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PURPOSE: Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters. RESULT: We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point. CONCLUSION: Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.

PURPOSE This phase I study was designed with the following objectives: (1) to describe the overall and dose-limiting toxicity (DLT) of suramin administered by intermittent short intravenous infusions until DLT or disease progression; (2) to determine the ability of an adaptive control with feedback (ACF) dosing strategy to maintain suramin plasma concentrations within a preselected range; (3) to develop a population model of suramin pharmacokinetics; and (4) to identify preliminary evidence of antitumor activity. PATIENTS AND METHODS Seventy-three patients with advanced, incurable, solid tumors (including 69 with hormone-refractory prostate cancer) received an initial 5- to 7-day daily loading treatment followed by intermittent infusions individually determined by ACF using a Bayesian algorithm and relying on population models of suramin pharmacokinetics. Treatment was given to three cohorts of patients based on target plasma suramin concentration ranges (peak, 30 minutes postsuramin, and trough on morning of the treatment day), as follows: cohort 1, 175 to 300 micrograms/mL (27 patients); cohort 2, 150 to 250 micrograms/mL (23 patients); and cohort 3, 100 to 200 micrograms/mL (23 patients). All patients were to receive suramin until DLT or disease progression. RESULTS The DLT was most commonly seen in cohort 1 and included a syndrome of malaise and fatigue, associated with weight loss, anorexia, and changes in taste. Other reversible toxicities were neurologic, renal, cutaneous, edema, lymphopenia and anemia, ophthalmologic, and alopecia. Forty of 67 assessable patients (60%) had a 50% reduction and 25 of 67 (37%) a 75% reduction in prostate-specific antigen (PSA) levels that lasted more than 4 weeks, seven of 18 (40%) had measurable responses, and 18 of 37 (49%) demonstrated major pain improvement. The overall times to disease progression and survival were 170 and 492 days, respectively. CONCLUSION We have characterized all toxicities with suramin in a pharmacologically guided phase I study designed to maintain plasma suramin concentrations of 100 to 300 micrograms/mL (cohorts 1 to 3). The incidence of grade 3 to 4 neurologic abnormalities was relatively low, particularly in cohorts 2 and 3 (100 to 250 micrograms/mL). Evidence of significant and durable antitumor activity was seen in all three cohorts.

We summarized and critically assessed all available data from phase III clinical trials on complete androgen blockade versus surgical or medical castration alone.Published results in journals and abstracts of phase III trials, and published meta-analyses were reviewed. We also reviewed quality of life and toxicity issues associated with the addition of antiandrogens to medical or surgical castration. Finally, we discuss the original rationale for complete androgen blockade in the context of current knowledge.A total of 27 clinical trials using various combinations of androgen deprivation were identified, of which 3 showed a statistically significant benefit for the complete androgen blockade arm. There were 5 publications of meta-analyses that each used different selection criteria for the inclusion of studies in the final analysis. Toxicity and quality of life have not been widely investigated in prospective fashion but the available data suggest a higher toxicity rate and decreased quality of life with complete androgen blockade.The extensive body of data does not support routine use of antiandrogens in combination with medical or surgical castration as first line hormonal therapy in patients with metastatic prostate cancer.

Hormone-refractory prostate cancer (HRPC) patients often have nonmeasurable disease. In such patients, predictive biomarkers other than tumor response may be required to compare therapeutic effects. We examined the predictive value for survival of various clinical and laboratory parameters, including prostate-specific antigen (PSA), in HRPC patients treated with suramin. Data from 103 HRPC patients were analyzed using various survival analyses, the likelihood ratio approach, and logistic regression analyses. When pretreatment factors, percentage decrease in PSA at 4 weeks from start of treatment (deltaPSA), and updated survival data were fit by a multivariate Cox proportional hazards model, acid phosphatase, lactate dehydrogenase, and deltaPSA were significant, with risk ratios close to 1. There was a decrease in likelihood ratio with increasing APSA. A logistic regression model was developed to predict the probability of1 year of survival from the start of treatment. Hemoglobin and deltaPSA were found to be significant variables. However, in view of the complexities involving the relationship between PSA expression and prostate cancer growth and possible selective effect of treatment on PSA, further prospective testing is necessary. Therefore, deltaPSA cannot necessarily be used as a biomarker for survival response in individual patients during the evaluation of the therapeutic response of HRPC to new antineoplastic drugs.

e15006 Background: The systemic management of patients with BRPC remains controversial. IAD is commonly employed. Aims: To evaluate the PSA dynamics and serum T in pts with BRPC treated with IAD un...

