Randomized, double-blind, vector-controlled study of targeted immunotherapy in patients (pts) with hormone-refractory prostate cancer (HRPC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2501-2501 ◽  
Author(s):  
P. W. Kantoff ◽  
L. M. Glode ◽  
S. I. Tannenbaum ◽  
D. L. Bilhartz ◽  
W. G. Pittman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Scan ◽  
Single Case ◽  
Phase 1 ◽  
Specific Antigen ◽  
Safety Data ◽  
Data Monitoring Committee ◽  
Controlled Study ◽  
Double Blind ◽  
Gm Csf

2501 Background: Therapeutic vaccines for prostate cancer have yielded encouraging data in uncontrolled Phase 1 and 2 studies. PROSTVAC-VF comprises 2 recombinant viral vectors each containing genes encoding the prostate-specific antigen (PSA) gene modified to optimize antigen presentation in HLA-A2+ pts and 3 T-cell costimulatory molecules (B7.1, LFA3, and ICAM-1 [TRICOM]). These vectors are administered in a heterologous prime-boost regimen with concurrent low-dose GM-CSF to enhance recruitment of antigen-presenting cells to the immunization site. Here we report results of a Phase 2 study in pts with metastatic HRPC. Methods: In this randomized, double-blind, controlled study, pts were randomized 2:1 to receive either PROSTVAC-VF plus GM-CSF or Control (empty vectors plus GM-CSF placebo) for 24 weeks. Eligible pts had rising PSA despite castrate testosterone levels and measurable, asymptomatic or non-narcotic-dependent metastases (positive bone scan or lymph node metastases on abdominal-pelvic CT scan). The primary endpoint is progression-free survival (PFS), with progression defined as appearance of new lesions on bone scan or RECIST-defined progression of nodal metastases. The planned sample size was 120 pts. The study was designed to detect a difference of 38% vs 12% PFS at Week 24 with a 2-sided α of 0.05 and 80% power. An independent Data Monitoring Committee evaluated safety data quarterly. Results: 125 pts were enrolled. Demographics are available for 122 pts (mean age, 73.3 years [range, 52–94]; ∼11% African American). Common adverse events (AEs) in 106 evaluable pts (blinded as of Jan 2006) included immunization site reactions (73%), fatigue (26%), fever (14%), and nausea (13%). The majority were of Grade 1/2 severity. Serious AEs attributed to immunization included 1 thrombotic thrombocytopenic purpura (TTP) event. Conclusions: A large, randomized, controlled study of therapeutic immunization with PROSTVAC-VF in 125 pts with metastatic HRPC has been completed. The therapy is well tolerated and findings are consistent with Phase 1 results, but also included a single case of TTP. Full efficacy data collection is ongoing. [Table: see text]

PROTEUS: A randomized, double-blind, placebo (PBO)-controlled, phase 3 trial of apalutamide (APA) plus androgen deprivation therapy (ADT) versus PBO plus ADT prior to radical prostatectomy (RP) in patients with localized high-risk or locally advanced prostate cancer (PC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5100-TPS5100 ◽  
Author(s):  
Mary-Ellen Taplin ◽  
Martin Gleave ◽  
Christopher P. Evans ◽  
Eleni Efstathiou ◽  
Philip W. Kantoff ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Specific Antigen ◽  
Data Monitoring Committee ◽  
Eligibility Criteria ◽  
Double Blind ◽  
End Points ◽  
Free Survival

