Prostate Cancer Clinical Trials Consortium Research Articles

Cilengitide (EMD 121974, NSC 707544) in asymptomatic metastatic castration resistant prostate cancer patients: a randomized phase II trial by the prostate cancer clinical trials consortium

Integrins are involved in prostate cancer metastasis by regulating cell adhesion, migration, invasion, motility, angiogenesis and bone metabolism. We evaluated the efficacy of two dose levels of cilengitide in patients (pts) with castrate resistant prostate cancer (CRPC). Chemotherapy-naïve, asymptomatic metastatic CRPC pts were randomized to cilengitide 500 mg or 2,000 mg IV twice weekly using parallel 2-stage design. The primary endpoint was rate of objective clinical progression at 6-months. Secondary endpoints included clinical and PSA response rates, safety and effects of cilengitide treatment on circulating tumor cells (CTCs) and bone remodeling markers. Forty-four pts were accrued to first stage (22/arm). Median number of cycles was three in both arms (500 mg arm: 1-8; 2,000 mg arm: 1-15). At 6 months, two pts (9%) on the 500 mg arm and five pts (23%) on the 2,000 mg arm had not progressed. Best objective response was stable disease (SD) in seven pts for 9.9[8.1,20.9] months. There were three grade 3 and no grade 4 toxicities. At 12 weeks, analysis of bone markers did not reveal significant trends. At progression, bone specific alkaline phosphatase and N-telopeptide increased in all pts, less so in pts on the 2,000 mg arm and in pts on both arms who obtained SD at 6 months. CTCs increased over time in both arms. Cilengitide was well tolerated with modest clinical effect in favor of the higher dose. The unique trial design including a shift from response rate to objective progression as the endpoint, and not acting on PSA increases was feasible.

Prostate cancer clinical trials consortium: A multicenter mechanism for the rapid design, development, and implementation of early phase clinical trials

e16065 Background: Leading investigators in prostate cancer have hypothesized that clinical trials (CT) are optimally conducted as multicenter studies. To test this, the Prostate Cancer Clinical Trials Consortium (PCCTC) was formed with support from the Prostate Cancer Foundation (PCF) and the Department of Defense Clinical Consortium Award (DOD). Since the PCCTC's inception in 2006, members have cooperatively designed, carried out, and evaluated phase 1 and 2 multicenter studies in prostate cancer. Methods: PCF and DOD awards support a consortium of 13 cancer research centers. Memorial Sloan-Kettering Cancer Center serves as the coordinating center and is charged with creating an infrastructure to conduct early phase, multicenter trials. Annually, each participating center is required to introduce at least one CT for consideration by the PCCTC and accrue at least 35 patients to PCCTC studies. Investigators meet face-to-face twice per year to discuss the PCCTC's progress, and hold monthly conference calls to discuss scientific objectives, trial design, and ongoing studies. Results: Since inception, the PCCTC has expanded from 8 to 13 leading research centers. Through September 2008, it has opened 47 trials and accrued 1,282 patients at member sites. Members utilize a CT management system for protocol tracking, electronic data capture, and data storage. A legal framework has been instituted, and standard operating procedures, administrative structure, editorial support, centralized budgeting, and mechanisms for scientific review have been established. Each year, the number of trials presented and patients accrued increases, and three concepts have progressed to the next phase of clinical testing. Conclusions: The PCCTC fulfills a congressional directive to create a CT instrument dedicated to rapid accrual to early-phase, multicenter studies in prostate cancer. The member institutions have built a shared administrative, informatics, legal, financial, statistical, and scientific infrastructure to support this endeavor. As the PCCTC has expanded and taken an increasingly active role in designing and evaluating protocols, clinical trials continue to open and accrue in excess of federally mandated goals. No significant financial relationships to disclose.

