymph nodes (4), visceral (3). 6 pts have been discontinued due to treatment failure after a mean of 5.3±1.9 cycles (range 3-8) - RECIST (1), symptomatic (2), combined (3). 4 pts are on cycle 1-2-8-9, respectively. TEM has been generally well tolerated without unexpected side-effects, but may have contributed to worsening lymphedema in 1 pt.

Conclusions: TEM maintenance therapy in CRPC pts that have responded to first-line TAX is well tolerated and appears to result in meaningful TTF.

No significant financial relationships to disclose.
Modulating autophagy using hydroxychloroquine (HCQ) in patients with hormone-dependent PSA progression after local therapy for prostate cancer (PC).
Authors: McCarthy T. , Mayer T. M. , Stein M. N. , Anand M. , Collins F. , Jeyamohan C. , Metzger D. , Moore D. , White E. , DiPaola R. S.
Published: February 2017

164

Background: Autophagy is conserved, genetically controlled catabolic response to starvation and stress whereby cells self- digest intracellular proteins and organelles by targeting them for degradation in lysosomes to generate energy and mitigate damage, thereby supporting cancer cell survival. We hypothesized that HCQ, by blocking autophagy, would slow PC growth.

Methods: Pts had rising PSA after primary therapy for PC, no radiographic evidence of metastasis, no (neo)adjuvant ADT within 3 months of enrollment and testosterone > 150 ng/dL. HCQ was dosed at 400 mg/day (cohort 1) or 600 mg/day (cohort 2). Endpoints were PSA response (defined as a change in slope of PSA rise by at least 25%, when log (PSA) is plotted vs. time) and assessment of safety and tolerability. Levels of p62 (which accumulates upon autophagy inhibition) and accumulation of autophagosomes (measured by EM) were assessed in blood mononuclear cells.

Results: 38 pts (35 cohort 1; 3 cohort 2) of planned 64 pts with median age 65 (52-81), Gleason scores: 5 (5%), 6 (18%), 7 (55%), 8 (8%), 9 (13%) have been accrued. 30 pts have completed 6 cycles of therapy and 2 pts have completed 4 cycles of HCQ. 14/32 (44%) pts included in the analysis had a decrease in doubling time after treatment. 2 (6%) had declining PSA. Treatment was well tolerated, with grade 1 rash (10%), grade 1 nausea (10%) and grade 1 diarrhea (20%) being the predominant side effects noted. 3 pts had grade 2 toxicities (rash and diarrhea). There were no grade 3/4 toxicities. EM and p62 was assessed in 12 and 20 pts, respectively, and showed evidence of mitochondrial dysfunction and p62 accumulation.

Conclusions: HCQ 400 mg/day appears to have some activity in PSA progression after localized therapy with minimal toxicity. Evaluation with higher doses of HCQ is ongoing. Assessing markers of autophagy including EM and p62 are feasible in pts and will require further validation in larger trials.

No significant financial relationships to disclose.
Multiple rechallenges (ReCs) with docetaxel (DOC) as an option after first-line therapy in patients (pts) with castration-resistant prostate cancer (CRPC).
Authors: Caffo O. , Brugnara S. , Caldara A. , Ferro A. , Frisinghelli M. , Murgia V. , Soini B. , Valduga F. , Veccia A. , Galligioni E.
Published: February 2017

165

Background: Responder pts to first-line DOC, who have stopped the treatment in absence of progression, usually experience a disease progression within few months. In recent years, ReC with DOC has emerged as a therapeutic option for these pts, able to achieve again a response. The available data usually report on the clinical outcome of pts who have received one or two ReCs, but it is unclear whether more ReCs may be offered to these pts and if there is a maximum number of affordable ReCs.

Methods: We retrospectively reviewed the clinical record of the pts with CRPC treated in our Department with DOC from March, 2002 to September, 2010. We selected pts who received multiple ReCs until the appearance of a true resistance to DOC: we consider as DOC-resistant pts showing a clinical and/or biochemical progression during DOC treatment.

