PSA Drop Research Articles

PD27-12 MULTICENTER INTERNATIONAL EXPERIENCE OF 180W LBO LASER PHOTO-VAPORIZATION IN MEN WITH VERY LARGE PROSTATES (PROSTATE VOLUME>200CC)

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Surgical Therapy & New Technology IV1 Apr 2017PD27-12 MULTICENTER INTERNATIONAL EXPERIENCE OF 180W LBO LASER PHOTO-VAPORIZATION IN MEN WITH VERY LARGE PROSTATES (PROSTATE VOLUME>200CC) Roger Valdivieso, Pierre-Alain Hueber, Malek Meskawi, Vincent Misrai, and Kevin Zorn Roger ValdiviesoRoger Valdivieso More articles by this author , Pierre-Alain HueberPierre-Alain Hueber More articles by this author , Malek MeskawiMalek Meskawi More articles by this author , Vincent MisraiVincent Misrai More articles by this author , and Kevin ZornKevin Zorn More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1233AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES According to EAU and AUA guidelines on management of male non-neurogenic lower urinary tract symptoms (LUTS), PVP XPS is superior to TURP with regard to intra-operative safety and postoperative complication rates such as bleeding. The experience of the GL system with very large glands (>200mL) is very limited. In the present study, we aimed to describe perioperative results as well as functional outcomes and complications of photo-vaporization of prostate glands bigger than 200 cc using the GL system. METHODS Retrospective analysis of prospectively maintained multi center database was performed to select subgroup of men having very large prostates (>200mL) treated with the Greenlight-XPS laser using PVP for the treatment of symptomatic BPH. IPSS, Qmax, PVR and PSA were measured at 6, 12, 24, 36 and 48 months. Durability was evaluated using BPH re-treatment rate at 12, 24 and 36 months. Additionally complications were recorded using the Clavien-Dindo classification. RESULTS A total of 38 (9%) men had prostates larger than 200mL. Men with very large prostates were older (76 vs 72 years, p=0.05), had higher PSA levels (9.9 vs 6.2 ng/dL, p=0.005) and had more indwelling catheters (55.6 vs 41.3, p=0.001). Patients with very large prostates had longer OR lasing times (94 vs 52 min), less energy density delivered (2.8 vs 3.4 kJ/mL) and longer time to removal of catheter (48 vs 24 hours). In terms of complications men with very large prostates had more LUTS at 6 months and the re-treatment rate were the same at 2 years (4.9 vs 5%). Finally, functional outcomes were similar however very large prostates had a smaller PSA drop in comparison (28 vs 50%). CONCLUSIONS PVP Greenlight XPS-180W is an acceptable technique for very large prostates (>200mL). However, OR times, energy density delivery, PSA drop at two years of follow up, catheterization time and LUTS are a concern in this particular subgroup. This should be used for patient counseling and surgery planning. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e516 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Roger Valdivieso More articles by this author Pierre-Alain Hueber More articles by this author Malek Meskawi More articles by this author Vincent Misrai More articles by this author Kevin Zorn More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

AR nuclear localization and microtubule bundling as markers of docetaxel and cabazitaxel sensitivity in metastatic castration-resistant prostate cancer (mCRPC): Prospective biomarker analysis from TAXYNERGY.

134 Background: A better understanding of taxane sensitivity/resistance in mCRPC is needed to optimize treatment. Preclinically, taxane efficacy has been linked to the ability of microtubules (MT) to inhibit AR nuclear trafficking. In this prospective biomarker study, we used circulating tumor cells (CTCs) from patients (pts) in TAXYNERGY to perform real-time analysis of AR nuclear localization (ARNL) and MT stabilization (bundling; MTB) in order to predict taxane sensitivity. Methods: TAXYNERGY (NCT01718353) is a phase 2 trial randomizing chemo-naïve mCRPC pts 2:1 to docetaxel or cabazitaxel, with a switch to the alternative taxane in the absence of a ≥ 30% PSA drop by C4. Here we present the co-primary biomarker endpoints. CTCs at baseline (C1D1) were compared to CTCs after 1 week of taxane treatment (C1D8), and were analyzed by multiplex confocal microscopy for %ARNL (integrated AR intensity in the cell and nuclear areas) and MTB (assessed for increase compared to C1D1 on a scale from 0–3 from no to most MTB increase). Associations between %ARNL and MTB with clinical outcomes were sought. Results: Of 63 randomized pts, 26 had evaluable CTCs both at C1D1 and C1D8. At C1D8, mean %ARNL was significantly lower in pts achieving a ≥ 50% PSA drop by C4 vs those without (44% vs 64%; p = 0.004). A taxane-induced decrease in mean %ARNL (C1D8 vs C1D1) was associated with a higher rate of ≥ 50% PSA response (73% vs 13%; p = 0.009); mean %ARNL decreased by 18% in responders and increased by 2% in non-responders (p = 0.02). Finally, a taxane-induced increase in mean MTB trended higher in pts achieving a ≥ 30% PSA drop by C4 vs those without (0.69 vs 0.09; p = 0.09); increase in mean MTB score was indicative of response and observed in pts who did not require a taxane switch after C4 (0.75 vs 0.09; p = 0.06). Conclusions: We provide the first prospective data suggesting that taxane-induced shifts in ARNL and MTB (measured in CTCs) may serve as an early biomarker of taxane sensitivity. Consistent with preclinical data, AR nuclear exclusion caused by microtubule bundling may be a clinically-actionable marker of taxane efficacy. Funding: Sanofi Genzyme. Clinical trial information: NCT01718353.