4576 Background: Loss of the PTEN tumor suppressor and subsequent activation of the PI3K pathway is common and has potential clinical and therapeutic value in CaP. We examined the PTEN status of pr...

e15007 Background: Intracrine conversion of adrenal androgens to testosterone play an important role in CRPC progression. Treatments (tx) that block adrenal steroid synthesis have shown significant...

150 Background: The systemic management of patients with BRPC remains controversial. IAD is commonly employed. Aims: To evaluate the PSA dynamics and serum T in pts with BRPC treated with IAD until the development of PSA refractoriness or clinical evidence of metastatic disease. Methods: Data were retrospectively analyzed in all pts with BRCP treated with GnRH at PSA thresholds according to pre-treatment PSADT (10-15ng/mL, 15-20, and 20-30 for PSADT ≤3 mos, 3-9 mos, and ≥ 9 ms, respectively) and continued until PSA nadir. Antiandrogen (AA) was added for PSA > 1.0 ng/mL after 3 mos). Follow-up (FU) consisted of PSA and T q3 mos. Cycles were repeated at the above preselected PSA thresholds and continued until lack of PSA response. Scans were obtained prior to cycles and at the time of CRPC state. Mixed effects model was used to study PSADT change over cycles. Multivariate cox regression model was used to identify prognostic variables. Results: From 1995-2010, with a mean FU of 71 mos (range 22-183 months), 96 pts received a mean of 2.8 cycles (range 1-9) of IAD; 58 (60%) remain on treatment and 38 (40%) were switched to continuous ADT due to PSA refractoriness (n=11) or positive scans (n=27). PSADT at the first off treatment (tx) interval (mean 3.1, 0.59-30.5 range, median 2.3) was significantly shorter than the baseline (p Conclusions: Our data suggest that PSADT becomes shorter after the initial cycle of IAD and correlate with T recovery. PSA dynamics and need for AA to enhance PSA nadir are associated with PSA refractoriness in pts BRPC treated with IAD. No significant financial relationships to disclose.

4641 Background: IAD is often applied in BRPC (M0) after local tx. Criteria for initiation of androgen deprivation therapy (ADT) and evaluation based on PSA dynamics remain poorly defined. Shorteni...

4554 Background: Preliminary data suggest that Len, an immunomodulatory agent and angiogenesis inhibitor, is active in prostate cancer. Aims: Evaluate the safety and efficacy of 6 months (mo) admin...

5130 Background: BR following LT is common in PC with no defined standard treatment. Lenalidomide (L) is an immunomodulatory agent with anti-angiogenic and direct antitumor effects. Methods: This trial was designed to evaluate a dose-effect relationship of L in BR PC. Pts were randomized to either 5 or 25 mg/day(d), PO, d 1–21 (28-d cycles); then stratified by PSADT (< 3, 3–8.9, ≥ 9 mos), LT and prior ADT. Eligible pts had: rising PSA (≥1 ng/mL), M0 disease, testosterone > 150 ng/mL, adequate bone marrow, renal, and hepatic function. Baseline and Q 2 mos PSA's were processed after Q 6 mos of L, along with CT and bone scan. Toxicity exams were Q mo. Primary endpoints are safety and progression after 6 mo of L (defined by a confirmed ↑ in PSA > 25% over the baseline value or mets). Secondary endpoints are changes of slopes in PSA related to pharmacokinetics (pk). A sample size of 30 pts/arm provides an 85% power to detect a PSA progression rate of 40% (compared to 80% predicted ) with a Type I error = 0.05 (Fishers exact test). Results: 59 pts were entered July 20, 2006-December 31, 2008. Pooled data from the 2 arms: median: age 64 (50–81), ECOG PS 0, baseline PSA 9.3 ng/ml (1.3–92.8 ng/ml). 16 pts had PSADT + d (9 +-887+d); # cycles = 6 (1–30). Thus far, 44/59 pts completed 6 cycles of L (1 had PD, 6 stopped L due to toxicity, 8 too early). 22 /44 who completed 6 mos of L remained on L > 6 mos ( 7+-30+ mos); including 7 pts ≥ 24 mos. Of 44 pts, blinded evaluation of PSA's at 6 mos: 4 pts had ≥ 50% ↓, 22 had stable PSA,17 had PD, 1 too early . Rash was DLT. Other Gr toxicities: appendicitis, abd pain, neck pain, venous thrombolic disease, fatigue, pruritus. Conclusions: Preliminary data prior to unblinding the study treatment arms, from pooled data, suggest that L may be administered > 6 mos with acceptable toxicity, and is associated with PSA declines and long term stabilization in pts with BR. Supported by a grant from Celgene Corporation. Data coordination infrastructure is supported by the Prostate Cancer Foundation and The James Stine research fund. [Table: see text]