TPS5100 Background: Patients (pts) with localized high-risk PC experience disease progression rates of approximately 50% after RP (Kane et al. J Urol. 2007). With the approval of next-generation androgen receptor inhibitors, neoadjuvant studies have shown that 6 months of androgen blockade may improve local disease control at the time of RP (McKay et al. Prostate Cancer Prostatic Dis. 2017; Taplin et al. JCO. 2014). The purpose of this study is to determine if treatment with APA plus ADT before and after RP in pts with localized high-risk or locally advanced PC results in an improvement in pathologic complete response (pCR) rate and metastasis-free survival (MFS) compared with PBO plus ADT. Methods: This international multicenter trial is enrolling pts with localized high-risk or locally advanced PC who are candidates for RP. Eligibility criteria: Any Gleason score (GS) ≥ 4 + 3 with ≥ 6 positive systematic biopsies (SB); any GS ≥ 4 + 3 with ≥ 3 SB and prostate-specific antigen (PSA) ≥ 20 ng/mL; GS ≥ 9 in ≥ 1 SB or targeted biopsies (TB); or ≥ 2 SB or TB with continuous GS ≥ 8, each with ≥ 80% involvement. Stratification: GS (7 or ≥ 8), cN0 or N1, and region (North America, Europe, or rest of world). Randomization: 1:1 to APA (240 mg) plus ADT (LHRHa) or PBO plus ADT. Pts will receive 6 treatment cycles, followed by RP, followed by an additional 6 cycles. Dual primary end points: pCR rate (to be assessed by blinded independent central pathology review) and MFS (to be assessed by blinded independent central radiology review [BICR]). Secondary end points: PSA-free survival and progression-free survival. Imaging with CT or MRI and bone scan will be conducted at baseline and then every 6 months following biochemical failure until documented distant metastasis by BICR, or death. Approximately 1500 pts will be enrolled globally over 3.0 years in 240 sites in 19 countries. An independent data monitoring committee is commissioned to review trial data. Clinical trial information: NCT03767244.

A phase 3, multicenter, randomized, double-blind, placebo-controlled study of rilotumumab in combination with cisplatin and capecitabine (CX) as first-line therapy for Asian patients (pts) with advanced MET-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The RILOMET-2 trial.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. TPS226-TPS226 ◽  
Author(s):  
Toshihiko Doi ◽  
Yoon-Koo Kang ◽  
Kei Muro ◽  
Yizhou Jiang ◽  
Rajul K. Jain ◽  
...  
Keyword(s):  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Data Monitoring Committee ◽  
Controlled Study ◽  
Rank Test ◽  
Phase 3 ◽  
Double Blind

TPS226 Background: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor, the only known ligand of the MET receptor. In a phase 2 study, trends toward improved progression-free survival (PFS) and overall survival (OS) were seen with rilotumumab plus epirubicin, cisplatin and capecitabine (ECX) vs ECX alone in pts with G/GEJ cancer; the treatment effect of rilotumumab was enhanced in MET-positive pts (Iveson et al. Lancet Oncol 2014;15:1007). In a phase 1/1b study, rilotumumab plus CX had manageable toxicities and a favorable pharmacokinetic (PK) profile in Japanese pts with MET-positive G/GEJ cancer (Doi et al. J Clin Oncol 2014;32:5s,abstract 4051). Methods: In this phase 3 study, 450 pts from Asian countries are randomized 1:1 to CX (intravenous [IV] cisplatin 80 mg/m2 on day 1 and oral capecitabine 1000 mg/m2 twice daily on days 1−14) plus double-blind rilotumumab 15 mg/kg or placebo IV on day 1 every 3 weeks for up to 6 cycles. After cycle 6, pts will receive capecitabine plus rilotumumab or placebo. Randomization is stratified by disease extent (locally advanced vs metastatic), prior surgery for G/GEJ or esophageal cancer (yes vs no), and country (China vs other). Key eligibility criteria include previously untreated, pathologically confirmed unresectable locally advanced or metastatic G/GEJ adenocarcinoma, ≥20 years, ECOG score ≤1, MET-positive by centralized immunohistochemistry, HER2-negative, adequate organ function, and ≥6 months since neoadjuvant/adjuvant therapy. The primary endpoints are PFS and OS. A log-rank test stratified by the randomization factors will compare PFS and OS between arms. Key secondary endpoints include 12-month survival rate, time to progression, objective response and disease control rates, duration of/time to response, safety, and PK. Enrollment began in July 2014, and the trial continues to recruit participants. The study is overseen by an independent data monitoring committee. ClinicalTrials.gov: NCT02137343. Sponsor: Amgen Inc. Clinical trial information: NCT02137343.