MP18-13 PRIMARY FOCAL CRYOTHERAPY IN THE TREATMENT OF PREDOMINANTLY ANTERIOR AND HIGH VOLUME INTERMEDIATE AND HIGH-RISK LOCALIZED PROSTATE CANCER IN THE UK

INTRODUCTION AND OBJECTIVES: Focal cryotherapy may offer good oncological outcomes with minimal side-effects. We recently commenced a focal cryotherapy program, primarily for anterior or transition zone lesions, to complement our focal HIFU programme. We assessed safety, adverse-events, functional outcomes and disease control. METHODS: Between October 2013 and June 2015, 56 patients underwent primary focal cryotherapy. All had pre-operative prostate multi-parametric MRI followed by transperineal template mapping or MRI-targeted biopsy. Patient reported outcome measures (PROMs) (IPSS, EPIC, IIEF-15) were collected prospectively, preand for up to 1 year post-operatively. Follow-up consisted of PSA blood tests and mpMRI at 12 months. Failure was defined as transition to radical or systemic therapy. A redo focal cryotherapy approach was permitted based on a positive post-focal cryotherapy mpMRI indicating residual in-field disease. Out-of-field disease progression could be treated by further focal cryotherapy but was defined as (staging) failure for purpose of this analysis. RESULTS: The median age, follow-up, prostate volume, PSA density and pre-operative PSA were 68 years, 13 months [5-24], 45cc, 0.24ng/ml/cc and 12ng/ml respectively. 38% were NCCN high-risk, 61% intermediate-risk and 1% low-risk (high-volume Gleason 6 disease). 15 (27%) underwent pre-operative cytoreduction with biclutamide. Their median post-operative PSA drop was 92% to 0.9ng/ml. Median post-operative PSA drop in the remaining 41 patients was 83% to 1.75ng/ml. Failure as defined by progression to radical therapy occurred in 1 patient (2%). 5 (9%) required further focal therapy: 2 (3.5%) had in-field residual disease whilst 3 (5.5%) had out-of-field disease detected on follow-up imaging. 48/56 patients (84%) returned at least 1 PROMs questionnaire. Mild post-operative incontinence requiring 1 pad/day occurred in 3 (5%) at 3-9 months, although at 12 months, none (0%) required padusage. Baseline median IIEF-15 was 36.5, with 5/48 patients (11%) taking PDE5i for pre-existing ED. Post-operatively median IIEF-15 decreased to 23 at 3 months before improving to 31.5 at 6 months and 28 at 9 and 12 months. 10/43 patients (23%) who were not previously on ED treatment were started on PDE5i. Overall 24/48 (50%) had erections sufficient for intercourse pre-operatively and 15/24 (37.5%) still had ED at last follow-up. Median IPSS scores improved from 8 pre-operatively to 5 at 12 months with a mild improvement in their QoL score from 2 to 1. Other adverse-events occurred in 11/56 patients (20%): 4 (7%) urinary retentions, 2 (3.5%) UTI’s, 2 (3.5%) urinary retention and UTI, 2 (3.5%) haematuria and 1 (2%) penile-tip numbness. CONCLUSIONS: In our study, predominated by large anterior intermediate and high risk lesions, focal primary cryotherapy confers low rates of side-effects, with a 0% 12-month incontinence rate and a 37.5% ED rate. Early oncological outcomes show a retreatment rate of 9% and conversion to radical treatment in only 2%. Continued follow-up will determine the medium to long-term disease control.