Results: We have identified a consecutive series of 26 pts, who have received a median number of 2 ReCs (range 2- 6). The median age was 68 yrs (range 58-82 yrs). The ReC consisted of DOC q 3 wks in 7 cases, DOC + estramustine q 3 wks in 38, weekly DOC + estramustine in 23. Multiple ReCs were well tolerated with no more than grade 1 hematological and non-hematological toxicities. To date, 11 pts are still DOC-sensitive (after 2-6 ReCs, median 2) and are receiving ReCs or are in the off-therapy period after ReCs. After a median follow-up of 30 months, 14 pts are dead and 12 alive. The median survival is 40 mos and the projected 3-years overall survival is 54%.

Conclusions: In our experience multiple DOC ReCs may be administered in DOC-sensitive pts with CRPC. This may provide a long-term disease control with remarkable survival rate compared to those of DOC pivotal studies (19 mos) and a second line treatment may be retarded until the appearance of a true DOC-resistance.

[Table: see text]

No significant financial relationships to disclose.
Correlation of serum cytokines with clinical responses in patients treated with BPX-101, a drug-activated vaccine for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Spencer D. M. , Lapteva N. , Levitt J. M. , Seethammagari M. , Sonpavde G. , McMannis J. D. , Bai Y. , Bull J. M. , Slawin K. M.
Published: February 2017

167

Background: We report the correlation of clinical and immune monitoring results for subjects enrolled in a phase I/IIa clinical trial of BPX-101, a drug-activated dendritic cell vaccine for mCRPC.

Methods: Men with progressive mCRPC were enrolled in a 3+3 dose escalation trial evaluating BPX-101 and activating agent AP1903. BPX-101 was administered intradermally every 2 weeks for 6 doses, during the induction phase, and for non-progressing patients, every 8 weeks for up to 5 doses during the maintenance phase. AP1903 (0.4 mg/kg) was infused 24 hours after each BPX-101 dose. Blood samples for immune monitoring were collected weekly during the induction phase, and before and one week after each maintenance dose. GM-CSF, TNF-α, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, and RANTES levels were measured by Luminex microspheres, and IL-6 by ELISA.

Results: Planned enrollment of 12 subjects is complete, including 3 each at 4 × 106 and 12.5 × 106 cells/dose, and 6 at 25 x 106 cells/dose. A pattern of spiking levels of serum cytokines one week after each dose, returning to baseline the following week, was observed in subjects with greater disease burden. In one low dose subject who experienced a PR after one year on study, panel cytokines spiked 4-fold on average after each induction phase dose, less than 2-fold after the first two boosters, and between 6-fold and 56-fold after the final three boosters. IL-6, which had declined during the induction phase to below 1 pg/mL through two boosters, spiked between 1,680-fold and 13,000-fold after each of the last three boosters. In a second, high dose subject (#1008), who experienced a near CR of multiple lung metastases with otherwise stable disease, panel cytokines spiked 150-fold on average during the induction phase. In both cases, TNF-α, MIP-1α and MIP-1β spiked the most, including a more than 1,000-fold average spike in TNF-α for subject 1008. Cytokine spikes were not associated with AEs.

Conclusions: BPX-101 induces a spiking pattern of cytokine elevations after each dose. In patients who experienced measurable disease reductions, more dramatic spikes in serum inflammatory cytokine levels were seen.

[Table: see text]
Phase I study of at-101 (R-(-)-gossypol) in combination with paclitaxel (P) and carboplatin (C) in solid tumors including castrate-resistant prostate cancer (CRPC).
Authors: Zhao Y. , Gounder M. , Lin H. , Harris Addo K. , Taber Levinson K. , LaRosiliere M. , Goodin S. , Moss R. A. , Tan A. R. , Stein M. N.
Published: February 2017

169

Background: The combination of paclitaxel (P) and carboplatin (C) has broad anti-tumor activity in multiple tumor types including prostate and bladder cancer. Overexpression of Bcl-2 is a common mechanism of resistance to cytotoxic chemotherapy. AT-101 is an oral inhibitor of Bcl- 2-family-anti-apoptotic proteins. We conducted a phase I study of the combination of AT-101, P and C.