Ixabepilone, mitoxantrone, and prednisone in patients with metastatic castration-resistant prostate cancer refractory to docetaxel-based therapy: A phase II study of the DOD Prostate Cancer Clinical Trials Consortium

5058 Background: Mitoxantrone (M) plus prednisone (P) and ixabepilone (Ix) each have modest, non cross-resistant activity as second line chemotherapy regimens in docetaxel-refractory patients with CRPC. These agents were therefore combined in a phase I study which demonstrated anti-cancer activity and defined the recommended phase II dose used in this trial. Methods: Patients with metastatic CRPC and progression after 3 or more cycles of docetaxel were enrolled in a phase II multicenter study of the combination of prednisone 5 mg BID, Ix (35 mg/m2) and M (12 mg/m2) administered intravenously on day 1 every 21 days, with pegfilgrastim (6 mg on day 2) support. Results: To date, 43 pts have been enrolled and have received a median of 4 cycles. Of 37 patients currently evaluable for response, 14 (38%; 95% CI: 22–55%) have had a confirmed ≥50% decline in PSA and 19 (51%; 95% CI 34–68%) have had a confirmed ≥30% decline in PSA. Two of 15 patients with evaluable measurable disease (13%) have had a RECIST-defined objective response. All 43 patients are evaluable for toxicity. Grade 3 or 4 neutropenia was seen in 6 pts (17%) and grade 3 or 4 thrombocytopenia was seen in 3 (8%). Nonhematologic grade 3/4 events possibly related to study drug have included grade 3 fatigue (3 pts), grade 3 pneumonia (2 pts), and grade 3 atrial fibrillation, grade 4 myocardial infarction, grade 4 prostatitis, grade 3 nausea/vomiting, grade 3 neuropathy, grade 3 elevated transaminases, grade 3 dizziness, grade 3 dehydration, grade 3 shortness of breath, and grade 4 vasovagal syncope (1 pt each). Grade 2 neuropathy has been seen in 4 patients. Conclusions: The Ix, M, P regimen is active as second-line therapy in CRPC patients with progressive disease after docetaxel therapy and is reasonably well tolerated. Further investigation of this regimen is warranted. This study was supported in part by CTEP/NCI and the DOD Prostate Cancer Clinical Trials Consortium. [Table: see text]

Pain and analgesic use in men with metastatic prostate cancer

e20515 Background: Pain is an important endpoint in metastatic prostate cancer and was the basis for the 1996 FDA approval of mitoxantrone. Standards for pain assessment have evolved, and a 2006 draft FDA guidance provides new recommendations for patient- reported outcomes. Contemporary palliation models generally require pain reduction starting from baseline worst pain scores of ≥4/10, and progression models require a sufficient proportion of patients’ pain scores to worsen in order to assure an adequate effect size. The prevalence and distribution of pain severity at specific points in the prostate cancer disease continuum are not well defined. Consequently, it is unclear if sufficient numbers of patients are available to conduct prospective studies using pain palliation or prevention as primary endpoints. Methods: A questionnaire that includes the Brief Pain Inventory and additional pain/analgesia items was developed as a collaboration between the DOD/PCF-supported Prostate Cancer Clinical Trials Consortium (PCCTC) and FDA Study Endpoints and Labeling Design (SEALD) team. IRB waivers were obtained for anonymous administration at 5 PCCTC institutions (Sloan-Kettering, Duke, Johns Hopkins, Anderson, OHSU). Administration is ongoing. Results: Between August-December 2008, 325 men with prostate cancers representing different disease states being seen in outpatient clinics of participating centers were each queried once. Median age was 70 (range 49–87). More than half (n=175) self-reported metastatic disease, including 129 with bone metastases. Among those with bone metastases, 76 (59%) reported experiencing any level of pain in the last week; 49 (38%) reported a worst pain score ≥4/10 of which 38 (78%) used analgesics over the past week and 31 (63%) used daily analgesia. In addition, 70 of the 76 (92%) noted that their pain interfered with work, sleep, or enjoyment of life, with 25 (33%) noting severe interference. Among the 49 patients with pain scores ≥4/10, current or past docetaxel use was reported by 32 (65%), androgen deprivation therapy by 47 (96%), and 28 (57%) had been or were currently enrolled in a clinical trial. Conclusions: Pain is sufficiently prevalent in men with metastatic prostate cancer to enable prospective assessment of palliation endpoints in clinical trials. No significant financial relationships to disclose.