952 - Sequential Androgen Deprivation and Chemotherapy in Metastatic Prostate Cancer: Discordant Responses in Pilot Study Suggest an Opportunity for Individualized Therapy

ABSTRACT Background CRPC is fatal but with recent better survival based on new agents. Optimal sequential therapy remains a challenge. We undertook a phase II pilot study of Mitoxantrone (MTX) followed by docetaxel, estramustine, carboplatin (DEC). Methods CRPC pts who progressed on/after MTX were given estramustine 280mg TID x 5d, docetaxel 60mg/m2, carboplatin AUC = 5 q28 days; ASA & warfarin daily, max 8 cycles. Endpoints: RR >30% with PSA fall >30% & Results 20 pts: Med. age: 66 yrs (53-83), Med. Gleason 8, ECOG PS: 0-1, 12 pts with RP and 8 pts de novo mets, Sites: bone (18), lung (3), liver (4), LN (6). Pts received 2-11 MTX cycles. Prior RT: 12 pts. On DEC 13/20pts PR by PSA, 5: SD, 1: PD; 1: NE. Toxicity: 9pts gr 3/4 neutropenia - 1 with fever, 3: gr 3 neuropathy, 3: gr3 infection, 6: gr 3/4 Hgb, 1: gr3 plats, 1 DVT. Non-heme tox: 4pts gr3 fatigue, 3: gr 3 UTI, 1 gr3 dehydration & diarrhea. Med PFS MTX: 5.5 mos (1.2, 15.3), Med PFS DEC: 5.3 mos (1.2-14.5). OS from MTX start: 20.3 mos (9.1-37.5). OS from DEC start: 12.3 mos (1.2-31). Regression analysis identified visceral mets, alk phos & PFS on MTX (but not PSA, ECOG, Hb or Gleason score) as independent factors for OS from start of MTX. Response to MTX & DEC only partly overlapped. PSA response >30% drop in PSA to MTX or DEC & median OS were: responders to MTX only (n = 4; 20.3 mos (18.4-25.4)); to docetaxel only (n = 10; 14.6 mos (9.1-43.7); both (n = 5; 28.9 mos (22.7-40.3); neither (n = 1; 12.3 mos (Fisher's exact p = 0.3 for response MTX vs DEC, logrank p = 0.028 for OS). Based on pts ADT PSAn, we found longer PFS for DEC and MTX with higher PSAn (log-rank p = 0.048 & 0.019) & trend to better OS on MTX/DEC sequence with PSAn >4 (p = -0.14, med OS 20.1 vs 25.8 months). Fall in Hgb between ADT & start of DEC associated with shorter PFS on DEC (p = 0.05) with a trend to shorter OS (p = 0.08). Conclusions DEC was effective in patients with CRPC given MTX. Pts benefited if they responded to either or both agents but there was limited overlap in response (25%). High PSA nadir on ADT maybe associated with a longer PFS & OS to chemotherapy. Biomarkers linked to hormonal & chemotherapy effect for individual agents in PC could have significant utility. Study with larger cohorts of sequential therapy is ongoing Disclosure All authors have declared no conflicts of interest.

A phase II study evaluating the toxicity and efficacy of single-agent temsorilmus (TEM) in chemotherapy-naive castration-resistant prostate cancer (CRPC): First report of suggested activity.