Methods: Ph I study in pts with refractory solid tumors, ECOG 0-1, using a standard 3+3 design to evaluate safety, tolerability and pharmacokinetics/pharmacodynamics (PK/PD). AT-101 was administered orally on Days 1-3 Q12 hr. P and C were administered intravenously on day 1 every 21 days. Dosing levels (DL) were 1: AT-101 40 mg BID, P 150mg/m2, C AUC 5; and DL 2: AT-101 40 mg BID, P 175/m2, C AUC 6. 12 additional pts treated at the MTD dose level were divided into two groups – with AT-101 omitted in the morning of C1D1 or C2D1 to assess apoptotic markers during P and C chemotherapy with and without AT-101.

Results: 24 pts (CRPC-11, colon-3, breast-3 melanoma-2, penile-1, esophageal adeno-1, thymus adeno-1, bladder neuroendocrine-1, NSCLC-1) with median age of 61.5 were enrolled. 6 pts were treated in DL1, and 18 in DL2 (the MTD). Dose limiting toxicities were G3 abdominal pain (1 pt, DL1) and G3 ALT (1pt, DL2). Common G1/G2 AEs were nausea, vomiting, fatigue, anorexia and neutropenia. 4 pts had dose reductions after cycle 1 due to AEs. 12 pts had GCSF added after C1 due to neutropenia. 4/11 (36%) pts with CRPC (all previously treated with docetaxel) had PSA declines of ≥50% and 4 pts had stable disease from 4 to 14 cycles. 2 pts with CRPC had a PR by RECIST. Additionally, 1 pt with esophageal CA had a CR and 1 pt with NSCLC had a PR. PK analysis demonstrated P PK was not influenced by co- administration of C and AT-101 when compared with historical reports (Siddiqui BJC 1997). The PK of AT-101 was not altered significantly by the P dose levels.

Conclusions: The addition of AT-101 to PC chemotherapy is well tolerated and clinically active in advanced cancer pts. The combination of AT-101 and PC may be appropriate for further study in pts with chemorefractory CRPC.

No significant financial relationships to disclose.
Phase I dose-escalation trial of tremelimumab in combination with bicalutamide in patients with recurrent prostate cancer.
Authors: Lang J. M. , Staab M. J. , Liu G. , Wilding G. , McNeel D. G.
Published: February 2017

174

Background: Antibodies targeting CTLA-4 have demonstrated anti-tumor efficacy in human clinical trials. The mechanism of this effect is presumably in part mediated by the expansion of tumor-specific T cells. Androgen deprivation (AD), the cornerstone of treatment for patients with metastatic prostate cancer, has been demonstrated to cause prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with AD, followed by an anti-CTLA-4 antibody, could have benefit by augmenting a tumor-specific immune response elicited with AD. We report the initial results from the dose-escalation portion of a phase I trial evaluating tremelimumab in combination with high-dose bicalutamide.

Methods: Eligible patients were those with clinical stage D0 prostate cancer (rising serum PSA but no evidence of metastatic disease). Subjects were treated in two courses, 3 months apart, in which they received bicalutamide 150 mg daily for 28 days and tremelimumab on day 29. Patients were treated in cohorts of six, defined by tremelimumab dose (3 mg/kg, 6 mg/kg, 10 mg/kg, 15 mg/kg). The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose (MTD).

Results: Eleven patients were enrolled and completed the dose-escalation portion of the trial and at least one year of follow up. Dose-limiting toxicities (DLTs) were observed in 2/5 subjects treated at 6 mg/kg, and included grade 3 diarrhea and a grade 3 skin rash. One of six subjects treated at 3 mg/kg tremelimumab required hospitalization for colitis. No other grade 3 or grade 4 events were observed. Common grade 1/2 events included fatigue, hot flashes, diarrhea, abdominal discomfort, rash, pruritis, and gynecomastia. Two patients experienced a prolongation in PSA doubling time detectable months after completing treatment.