Pharmacodynamic (PD) study of pre-prostatectomy rapamycin in men with advanced localized prostate cancer (PC): A DOD Prostate Cancer Clinical Trials Consortium Trial

5001 Background: Rapamycin is an orally bioavailable and generic mTOR inhibitor with an MTD of 6 mg daily and anticancer activity in solid tumors. We sought to determine the optimal biologic dose (OBD) in the pre-operative setting in men with PC. Methods: We explored the safety and PD activity of 3 and 6 mg of daily oral rapamycin for 14 days prior to radical prostatectomy (RP) in cohorts of 21 men with intermediate risk localized PC. Ten untreated control subjects were included using identical inclusion criteria. Men had Gleason >6 PC involving multiple cores. PD markers in pre-treatment prostate biopsies and RP specimens included p-S6 and p-Akt, 4EBP-1, PTEN, p27, Ki-67, and cleaved caspase-3. Tissue and whole blood sirolimus levels were measured. A Simon 2-stage design using PD efficacy (tumor S6 inhibition > 60%) was utilized. Results: 32 subjects were accrued to this 2 stage pharmacodynamic trial, including 10 control subjects. Median pre-treatment PSA was 6.4 ng/dl, age 60y, Gleason 7 in 85%. 20 accrued to the 3 mg cohort without DLT. However, 2/2 men enrolled at the 6 mg dose level experienced DLT consisting of thrombocytopenia leading to a delay in surgery (<100K) and fever with grade 3 stomatitis. AEs observed in the 3 mg cohort included stomatitis (2), rash (1), post-operative ileus (2), and mild neutropenia (2). One post-operative ileus was observed among control patients. PD studies demonstrated tumor S6 inhibition in >50% of subjects (median 60% decline, p=0.026 vs. baseline) with no negative effect on the state of Akt phosphorylation (p=0.82) or p27 levels (p=0.10). Prostate sirolimus levels (range 7.1–47.2 ng/g) were two-fold higher than whole blood concentrations (range 3.2–19.2 ng/ml). There was no effect of rapamycin on rates of post-operative wound healing or bleeding. PBMC S6 activity inhibition did not correlate with tumor S6 inhibition. Conclusions: The MTD/OBD of daily rapamycin in the pre-operative or prevention setting is 3 mg. This dose demonstrated downstream mTOR inhibition in tumor tissue and achieved adequate prostate tissue levels. Additional PD and genomic studies will be presented. Conducted through the DOD PCCTC and registered at clinicaltrials.gov as NCT00311623 . [Table: see text]

A phase II study of neoadjuvant chemotherapy with docetaxel and bevacizumab in patients (pts) with high-risk localized prostate cancer: A Prostate Cancer Clinical Trials Consortium trial