165 Background: PTEN tumor suppressor gene is mutated in CRPC allowing for downstream protein activation including mammalian target of rapamycin (m TOR) leading to tumor cell growth and survival. We investigated TEM; an mTOR inhibitor, in chemotherapy-naïve CRPC patients (pts). Methods: Eligible pts received TEM at 25 mg weekly until disease progression. Responses were assessed every 8 weeks and toxicity every 4 weeks using CTCAE v.3. Quality of life (QOL) data were collected every cycle using two previously validated scales. Primary end point: Clinical Benefit (CB) [sum of complete response (CR), partial response (PR), and stable disease (SD)]. Secondary end points: Toxicity, time to next treatment (TTNT), time to radiographic and PSA progression (TTP and TTP-PSA respectively), impact on QOL, and overall survival (OS) Results: To date, 18 pts have been enrolled. Median age was 75 (57–89) with Gleason ≥7 in 14 (77%), and median PSA 211.3 (10.8-1,449). Ten pts (55.5%) had bone and visceral disease. Median time on androgen deprivation therapy (ADT) was 60 months (17–240). Previous therapy included: surgery 3, brachytherapy 3, external radiation 5, ADT 7. All pts were evaluable for toxicity and 16 for response. Six pts (33%) were taken off study without progression (2 withdrew, 3 persitsant thrombocytopenia, 1 non-compliance). Biochemical response data was available for 15 pts (2 not evaluable, 1 refused), of which 4 (26%) had PSA decline and 1 (6%) had >50% drop in PSA. TTP-PSA was 2 months (2-12). Sixteen pts were evaluable by RECIST; 2 PR and 9 SD for a CB of 69% (11 of 16). TTP or event (toxicity that took pts off study was an event) was 3 months (3–10) and TTNT was 4 months (2–11). With a median follow up of 18 months, 8 pts (44%) remain alive for a median OS of 13 months. Most commonly reported grade 3/4 toxicities: Thrombocytopenia (22%), hyperglycemia, hypophosphatemia, and fatigue (17% each), pneumonia and anemia (12% each). TEM did not impact QOL adversely without treatment-related mortality. Conclusions: TEM has activity in CRPC; some pts have CB without adverse impact on QOL. TEM should be further investigated in combination therapy in CRPC.

Effect of lenalidomide (LEN) on biochemical responses and clinical benefit (CB) as a single agent in chemotherapy-naive castration-resistant prostate cancer (CRPC).

128 Background: LEN has anti-angiogenesis and immunomodulatory properties making it ideal to investigate in CRPC. We report on a phase II study investigating LEN in chemotherapy-naïve CRPC patients (pts) Methods: Eligible pts received LEN at 25 mg daily on days 1 – 21 every 28-days until progression. Daily aspirin or coumadin were required. Responses were assessed every 2 cycles. Toxicity was assessed every cycle. Primary end point: The CB of LEN [Sum of complete response (CR), partial response (PR) and stable disease (SD)]. Secondary end points: Toxicity, time to radiographic and PSA progression (TTP and TTP-PSA), time to next treatment (TTNT), overall survival (OS), and LEN’s impact on quality of life (QOL). Results: 31 pts were enrolled; 27 response-evaluable (1 withdrew consent, 3 off per choice after adverse events). Median age is 74 (range 58-89) with 24 (77%) having Gleason ≥ 7 disease. Median PSA is 66 (2.1-918.6). Six pts (19%) had liver/lung involvement. Fourteen pts (51%) showed biochemical response with 4 (15%) having >50% PSA drop. TTP-PSA is 4 months (2-11). No radiographic responses seen but 17 pts had SD for a median of 4 months (2-16) (CB=55%). Median number of LEN cycles was 3 (2-15). With a median follow-up of 18 months (5-38), 17 patients (55%) remain alive; median OS of 18 months. Grade 3/4 hematologic toxicities were most common (neutropenia 41%, leukopenia 12%, anemia 9%, thrombocytopenia 9%). Other grade 3/4 toxicities: venothromboembolism, atrial fibrillation, and dehydration (6% each). Serious adverse events (SAEs) were witnessed in 10 pts (32%) with only 1 (3%, rash) definitely related to LEN. Others were not related or possibly related. Of 27 pts, 7 (26%) had a dose reduction and 2 (7%) required two dose reductions. Dose reductions occurred after cycle 3. QOL scales suggested no adverse impact. Median TTNT is 2 months (9 pts received chemotherapy, 10 pts went onto studies, 3 pts received hormonal therapies, 4 pts received radiation, 3 pts had no therapy yet, and 2 pts remain on LEN). Conclusions: LEN is active as monotherapy in CRPC. Biochemical responses are witnessed and clinical benefit is observed. Myelosuppression is the most common toxicity.

Influence of body mass index (BMI) on PSA kinetics in castrate-resistant prostate cancer (CRPC).