5155 Background: Bone targeted therapy holds great promise for improving outcomes in mCRPC. Preclinical data strongly supported biological synergism of docetaxel (Tax) and 153Sm-EDTMP (Sm) in mCRPC. Concurrent Tax and Sm regimens were reported feasible and tolerable in phase I studies. This study was designed to evaluate toxicity and preliminary efficacy of 2 cycles (12 wks/cycle, C) of concomitant standard dose/schedule of Sm plus Q3 wks schedule of Tax in mCRPC. Methods: mCRPC pts with progressive bone metastases were treated in 4 cohorts ( CH). Previous Tax and palliative RT to bone was admissible. Dose escalation of Tax was implemented if no DLT was observed in the preceding CH. Tax doses (on days 1, 22, per 12 wk cycle) were given as follows: CH 1- 50mg/m2 (C1 and 2); CH 2–75mg/m2 (C1) and 50mg/m2 (C2); CH3 - 75mg/m2 (C1 and 2) and CH4 ( Tax day 1, 22, 43 per 12 wk C) 75mg/m2 (C1 and 2). Sm was administered on days 2 (Q12 wks X 2) at dose of 1 mCi/kg/cycle (max. of 2 cycles). Disease status was assessed (with bone /CT scans and PSA) after every cycle. Results: Thirteen pts with progressive bone metastases were enrolled. Three had prior Tax and 3 had prior palliative radiation. Thirteen pts received total 20 cycles in 4 cohorts. Toxicity was primarily hematological. There were total 34 episodes Grade 3/4 neutropenia with a median 7 (range 7 -14) days to recovery to ≤ grade1. Tax dose was reduced to 50% in 2 CH4 pts at C2. Only 1 DLT G3 thrombocytopenia occurred on cohort 4 with duration of 9 wks. Median baseline PSA was 100.4 ng/ml (range 8.6 - 1064), 9/13 (69%) pts had PSA>50% decrease. Median time to disease progression was 147 days (range 72 days - 10 months+); 6/13 (46%) pts had stable/improved bone scans at 6 months and 8/8 (100%) symptomatic pts had improvement in pain. Conclusions: Concurrent 6-month administration of 2 and possibly 3 full dose /standard schedule of Tax with 2 full doses of Sm is feasible with reversible bone marrow suppression. The combination may provide additional clinical benefits for mCRPC pts with extensive bone metastasis. No significant financial relationships to disclose.