5060 Background: Treatment options for high-risk localized prostate cancer remain inadequate, with the majority of pts relapsing despite surgery or radiation therapy. We conducted a phase II multicenter trial of neoadjuvant docetaxel and bevacizumab prior to radical prostatectomy in pts with high risk localized prostate cancer. Methods: Eligibility included any of the following: PSA > 20 ng/ml or PSA velocity > 2 ng/ml/yr, cT3 disease, any biopsy Gleason 8–10, Gleason 7 with T3 disease by endorectal (er) MRI. Also, >50% biopsy cores involved and either Gleason 7 or PSA >10 or cT2 disease were eligible. Pts were treated with docetaxel 70 mg/m2 q 3weeks x 6 cycles and bevacizumab 15 mg/m2 q 3 weeks x 5 cycles. The primary endpoint was erMRI partial response (PR, defined here as >50% decrease in tumor volume) in a single target lesion after chemotherapy. Results: 42 pts were registered and treated with 220 cycles so far. Median age was 55 yrs (range 41–67). Median Gleason score was 8 (69% with Gleason 8–10 cancer). Median PSA was 10.5 ng/ml (range 2.1–72.5). Clinical stage was T2 in 46% and T3 in 32%. Of 23 evaluable pts to date, the median decline in the maximal tumor volume by erMRI was -45% (range -84% to 110%). 9/23 (39%) patients had PR, and only 1 pt had radiographic progression. Any PSA decline was noted in 22/34 (65%) evaluable pts, with 18% having a >50% decline. Treatment was well-tolerated: 2 pts had grade 3 allergic reactions requiring discontinuation, 3 had febrile neutropenia and 1 had grade 3 hyperglycemia. Mild fatigue was common. Only 1 pt stopped treatment because of a rising PSA. To date, 31 pts have had radical prostatectomy. One had intraoperative bladder neck injury and was treated instead with radiation + hormone therapy. A second pt had an intraoperative rectal injury but completed surgery. Conclusions: Neoadjuvant docetaxel and bevacizumab demonstrates clinical evidence of activity in men with high-risk localized prostate cancer, with a 39% PR rate by erMRI and PSA declines noted in 65%. Treatment was well-tolerated. The study is ongoing and updated data on response, toxicity and pathology will be presented. [Table: see text]

A randomized, phase II study of ATN-224 in patients with biochemically relapsed, hormone-naive prostate cancer: A DOD/PCF Prostate Cancer Clinical Trials Consortium trial

5135 Background: ATN-224 (choline tetrathiomolybdate) is an orally active, small molecule that has antiangiogenic and antitumor effects in prostate cancer (PCa) models. ATN-224 targets Cu2+/Zn2+superoxide dismutase 1 (SOD1) and suppress the generation of H2O2 leading to activation of a number of phosphatases, a group of negative growth regulatory enzymes. We hypothesized that ATN-224 may induce antitumor effect as an antiangiogenic (at 30 mg dose level) and possesses direct antitumor activity at higher dose (300 mg/day). Methods: PCa pts with PSA doubling time (PSADT) of < 12 months, no radiographic evidence of metastasis, no hormonal therapy within 6 months were enrolled. All pts had testosterone > 150 ng/dL at baseline. ATN-224 was administered at 2 dose levels. PSA progression was defined as at least a 50% increase in PSA and >5 ng/mL increase from baseline or post-treatment nadir and confirmed. Endpoints included the proportion of pts who did not have PSA progression for 24 weeks, change in PSA slope/PSADT, and assessment of safety and tolerability. The study was not powered to detect difference between the two groups. Results: 52 pts were enrolled at 6 centers. Fourteen of 27 (52%) in the low dose and 6/25 (24%) in the high dose cohort were PSA progression free for 24 weeks. One patient in high dose cohort showed PSA >50% decrease of 40 days duration. Pre- and on-treatment PSA kinetics are shown below. Median duration on study was 134 days in both groups. ATN-224 was well tolerated with a few reversible Grade 3/4 neutropenia and Grade 3 skin rash (both 4%). Conclusions: ATN-224 may have biologic activity in men with androgen-dependent PCa at low doses, as demonstrated by > 50% of pts being PSA progression free at 6 month and a significant decrease in mean PSA slope. The implication of this study is not clear without a comparative design and ceruloplasmin correlation which is still pending. [Table: see text] [Table: see text]

Phase I Study of Ixabepilone, Mitoxantrone, and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Therapy: A Study of the Department of Defense Prostate Cancer Clinical Trials Consortium