209 Background: Understanding of the role of host energetics in cancer outcomes has been increasing in recent years. In early stage prostate cancer trials obesity is associated with worse outcome. Its effect on treatment response and survival in advanced disease is largely unexplored. We sought to explore the relationship between BMI, the most validated measure of obesity, and biochemical response as well as overall survival in patients receiving first-line chemotherapy. Methods: We reviewed a prospectively-maintained institutional database identifying patients who received docetaxel (D) for CRPC. Demographics and PSA levels during treatment were extracted. Pts were divided into 2 BMI groups (> and < 30 kg/m2). We calculated biochemical responses as per historically validated surrogates: PSA decrease > 30% at 3months; overall decrease > 50%; time to PSA nadir and PSA half-life after 4 cycles, for each group. Results were compared with unpaired t-test and chi-square test. Results: 33 pts were identified between June ‘04 and Sept ‘10, 16 pts with BMI > 30 (hBMI) (range 30.1-34.2) and 17 with BMI < 30 (nBMI) (21.5-29.6). Median age for the entire cohort was 67.9 yrs (47.7-79.8), median Gleason score 8, median cycles of D received was 6 (3-20) with median duration of 3.7 months (1.4-8.7), p>0.05. Baseline PSA was 89.1 ng/ml (0.34-417) and 259.2 (16.1-1,589) for hBMI and nBMI respectively, p = 0.023. For hBMI group, only 56.3% (9/16) of patients demonstrated biochemical response, compared with 88.2% (15/17) in nBMI group(p = 0.039). Of the biochemical responders, 6/16 (38%) of hBMI and 9/7 (53%) of nBMI achieved >50% fall in PSA (p = 0.743) while 8/16 (50%) patients in hBMI group and 10/17 (59%) in nBMI group had a PSA drop >30% at 3 months (p = 0.61); Median time to PSA nadir was 3.4 months (0.7-4.9) and 2.7 (0.7-7.5), and median PSA half life was 56.4 days (16-138) and 46.1 days (16-302) for hBMI and nBMI groups, respectively, p > 0.05. Conclusions: Obese patients with CRPC have lower pre-D PSA levels. However, they also experience a lower rate of biochemical response to therapy. PSA kinetics in biochemical responders do not appear to be influenced by BMI. Survival data will be presented. No significant financial relationships to disclose.

405 IS 3-MONTHS PROST-TREATMENT RECIST EVALUATION OF BONE METASTASES BY MRI OF THE AXIAL SKELETON (ASMRI) A SURROGATE ENDPOINT FOR PREDICTING OVERALL SURVIVAL (OS) OF PROSTATE CANCER (PCA) PATIENTS?

You have accessJournal of UrologyProstate Cancer: Staging III1 Apr 2010405 IS 3-MONTHS PROST-TREATMENT RECIST EVALUATION OF BONE METASTASES BY MRI OF THE AXIAL SKELETON (ASMRI) A SURROGATE ENDPOINT FOR PREDICTING OVERALL SURVIVAL (OS) OF PROSTATE CANCER (PCA) PATIENTS? Bertrand Tombal, Jean-Pascal Machiels, Annabelle Stainier, Bruno Vande Bergh, and Frederic Lecouvet Bertrand TombalBertrand Tombal More articles by this author , Jean-Pascal MachielsJean-Pascal Machiels More articles by this author , Annabelle StainierAnnabelle Stainier More articles by this author , Bruno Vande BerghBruno Vande Bergh More articles by this author , and Frederic LecouvetFrederic Lecouvet More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.474AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Correct evaluation of tumor response in patients with metastatic PCa is confounded by a high frequency of bone metastases. Here we have analyzed whether RECIST criteria calculated on bone metastases using asMRI can be developed as a potential surrogate for OS METHODS We have prospectively enrolled 65 metastatic PCa patients scheduled to received treatment within 2 weeks, including 38 hormone naïve PCa (HNPC) scheduled to receive androgen deprivation therapy (ADT) and 27 castration-resistant PCa (CRPC) scheduled to received docetaxel based chemotherapy. In addition to standard follow-up, asMRI was performed 2 wks before and 3 mths after treatment. RECIST were performed on focal lesions the two sequential asMRI to define complete response (CR), partial response (PR), stable disease (SD) or progression (PROG). PSA is define as drop ≥ 80% in HNPC and ≥ 30% in CRPC. RESULTS Mean OS is 43 (95%CI 32-54) mths in HNPC. PSA drop ≥ 80% occurred in 78% HNPC. This does not predict OS (HR 1,6; 95%CI 0,7-4,1; p=0,271). Only 5 HNPC patients experienced a CR on asMRI, 3 a PR, 7 a SD and 15 a PROG. Progression at 3 months was significantly associated with a shorter OS, 33 (95%CI 20-47) months for PROG vs. 50 (95%CI 39-60) months for CR/PR/SD (p for log-rank: 0,033). The HR of PROG for OS is 2,6; 95%CI 1,1- 6,5; p=0,040). Mean OS is 22 (95%CI 15-28) mths in CRPC. Nineteen (70%) CRPC patients experienced a PSA response ≥ 30%; this does not predict OS (HR 2.1; 95%CI 0.8-5.6: p= 0.105). In patients experiencing a PSA decrease ≥ 30%, asMRI demonstrate CR in only 2 patients, SD in 7 and PROG in 10. In those with a PSA drop < 30%, there were no CR, SD and 6 PROG. Progression at 3 months was significantly associated with a shorter OS, 17 (95%CI 11-23) for PROG vs. 34 (95%CI 21-46) months for CR/PR/SD (p for log-rank: 0,037). The HR of PROG for OS is 2,8; 95%CI 1,0- 8,0; p=0,045) CONCLUSIONS This suggests that RECIST progression in bone metastases, defined by asMRI is of potential interest as a surrogate for OS in clinical trials of metastatic prostate cancer. In addition, no CR or PR were observed in patients presenting with diffuse infiltration of the bone marrow, suggesting a very poor prognostic group in which alternative treatment strategies could be initiated earlier. Brussels, Belgium© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e160-e161 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bertrand Tombal More articles by this author Jean-Pascal Machiels More articles by this author Annabelle Stainier More articles by this author Bruno Vande Bergh More articles by this author Frederic Lecouvet More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abstract A221: Results of preclinical and clinical phase I/II open-label dose-ranging trial with HE3235, a synthetic adrenal hormone, in castrate-resistant prostate cancer