Conclusions: Tremelimumab, administered at 3 mg/kg every 3 months in combination with AD, was found to be the MTD and with reasonable safety in this population. The identification of patients with prolonged stable disease following treatment suggests that future studies could explore repetitive administration of this combination.

[Table: see text]
ECF chemotherapy for liver metastases due to castration-resistant prostate cancer (mCRPC).
Authors: Gupta S. , Potvin K. R. , Whiston F. , Winquist E.
Published: February 2017

175

Background: Although 45% of mCRPC patients (pts) achieve prostatic-specific antigen (PSA) response with docetaxel, the objective response rate (ORR) is only 12% (Tannock 2004). Liver metastatic CRPC is uncommon and associated with shorter survival (Armstrong 2010). More active treatment might benefit these pts. ECF is highly active in gastric cancer (Findlay 1994) and response was reported in 3 of 5 liver mCRPC pts (Chao 1997). ECF has been used selectively for mCRPC pts at our centre and we retrospectively reviewed our results in pts with liver metastases with the primary objective of determining its antitumor activity.

Methods: Patients with mCRPC who received ECF were identified from electronic databases. ECF (epirubicin 50 mg/m2 IV day 1, cisplatin 60 mg/m2 IV day 1 and fluorouracil 200 mg/m2 IV daily as a continuous infusion) q21d was given as per Findlay et al. Patient, tumor, treatment and outcome data were extracted from medical records.

Results: 14 mCRPC pts were treated with ECF 1996-2010. 7 pts had liver metastases: median age 57 years (42-76), median PSA 320 μg/L (17-494) and ECOG PS 1:2 (6:1). All 7 pts had multiple other poor prognostic features: pain (6), >2 metastatic sites (6), anemia (6), ALP >200 IU/L (6) and less than 3 years from diagnosis (6). A median 6 cycles (4-10) of ECF were administered. PSA dropped > 50% for > 4 weeks in 5 pts (71%) with a PSA drop >90% in 4 pts. The ORR was 57% (95%CI, 20-94%) with 4 PR, 1 SD and 2 PD. Response was associated with improved symptoms and hepatic function. Adverse effects were similar to previous reports. Median PFS was 5.2 months (1.3-7.8+) and median overall survival 7.4 months (3.8-31.9). Pooling ORR data with that of Chao et al suggested a higher ORR than expected with docetaxel (58% vs 12%, p=0.03 Fisher's exact test).

Conclusions: ECF was highly active in this small selected group of younger men with liver mCRPC and multiple poor prognostic features, and may be of interest for further study as a therapeutic alternative to docetaxel in mCRPC pts with liver metastases when prompt tumor shrinkage is necessary.

No significant financial relationships to disclose.
Antigen-specific immunity and tumor inflammation after vaccination with BPX-101, a drug-activated dendritic cell vaccine for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Wheeler T. M. , Zhao B. , Sonpavde G. , McMannis J. D. , Bai Y. , Lapteva N. , Seethammagari M. , Levitt J. M. , Spencer D. M. , Slawin K. M.
Published: February 2017

176

Background: We report evidence of antigen-specific immunity and severe prostate cancer inflammation and necrosis after vaccination in patients enrolled in a phase I-IIa clinical trial of BPX-101, a drug-activated DC vaccine for mCRPC.

Methods: Twelve men with progressive, mCRPC were enrolled in a 3+3 dose escalation trial evaluating BPX-101 and activating agent AP1903. BPX-101, which targets prostate-specific membrane antigen (PSMA), was administered intradermally every 2 weeks for 6 doses, followed 24 hours after each dose by infusion of AP1903 (0.4 mg/kg). Injection site skin biopsies were performed after the fourth vaccination. T cells cultured from the skin biopsy ex vivo were stimulated with PSMA protein or control antigens, and were analyzed using Luminex microspheres for 30 inflammatory cytokines/chemokines. One patient (#1007) with an intact prostate developed lower urinary tract bleeding after the fifth vaccination and underwent a transurethral resection of bleeding prostate cancer tissue. Paraffin-embedded blocks were stained for hematoxylin and eosin (H&E). Immunohistochemical stains for CD3, CD4, CD8 and CD34 were also performed.