15547 Background: Bone targeted approaches hold great promise for improving outcomes in HRPC. Docetaxel (D) and samarium 153 (Sm153 ) have individually demonstrated a clinical benefit and preclinical data strongly support biological synergism in HRPC. Preclinical data suggests that 24 hour after a dose of D, there is maximum G2M arrest. This results in the accumulation of cells in the most radiosensitive phase of the cell cycle. This phase I trial was designed to evaluate toxicity and preliminary efficacy of combined D and Sm153 administered sequentially in advanced HRPC. Methods: HRPC pts progressing after anti-androgen withdrawal; = 2 prior chemotherapy regimens; acceptable bone marrow, renal and hepatic function were eligible. Planned D treatment in 4 cohorts (N=3/cohort) includes: Cohort 1: D 50mg/m2 IV on days 1, 22, 91, and 112; cohort 2: D 75mg/m2 IV on days 1 and 22 followed by 50mg/m2 IV on days 91 and 112; cohort 3: D 75mg/m2 IV on days 1 and 22 followed by 75mg/m2 IV on days 91 and 112; cohort 4: D 75 mg/m2 IV on days 1, 22, 42, 91, 112, and 133. Sm 153 (1.0 mi/Kg) is administered IV days 2 and 92 of each cycle. Cycles are repeated Q 12 wks (max 2 cycles). The endpoint for this trial is dose limiting toxicity and maximal tolerated dose. Results: From 5/11/05 - 1/7/07 ten pts were enrolled. Median: age 69.5 yrs (range 58–76), ECOG performance status 1 (range 0–1), baseline PSA 76.65 ng/ml (range 9.6–1064 ng/ml ), prior hormonal manipulations 3 (range1–6). Three pts had prior taxotere and 3 pts had prior palliative RT. All had bone metastases and 2 also had soft tissue disease. Five pts completed 2 cycles of treatment as planned. Five pts had 1 cycle (one pt is on treatment, 3 pts had PD and 1 had prolonged grade 1 thrombocytopenia =3 wks). Nine of 10 pts had reversible grade 3 / 4 neutropenia (1 pt had reversible episode of neutropenia with fever). Seven of 7 symptomatic pts had improvement in pain. Four of 10 of pts had a 50 % decline in PSA level lasting = 4 weeks; no soft tissue disease responses. Conclusions: Our preliminary data suggest that Q 3 wk D and Q 3 month Sm153 may be administered simultaneously at full doses in extensively pretreated HRPC pts, with acceptable toxicity and significant activity. This study is supported by a grant from sanofi- aventis and Sm153 is provided by Cytogen. No significant financial relationships to disclose.

14612 Background: Imatinib mesylate (Gleevec, G) is a potent inhibitor of the tyrosine kinases and other signaling mediated events. Preclinical models suggest that G inhibits platelet derived growth factor (PDGF) and stem cell factor (SCF) which are important for prostate cancer growth. This trial was designed to evaluate the safety and efficacy of G in PCA pts on HT with stage M0 disease. Methods: Eligible PCA pts included: stage M0 disease with rising PSA levels while on hormonal therapy, no prior chemotherapy. Planned treatment included G 400 mg PO BID given up to a maximum of 12 months. The statistical endpoint for this trial was the% of pts with a ↓ in prostate specific antigen (PSA) ≥ 50% lasting ≥ 4 wks. A 2 stage trial was designed where the study would terminate if the% of pts meeting the endpoint was not convincingly > 30% with 5% chance for error. Pts with a > 50% rise in PSA from baseline were removed from study. Follow-up included monthly toxicities and PSA (specimens frozen/stored until completion of each 3 months of therapy). Results: From 10/1/02–10/11/04, nine pts were enrolled. Pt characteristics included median: age of 67 years (range 52–80), ECOG performance status of 0 (range 0–1), baseline PSA of 29.6 ng/ml (range 2.69–39.52), # prior hormonal manipulations of 3 (1–5). Prior local therapies included: 1 status post (s/p) RP alone, 2 s/p RT alone, 2 s/p neoadjuvant HT plus RP, 2 s/p neoadjuvant HT plus RT. Two pts had no prior local therapy. Two pts had prior salvage RT, 1 had prior palliative RT. Eight of 9 pts evaluable for response and toxicity. One patient never received treatment. None of the pts had a decline 50% decline in PSA level lasting ≥ 4 weeks. Three of 8 pts (38%) had rapid increases in PSA and 4/8 pts (50%) developed metastatic disease after 3 months of therapy. Only one pt completed 12 months of planned therapy. Grade 3/4 toxicities included: fatigue (25%), rash (25%), arthralgias (12.5%), peripheral edema (25%), depression (12.5%), necessitating dose delays and/or discontinuation of G in 4/8 pts (50%). Conclusions: These data suggest significant toxicity and low clinical benefit. Further evaluation of Gleevec in this pt population is not warranted. No significant financial relationships to disclose.