Mitoxantrone plus prednisone and ixabepilone each have modest activity as second-line chemotherapy in docetaxel-refractory castration-resistant prostate cancer (CRPC) patients. Clinical noncrossresistance was previously observed. Metastatic CRPC patients progressing during or after taxane-based chemotherapy enrolled in a phase I multicenter study of ixabepilone and mitoxantrone administered every 21 days along with prednisone. Ixabepilone and mitoxantrone doses were alternately escalated in a standard 3 + 3 design. Patients were evaluated for toxicity and disease response. Dose-limiting toxicities (DLTs) were defined as treatment related, occurring during cycle 1, and included grade 4 prolonged or febrile neutropenia, thrombocytopenia (grade 4 or grade 3 with bleeding), or > or = grade 3 nonhematologic toxicity. Thirty-six patients were treated; 59% of patients experienced grade 3/4 neutropenia. DLTs included grade 3 diarrhea (n = 1), prolonged grade 4 neutropenia (n = 4), and grade 5 neutropenic infection (n = 1). Due to prolonged neutropenia, the highest dose levels were repeated with pegfilgrastim on day 2 of each cycle. The maximum tolerated dose in combination with pegfilgrastim was not exceeded. The recommended phase II dose is mitoxantrone 12 mg/m2 and ixabepilone 35 mg/m2 every 21 days, pegfilgrastim 6 mg subcutaneously day 2, and continuous prednisone 5 mg twice per day. Thirty-one percent of patients have experienced > or = 50% prostate-specific antigen (PSA) declines, and two experienced objective responses. Of 21 patients treated with mitoxantrone 12 mg/m2 plus ixabepilone > or = 30 mg/m2, nine (43%) experienced > or = 50% PSA declines (95% CI, 22% to 66%). These results suggest that the combination of ixabepilone and mitoxantrone is feasible and active in CRPC and requires dosing with pegfilgrastim.

Department of Defense Prostate Cancer Clinical Trials Consortium: A New Instrument for Prostate Cancer Clinical Research

Background In 2005, the US Department of Defense, through the US Army Medical Research and Materiel Command, Office of the Congressionally Directed Medical Research Programs, created a funding mechanism to form a clinical trials consortium to conduct phase I and II studies in prostate cancer. This is the first report of the Prostate Cancer Clinical Trials Consortium (PCCTC). Patients and Methods The Department of Defense award supports a consortium of 10 prostate cancer research centers. Memorial Sloan-Kettering Cancer Center was awarded the Coordinating Center grant for the consortium and charged with creating an infrastructure to conduct early-phase multicenter clinical trials. Each participating center was required to introduce ≤1 clinical trial per year and maintain accrual of a minimum of 35 patients per year. Results The PCCTC was launched in 2006 and now encompasses 10 leading prostate cancer research centers. Fifty-one trials have been opened, and 1386 patients have been accrued at member sites. Members share an online clinical trial management system for protocol tracking, electronic data capture, and data storage. A legal framework has been instituted, and standard operating procedures, an administrative structure, editorial support, centralized budgeting, and mechanisms for scientific review are established. Conclusion The PCCTC fulfills a congressional directive to create a clinical trials instrument dedicated to early-phase prostate cancer studies. The member institutions have built an administrative, informatics, legal, financial, statistical, and scientific infrastructure to support this endeavor. Clinical trials are open and accruing in excess of federally mandated goals.

Department of Defense prostate cancer clinical trials consortium: A new instrument for prostate cancer clinical research

Department of Defense prostate cancer clinical trials consortium: A new instrument for prostate cancer clinical research

160 POSTER Phase I-II study of MDV3100 in castration resistant prostate cancer. The Prostate Cancer Clinical Trials Consortium

160 POSTER Phase I-II study of MDV3100 in castration resistant prostate cancer. The Prostate Cancer Clinical Trials Consortium

Suberoylanilide hydroxamic acid (vorinostat) post chemotherapy in hormone refractory prostate cancer (HRPC) patients (pts): A phase II trial by the Prostate Cancer Clinical Trials Consortium (NCI 6862)