Results: Of 5 subjects with evaluable injection site biopsy results, all exhibited PSMA-specific immunity (3 TH1-biased and 2 TH2- biased). Subject 1007's injection site biopsy demonstrated a significant >10-fold increase in IFN-gamma and IL-2 after stimulation by PSMA, compared to stimulation by ovalbumin, consistent with induction of a strong PSMA-specific CTL or TH1-biased immune response. H&E stained resected prostate tissue demonstrated Gleason 8 (4+4) prostate adenocarcinoma exhibiting a severe inflammatory response, consisting of infiltrating plasma cells and CD4+ and CD8+ T cells. Large areas of necrosis were seen adjacent to inflamed prostate cancer tissue.

Conclusions: Vaccination with BPX-101 followed by AP1903 can induce a strong, PSMA-specific immune response. Furthermore, evidence of severe prostate cancer-specific inflammation and necrosis, associated with a strong PSMA-specific immune response has been observed after multiple doses of BPX-101.

[Table: see text]
A phase II, open-label, single-arm, efficacy, and safety study of MDV3100 in patients with hormone-naïve prostate cancer.
Authors: Baskin-Bey E. S. , Holtkamp G. M. , Smith M. R. , Ouatas T. , Phung D. , Tombal B.
Published: February 2017

177

Background: MDV3100 is a novel androgen receptor (AR) antagonist in clinical development for the treatment of prostate cancer (PCa). Compared to bicalutamide, MDV3100 has higher in vitro AR binding affinity and no evidence of partial agonism. Preliminary phase I-II data show antitumor activity with MDV3100 in men with advanced PCa who were concurrently using androgen deprivation therapy (ADT; Scher HI, et al. Lancet. 2010;375:1437-46). Phase II and III studies in men with progressive and earlier-stage PCa are ongoing. This abstract describes the design of a phase II study of MDV3100 in men with hormone-naïve PCa (HNPCa) who are candidates for ADT.

Methods: This 25-week, open-label, single-arm, efficacy and safety study of MDV3100 (160 mg/d orally) will be initiated at ∼20 investigational sites in late 2010 (planned countries: Austria, Belgium, Czech Republic, Denmark, Germany). Inclusion criteria include histologically confirmed, locally advanced PCa (all stages), noncastrate testosterone (T; ≥230 ng/dL), prostate-specific antigen (PSA) ≥2 ng/mL (screening), Eastern Cooperative Oncology Group score of 0, and life expectancy ≥1 year. Exclusion criteria include, among others, previous/current hormonal therapy or chemotherapy for PCa. The primary endpoint is PSA response, defined as an ≥80% decrease from baseline to wk 25. A binary PSA response per patient (wk 25) will be determined, allowing for generation of a PSA response rate (95% CI) from all patients for the study. Secondary endpoints include: PSA dynamics; pharmacokinetics; change in gonadotropin, T, dihydrotestosterone, estradiol, sex-hormone binding globulin, and prolactin levels; and safety/tolerability. Exploratory endpoints include changes in bone mineral density, bone turnover markers, metabolic parameters, and quality of life.

Results: The planned enrollment is 60 patients. With a 20% dropout rate, the study will have 80% power to reject the unwanted PSA response rate of ≤50% (5% significance). Efficacy and safety data will be published later.

Conclusions: Previous data were in men with castrate levels of T (≤50 ng/dL). This trial will be the first to investigate the use of MDV3100 monotherapy in HNPCa.