4758 Background: Preclinical data suggested synergistic anti-tumor activity with the combination of D + E in AIPC. E is a GMP phosphodiesterase inhibitor administered orally. We designed a trial evaluating tumor response (↓PSA ≥50% lasting ≥4 wks) to D given on a weekly schedule + E daily. Methods: AIPC pts showing progressive disease after anti-androgen withdrawal were enrolled. Up to 2 prior chemotherapy (chemo) regimens were allowed. Planned treatment included 6 cycles of D 35 mg/m2 IV Q wk × 4 followed by 2 wks of rest. E 250 mg PO BID was initiated D 8. The statistical endpoint for this trial was the % of pts with ↓ in PSA ≥50% lasting ≥4 wks. A 2 stage trial was designed where the study would terminate if the % of pts meeting the endpoint was not convincingly >40%. If ≤3/14 pts responded in stage 1, this criterion would be met. During wks 1 and 3 serial plasma samples were obtained (last sample 168h). [D] were measured using a validated LC/MS/MS method and D pharmacokinetic (PK) parameters were dete...

3092 Background: Biochemical recurrence of prostate cancer after definitive or salvage local therapy in the absence of metastatic disease represents a group of men well suited for a novel therapeutic intervention. Imatinib mesylate (Gleevec) is a protein-tyrosine kinase inhibitor which has previously been tested in men with androgen-independent and metastatic prostate cancer. This phase II study was undertaken to determine the safety and efficacy of imatinib mesylate in men with biochemical relapse of non-metastatic, androgen-sensitive prostate cancer following local therapy. Patients and Methods: Twenty-seven patients were treated with imatinib mesylate 400mg twice daily for 12 months or until evidence of disease progression or dose limiting toxicity. All patients had evidence of biochemical progression with a rising PSA after definitive radiation therapy, prostatectomy, or prostatectomy and salvage radiation therapy. Three patients (11%) completed less than 4 weeks of therapy and were not evaluable. Res...

4608 Background: D is registered for the treatment of MPC at a dose of 75mg/m2 once every 3 wks with daily low-dose prednisone (LDP). Standard treatment involves androgen-ablation (AA) therapy as maintenance with D therapy. Grade 3/4 neutropenia occurs in 32% of patients (pts) with MPC, which is approximately one-half that in lung cancer pts receiving D monotherapy at 75mg/m2. The objective was to evaluate D clearance (CL) in the presence of AA compared to cycling of testosterone (T) in patients with MPC. Methods: Twenty pts receiving AA therapy were treated with D 25–35 mg/m2 (N=16) or D 75 mg/m2 (N=4) (study 1); serial plasma samples were obtained during wk1 (last sample 168h). Ten non-castrate pts received triptorelin immediately followed by D 75 mg/m2 on d1 of wk 1, T gel was administered for 7d during wk 4, and triptorelin and D were given again on d1 of wk 5 (study 2); during wks 1 and 5, serial plasma samples were obtained (last sample 168h). D concentrations were measured using a validated LC/MS/M...

4555 Background: Patients (pts) with biochemical (PSA) relapse after RP represent a rapidly rising population in whom appropriate standards of care remain undefined. Over the past several years we have focused on studying the natural history of these pts. Our previous report (Pound et al; JAMA 1999) suggests that the Gleason score, time of PSA relapse (>0.2 ng/ml) and PSADT are the strongest predictors of the probability of distant metastasis (DM) (Cox model). A recent update (Partin; AUA 2003, Eisenberger; ASCO 2003) suggests that PSADT overrides the other parameters in the prediction of DM. Our experience has been expanded (> 1000 additional pts and longer follow-up). We evaluate the relationship between PSADT and PCSS. Methods: 4,415 pts underwent a RP from 1982–2003 and 825 demonstrated evidence of PSA relapse. All pts were followed with yearly PSAs with no androgen deprivation given until development of DM. Cox-proportional hazards and Kaplan-Meier survival analyses were completed with time from PSA ...