Abstract Background: HE3235 (17α-ethynyl-5α-androstane-3α, 17β-diol) is an androstenediol analog, which shows activity in preclinical CRPC and breast cancer models. HE3235 decreased AR expression in LNCaP cells in vitro, in the CRPC LuCaP 35V xenograft, and suppressed ER-a expression in MNU-induced breast tumors in rats. HE3235 also decreased intra-tumoral androgen synthesis (both T and DHT) in the LuCaP 35V tumors. In toxicology studies, it decreased steroidogenesis (DHEA and T in male dogs and sex steroids in female rats). HE3235 did not inhibit CYP17 in H295R adrenal tumor cells, but inhibited the conversion of d-cholesterol to d-pregnenolone. We are therefore conducting a Phase I/II clinical study in CRPC patients to determine safety, tolerance, pharmacokinetics, maximum tolerated dose and activity of this compound. Methods: Men with CRPC and an ECOG PS of &amp;lt;2 who progressed either radiographically or biochemically through at least one taxane-containing chemotherapy regimen are eligible. HE3235 is given orally, twice daily in cohorts of 3–6 pts. Cohorts were defined by doses of 10 mg, 20 mg, 30 mg, 50 mg or higher until MTD is observed. Cohorts may be expanded based on dose limiting toxicity, activity or pharmacokinetics demonstrating adequate blood concentrations of drug to deliver a therapeutic effect. Subjects were treated on 28-day cycles until toxicity or disease progression. Scans were obtained every 2 cycles. The Prostate Cancer Consortium Clinical Trials consortium sites were supported by a grant form the Department of Defense. Results: 22 subjects have been treated to date at doses of 10 mg/day (n=7), 20 mg/day (n=9) and 30 mg/day (n=6). Dose escalation continues to determine the MTD. Pharmacokinetics was dose proportional with a drug half-life of 11–14 hours. HE3235 was well tolerated. Nine of 22 subjects experienced a drop in PSA during treatment with 6 of 22 equal to or greater than 20%. No patient had a 50% decline in PSA. Eight of 17 (47%) subjects who were evaluable for response had stable disease. Median time to progression was 56 days (IQR 55, 224) for 10 mg/day, 112 days (IQR 56, 168) for 20 mg/days, 112 days (IQR 56, &amp;gt;122) for 30 mg/day and 112 days (IQR 56, 168) for all 22 subjects. Conclusion: HE3235 is a novel, small orally delivered compound with preclinical activity for CRPC. It is well tolerated through a dose of 30 mg, and has a T1/2 linear to dose in cohorts tested to date. The trial continues to accrue, and a cohort of patients with chemotherapy-naïve CRPC will be enrolled into the ongoing Phase I/II Study. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A221.

Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of LBH589, a novel deacetylase (DAC) inhibitor given intravenously on a new once weekly schedule

14019 Background: LBH589 is a novel deacetylase inhibitor that inhibits proliferation of tumor cells at nanomolar levels. This phase I study tested the safety and tolerability of IV LBH589 once each week for 3 of 4 wks in pts with advanced solid tumors or lymphoma. Methods: LBH589 was administered IV over 30 min. on days 1, 8 and 15 of a 28-day cycle. Western blots on peripheral blood lymphocytes were used to study histone acetylation (HA). Plasma PK profiles were analyzed on Days 1 and 8. Results: Thirty five pts (median age: 70 yrs; 23M, 12F) have been treated on 3 dose levels [10 mg/m2 (8pts), 15 mg/m2 (8 pts), 20 mg/m2 (19 pts)] with the following tumor types: Cutaneous and peripheral T cell lymphoma (7 pts), prostate (6 pts), mesothelioma (4 pts), colon (3 pts) and other (15 pts). There was one dose-limiting toxicity (transient grade 4 thrombocytopenia) at 20 mg/m2, none at the lower doses. Other G3/G4 toxicities (all cycles) include: transient thrombocytopenia (G4–5 pts, G3–5 pts), neutropenia (G3–2 pts), anemia (G3–5 pts), G3 hypophosphatemia (1 pt), G3 hypokalemia (1 pt), G3 nausea (1 pt) and G3 pruritus (1 pt). Thrombocytopenia was transient. Of 2,042 ECGs, 1 pt had an increase in QTcF from baseline of &gt; 60 msec another with a QTcF &gt;500 msec, both at 20 mg/m2. There was a dose-dependent increase in HA 7 days after one dose with 43% (10 mg/m2), 50% (15 mg/m2) and 60% (20 mg/m2) of pts with increased acetylation. The LBH589 plasma conc. peaked at the end of the 0.5 hr infusion with a mean terminal half-life of 16 hr. Median Cmax achieved with 20 mg/m2 was 1,000 ng/mL (2.86 μM). The AUC0-inf increased linearly with IV doses of 10–20 mg/m2. One pt with CTCL achieved a complete response (CR) on cycle 3, Day 1; this pt had previously received oral LBH589 at 20 mg MWF, achieving a CR on cycle 6, Day 28 that lasted for 7 months. One peripheral T-Cell lymphoma pt achieved a partial response that has persisted for &gt;7 months. One pt with prostate cancer has had a 26% reduction in nodal disease and &gt; 50% drop in PSA in the first 2 cycles. Conclusions: The maximum tolerated dose of LBH589 given IV wkly on a 3 of 4 wk schedule is 20 mg/m2. This dose produced sustained PD effects and higher systemic exposure compared to oral LBH589. Preliminary evidence of antitumor activity has been observed. No significant financial relationships to disclose.

PSA bounce phenomenon after transperineal interstitial permanent prostate brachytherapy for localized prostate cancer

We described the temporarily increase phenomenon in prostate-specific antigen level (PSA bounce) after transperineal interstitial permanent prostate brachytherapy (TIPPB) for localized prostate cancer. From December 1998 to May 2003, 500 consecutive patients with localized prostate cancer were treated with TIPPB using iodine-125 or palladium-103. We examined 200 patients who have more than 2-year PSA follow-up. Median follow-up length was 1,069 days (range, 712-1,411 days). No patient received neoadjuvant or adjuvant hormone therapy. PSA determinations were performed every 3 months for the first 2 years after procedure, and every 6 months hereafter. PSA bounce was defined as an increase of 0.1 ng/ml or greater above the preceding PSA level after implant followed by a subsequent decrease below that level. The American Society for Therapeutic Radiology and Oncology (ASTRO) consensus panel criteria 1996 were used to define biochemical failure. PSA bounce was observed in 40% (80/200) of the cases receiving TIPPB. The median time to PSA bounce was 13 months from the day of implant. The median magnitude of the PSA bounce was 0.3 ng/ml from the pre-bounce level. Twelve cases demonstrated biochemical failure according to the ASTRO consensus guidelines of three consecutive rises in PSA. Ten of these subsequently showed a drop in PSA, consistent with biologic control of their disease. Two cases remain classified as apparent biochemical failures. A transient rise in the PSA following TIPPB, the so-called "bounce" is a common occurrence. The apparent PSA control of ten of twelve cases failing by the ASTRO criteria raises some concern. Further observation will be necessary to determine ways to discriminate these from true disease progression.