[Table: see text]
Cost of care for prostate cancer patients: An observational cohort study comparing clinical trials to standard care.
Authors: Jones B. , Syme R. , Eliasziw M. , Eigl B. J.
Published: February 2017

184

Background: Monetary support of clinical trials is a fundamental necessity for improving treatment and prevention methods; however, current economic data pertaining to the per-patient costs of treating prostate cancer are limited. A concurrent lack of certainty regarding the cost requirements of standard care patients makes it difficult for healthcare professionals and policy makers to generate informed decisions regarding budgets and funding needs. Prostate cancer clinical trials are facing a national funding crisis due to the perception that patients enrolled in clinical trials consume more resources than patients receiving standard care.

Methods: A retrospective observational cohort study was conducted to examine the costs incurred by prostate cancer patients at the Tom Baker Cancer Center over one year. Costs for 36 patients enrolled in one of nine cancer trials were compared with costs for 36 matched control subjects who received standard care. Resource utilization was tracked using medical charts and quantified by prices listed in the TBCC's 2009 Clinical Trials Budget template.

Results: No evidence was found to support a difference in overall resource utilization between clinical trial patients and standard of care patients (Paired two-tailed t- test, N= 36, p =0.90). There was, however, variability in the types of resources used by each patient population, indicating that, while trial patients may take up significantly more clinic time (p =0.04), undergo more tests and procedures (p < 0.001) and require more diagnostic imaging (p = 0.01), standard care patients are more likely to receive costly interventions such as radiation therapy (p =0.06). Pharmaceutical costs have not yet been included in the analysis and could drastically alter the final results.

Conclusions: This study revealed differences in the cost distribution of clinical trials patients versus standard of care patients, which could be used by administrators to improve budgeting and time allocation. The lack of difference in overall cost may be helpful to research advocates attempting to encourage centers to take on more trials. Further analysis is required before definitive conclusions can be drawn.

No significant financial relationships to disclose.
Patient preference for prostate-specific antigen testing: A population-based analysis.
Authors: Chang S. L. , Presti J. C. , Richie J. P.
Published: February 2017

188

Background: The AUA and American Cancer Society both recommend a shared decision-making process between clinicians and patients for prostate cancer screening with PSA testing. Data are limited data regarding patient preferences for PSA evaluation in the United States. We assessed the sociodemographic and clinical characteristics of men who proceeded with or opted out of PSA testing in a nationally representative population-based cohort.

Methods: We analyzed male participants from the 2001 to 2008 cycles of the National Health and Nutrition Examination Survey (NHANES) who were 40 years old or older without a history of prostate cancer, recent prostate manipulation, or hormone therapy use (n = 6,032). All men underwent or refused PSA testing after a standardized explanation about prostate cancer screening by a physician. A multivariate logistic regression was conducted after adjusting for survey weights to identify independent sociodemographic and clinical predictors for opting out of PSA testing.

Results: Overall, 5% of the study cohort refused PSA testing. The analysis revealed predictors for refusing PSA testing (Table). PSA testing preference was not influenced by a family history of prostate cancer, previous prostate cancer screening, education level, socioeconomic status, insurance status, or tobacco history. There were no significant time trends for PSA testing.

Conclusions: Despite equal access to PSA testing in our study, there was unequal utilization. We found that Black men were more likely to refuse PSA testing. Our analysis also suggests that a perception of suboptimal health or uncertain future outlook may discourage men from undergoing PSA evaluation. These patient preferences for PSA evaluation should be factored into the shared decision-making process for prostate cancer screening.

[Table: see text]

No significant financial relationships to disclose.
The impact of screening for prostate cancer on the development of metastatic disease.
Authors: Ciezki J. P. , Reddy C. A. , Kupelian P. , Klein E. A.
Published: February 2017

192

Background: Routine screening for prostate cancer (CaP) was first advocated in 1993 in the US. Opponents of screening argue that the implementation of routine screening has not resulted in a meaningful improvement in survival. Since we are essentially unable to cure metastatic disease, the best measure of the efficacy of screening may not be overall survival but instead its ability to lessen the metastatic disease burden of the screened population. We assess the effect of screening on this endpoint.