5132 Background: Histone deacetylases (HDACs) are key regulators of histone acetylation status, which is critical to expression of genes implicated in the regulation of cell survival, proliferation, differentiation and apoptosis. Vorinostat is a potent oral HDAC inhibitor with anti-tumor activity in PC models and in phase I clinical trials. A phase II trial is assessing vorinostat in HRPC pts. Methods: Eligible pts had disease progression on 1 prior chemotherapy for HRPC, a PSA of ≥ 5ng/ml, and adequate organ function. Vorinostat was administered orally at 400 mg daily in 21-day cycles. Response was assessed every 12 weeks. The primary endpoint is proportion of pts without progression at 6 months by objective and biochemical measures. This study is designed to accrue 29 pts (80% power at the 5% significance level to distinguish between a rate of 10% vs 30%). If ≥ 7/29 pts are progression-free at 6 months, the drug will be recommended for further study. Secondary endpoints include safety, rate of PSA decline, objective response rate and overall survival. Correlative studies assessing the effect of vorinostat on serum levels of IL-6, soluble IL-6 receptor and gp130 levels were conducted. Results: To date 23/29 pts have been accrued. Median age is 68 years (range 54–77), 70% had performance status 1 and 78% are white. At registration disease progression was defined by: PSA in 83%, bone in 74% and soft tissue in 43%. Median number of cycles is 2 (range 1–6), 57% of pts required at least 1 dose reduction. At time of this report 39% of pts remain on therapy. 19 pts are toxicity evaluable. Most common treatment related adverse events (AEs) were: fatigue (74%), anorexia (63%), nausea (58%), diarrhea (32%), dehydration, taste alteration and vomiting (26% each). There was 1 grade (G) 4 thrombosis and 11 pts had G 3 AEs, the most common were: fatigue (32%) and nausea and anorexia (11% each). 3/9 response evaluable pts achieved stable disease. Conclusions: Vorinostat is feasible post chemotherapy in pts with HRPC, however it is associated with significant toxicities requiring dose reductions. Final efficacy, safety and correlative studies will be reported. Support: CTEP, N01-CM-62201, PC051375, PC 051382 No significant financial relationships to disclose.

EMD121974 (NSC 707544, cilengitide) in asymptomatic metastatic androgen independent prostate cancer (AIPCa) patients (pts): A randomized trial by the Prostate Cancer Clinical Trials Consortium (NCI 6372)

5137 Background: Integrins avβ3 and avβ5 are essential to PCa metastasis by regulating cell adhesion, migration, invasion and motility. Cilengitide is a potent and selective avβ3 and avβ5 integrin receptor antagonist that in phase I studies has shown clinical activity. Methods: Pts with asymptomatic, metastatic chemo-naive AIPCa with PSA or objective progression, no visceral disease, minimum PSA of 5ng/ml, and adequate organ function were randomized to cilengitide 500 mg or 2,000 mg IV 2X weekly in 6-week cycles, using modified randomized selection design. Disease status was assessed every 12 weeks. The primary end point is objective progression rate (not including PSA) at 6 months. The Simon 2-stage optimal design is used to accrue 53 pts/arm. After first stage (20 pts/arm), accrual continues if ≥ 6 pts have not progressed. If second stage accrual is initiated, at end of study, the better performing arm will be chosen for further study provided at least 18/53 pts in that arm have not progressed. Secondary end points include safety, response rates and correlative measures of cilengitide effect on circulating and bone marrow tumor and endothelial cells and on bone remodeling markers. Results: First stage accrual is complete with 42 pts registered. Median performance status is 0, median age is 71 years (range 52–85), and median PSA is 44ng/ml (range 5–870). Disease progression at registration was defined by PSA in 90%, soft tissue in 36% and bone in 31% of pts. Median number of cilengitide cycles is 3 (range 1–8). To date, 32/42 pts have received ≥ 2 cycles. The most common (>5%) treatment related adverse events (AE): fatigue (38%), constipation (13%), anorexia (10%), leucopenia (8%) and nausea (8%). There were only 3 grade (G) 3 AEs (neutropenia, lymph node pain, lymph NOS) and no G4 AEs. Only 3 pts required dose modification. 25/42 pts were removed from protocol on or before 6 months, 6 pts received therapy for more than 6 months, and 11 are too early to assess. Conclusions: Cilengitide is well tolerated. Final results (efficacy, safety, correlative studies) of the first stage of accrual will be reported. Supported by CTEP, Prostate SPORE Grant P50 CA069568- 09, PC051375, Merck KGaA, PC051382. [Table: see text]