Methods: From 1986-1996, 1,721 patients with CaP were definitively treated with radical prostatectomy (RP) or radiotherapy (RT) at our institution. The cohort was divided into a pre screening era group (1986-1992; PRE, n=575) and a post screening era group (1993-1996; POST, n=1,146). Due to the potential for an imbalance in follow up time between the two groups, all patients were censored at ten years. Kaplan- Meier analysis was used to calculate the ten year metastases free survival rates (MFSR). Cox proportional hazards regression was used to examine if screening era along with disease, treatment, and follow-up characteristics was associated with an increased risk of developing metastatic disease.

Results: The median follow up for all patients was 10 yrs (range: 0.1-10), 9.6 yrs (range: 0.1-10) for PRE patients, and 10 yrs (range: 0.1-10) for POST patients. The distribution by NCCN risk classification for the PRE patients was 44% high risk (H), 21% intermediate risk (I) and 28% low risk (L) vs. 36% H, 27% I, and 37% L for the POST patients (p < 0.0001). Within 10 years of treatment, 13% of all patients had developed metastatic disease. The 10 year MFSR for high risk PRE vs POST patients was 58% vs. 82% (p < 0.0001), 79% vs. 93% for I (p < 0.0001), and 90% vs. 98% (p = 0.0001) for L patients. On multivariable analysis, screening era (p < 0.0001, HR = 4.6, 95% CI = 3.4-6.1), T-stage, biopsy Gleason score, and post-treatment PSA testing frequency were significant.

Conclusions: Screening for CaP results in a significant decrease in the risk of a patient developing metastatic disease within 10 years of treatment even after controlling for severity of disease. This risk reduction may yield improved quality of life and a cost savings to the medical care system.

No significant financial relationships to disclose.
Got central prostate pathology review? A cross-sectional audit of 2009 versus 2003 outcomes.
Authors: D'Souza N. , Loblaw D. A. , Mamedov A. , Klotz E. , Sugar L. , Nam R.
Published: February 2017

196

Background: Prostate cancer is the most common non-cutaneous cancer in Canadian men; over 24,000 will be newly diagnosed and 4,300 will die from it in 2010. Estimating an individual's risk of disease spreading across the capsule and probability of recurrence with different treatment modalities is common practice in prostate cancer management and often drive the choice or extent of treatment options. A strong predictor of recurrence and organ confined disease is tumor grade. The literature recognizes differences in grading prostate cancer between genitourinary and non-specialized pathologists; we previously reported a 30% change in risk category (Low, GS 2-6; Int., GS 7; High, GS 8-10). However, this report was based on data from 2003/2004. A repeat audit was necessary given Gleason grading practice changes following the 2005 ISUP Consensus Conference.

Methods: Log books from 2009/10 where our Genitourinary Pathologists (GUP) reviewed prostate needle core biopsies were used to identify cases; a retrospective chart review was completed. The following variables were extracted: 1° Gleason score; 2° Gleason score; number of sites; % Gleason 4/5 pattern (overall); perineural invasion (present/absent); extracapsular extension (present/absent). Descriptive statistics were used to summarize the results.

Results: The charts of 132 patients having a GUP biopsy review were extracted. Seventeen percent (22/132) of cases changed risk category. Of the 47 low risk cases, 23% (11/47) were up-graded in risk category (21% by 1 category; 2% by 2 categories). Of the 46 intermediate risk cases, 15% (7/46) were up-graded and 2% (1/46) were down-graded. Of the 39 high risk cases, only 8% (3/39) were down-graded by 1 risk category. Comparatively, there was a 43% reduction in risk category change between 2003/04 (30%) and 2009/10 (17%).

Conclusions: Despite this reduction, a clinically significant proportion of patients changed pathologic risk category upon GUP review. Thus, it is recommended that prostate cancer pathology be routinely reviewed by a GUP as a best practice to optimize management and quality of care. Strategies are still needed to address disparities in pathologic grading and represent a potential area for further investigation.

No significant financial relationships to disclose.
Risk of death from prostate cancer after radical prostatectomy or brachytherapy in men with low- or intermediate-risk disease.
Authors: Arvold N. D. , Chen M. , Moul J. W. , Moran B. J. , Dosoretz D. E. , Banez L. L. , Katin M. J. , Braccioforte M. H. , D'Amico A. V.
Published: February 2017

198

Background: Radical prostatectomy (RP) and brachytherapy (BT) are widely utilized treatments for favorable-risk prostate cancer (PC). We estimated the risk of PC-specific mortality (PCSM) following RP or BT in men with low- or intermediate-risk PC using prospectively collected data.

Methods: The study cohort comprised 5,760 men with low-risk PC (prostate-specific antigen [PSA] level ≤ 10 ng/mL, clinical category T1c or 2a, and Gleason score ≤ 6), and 3,079 men with intermediate-risk PC (PSA level 10-20 ng/mL, clinical T2b or T2c, or Gleason score 7). Competing risks multivariable regression was performed to assess risk of PCSM after RP or BT, adjusting for age, treatment year, cardiovascular comorbidity, and known PC prognostic factors.

Results: There was no significant difference in the risk of PCSM among men with low-risk PC (11 vs. 6 deaths: adjusted hazard ratio [AHR], 1.62; 95% CI, 0.59–4.45; P = 0.35) who received BT compared to RP. However among men with intermediate-risk PC, despite significantly shorter median follow-up for men undergoing BT as compared to RP (4.1 vs. 7.2 years, P < 0.001), there was a trend toward an increased risk of PCSM (18 vs. 9 deaths: AHR, 2.30; 95% CI, 0.95–5.58; P = 0.07) for men treated with BT.

Conclusions: The risk of PCSM among men with low-risk PC was not significantly different following RP or BT, however there may be a reduced risk of PCSM after RP as compared to BT in men with intermediate-risk PC.

[Table: see text]

No significant financial relationships to disclose.
Factors associated with vertebral fractures in men treated with androgen-deprivation therapy (ADT) for prostate cancer.
Authors: Saylor P. J. , Hancock M. L. , Barnette G. , Steiner M. S. , Morton R. A. , Smith M. R.
Published: February 2017

205

Background: Fragility fractures are common among men and have the potential to cause considerable morbidity and mortality. Androgen deprivation therapy (ADT) for prostate cancer causes accelerated loss of bone mineral density (BMD) and is associated with increased risk for fractures. We evaluated clinical risk factors associated with fracture among men receiving ADT and at elevated risk for fracture due to age and/or BMD.

Methods: Analysis included men receiving ongoing ADT for prostate cancer and enrolled in a phase III fracture prevention trial. All men were either age ≥ 70 years or had low BMD (T-score < −1.5 for the lumbar spine or total hip). We analyzed baseline demographic and laboratory characteristics of those with and without vertebral fractures at the time of study entry. Given that the trial enrolled patients who were age < 70 only if BMD was low, we conducted additional analyses confined to the portion of the cohort that was age ≥ 70.

Results: A total of 162 of the 1,244 subjects (13.0%) had a vertebral fracture at baseline. Two factors were significantly associated with prevalent fractures: white race (p = 0.028 when compared with non-white race) and osteoporosis (p = 0.002 for osteoporosis at any site; p = 0.053 for osteoporosis at the spine; p = 0.002 for osteoporosis at the hip). Lower BMD was also significantly associated with fractures when analyzed as a continuous variable. Factors not associated with fractures included age, country of residence, ADT duration at baseline, ADT mode, body mass index, testosterone, estradiol, C-terminal telopeptide of type I collagen (CTX), bone-specific alkaline phosphatase, and osteocalcin. Results were similar in analyses limited to men ≥ 70 years old (n = 1,002).

Conclusions: Vertebral fractures cause substantial morbidity and mortality among men treated with ADT for prostate cancer. In this study of men receiving ADT, white race and low BMD were significantly associated with vertebral fractures. These observations should inform the assessment of fracture risk in this vulnerable population.

[Table: see text]