Phase III, Randomized, Placebo-Controlled Study of Docetaxel in Combination With Zibotentan in Patients With Metastatic Castration-Resistant Prostate Cancer

2013 ◽  
Vol 31 (14) ◽  
pp. 1740-1747 ◽  
Author(s):  
Karim Fizazi ◽  
Celestia S. Higano ◽  
Joel B. Nelson ◽  
Martin Gleave ◽  
Kurt Miller ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Controlled Study ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
End Points ◽  
Castration Resistant ◽  
Endothelin A

PurposeAs part of the ENTHUSE (Endothelin A Use) program, the efficacy and safety of zibotentan (ZD4054), an oral specific endothelin A receptor antagonist, has been investigated in combination with docetaxel in patients with metastatic castration-resistant prostate cancer (CRPC).Patients and MethodsIn this randomized, double-blind, placebo-controlled, phase III study, patients received intravenous docetaxel 75 mg/m2on day 1 of 21-day cycles plus oral zibotentan 10 mg or placebo once daily. The primary end point was overall survival (OS). Secondary end points included time to pain and prostate-specific antigen (PSA) progression, pain and PSA response, progression-free survival, health-related quality of life, and safety.ResultsA total of 1,052 patients received study treatment (docetaxel-zibotentan, n = 524; docetaxel-placebo, n = 528). At the time of data cutoff, there had been 277 and 280 deaths, respectively. There was no difference in OS for patients receiving docetaxel-zibotentan compared with those receiving docetaxel-placebo (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P = .963). No significant differences were observed on secondary end points, including time to pain progression (median 9.3 v 10.0 months, respectively) or pain response (odds ratio, 0.84; 95% CI, 0.61 to 1.16; P = .283). The median time to death was 20.0 and 19.2 months for the zibotentan and placebo groups, respectively. The most commonly reported adverse events in zibotentan-treated patients were peripheral edema (52.7%), diarrhea (35.4%), alopecia (33.9%), and nausea (33.3%).ConclusionDocetaxel plus zibotentan 10 mg/d did not result in a significant improvement in OS compared with docetaxel plus placebo in patients with metastatic CRPC.

Limitation of prostate-specific antigen doubling time as a predictor of outcome in hormone-naive prostate cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4566-4566 ◽  
Author(s):  
J. B. Nelson ◽  
D. J. Sleep ◽  
J. D. Isaacson ◽  
M. A. Carducci
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Doubling Time ◽  
Controlled Trial ◽  
Specific Antigen ◽  
Controlled Study ◽  
Primary Therapy ◽  
Double Blind ◽  
Psa Velocity ◽  
Baseline Psa

4566 Background: Prostate-specific antigen doubling time (PSADT) is used to monitor progression after primary therapy for prostate cancer. Increasingly in this population, PSADT is an efficacy measure in therapeutic trials, many of which are uncontrolled. Examination of PSADT response on placebo in a randomized controlled study may evaluate the utility of PSADT as an outcome measure in patients with hormone-naive prostate cancer. Methods: Patients with biochemical failure post radical prostatectomy were enrolled in a randomized, double-blind, placebo-controlled trial of atrasentan 10 mg. Eligibility criteria included baseline PSA between 0.4 ng/mL and 5 ng/mL with a PSADT ≤12 months based on two PSA values at least 2 weeks apart. On-treatment PSADT was compared between treatment groups in patients with at least 3 on-treatment PSA values collected every 12 weeks while on study drug. Categorical analysis comparing PSADT between groups was performed using Cochran-Mantel-Haenszel methodology. Mean change from baseline in PSA velocity (log PSA vs time) was analyzed using a one-way analysis of variance with treatment as the factor. Results: Of 222 patients enrolled, 209 had 3 PSA values on study: N=107 for placebo; N = 102 for atrasentan. Baseline PSA was lower for patients in the placebo arm than for those in the atrasentan arm (mean of 1.4 ng/mL [SE 0.1] vs 1.8 ng/mL [SE 0.1] P =.012). On-treatment PSADT was similar between treatment arms (P =.363); the proportion of patients whose PSADT was >1 year on study was 55% with placebo and 51% with atrasentan. More notably, PSADT lengthened on study for most patients in both arms (76/107, 71% for placebo and 68/102, 64% for atrasentan). PSA velocity was also protracted for patients in both treatment arms (placebo: slope = 1.47 at baseline to 0.96, P < .001; atrasentan: slope = 1.56 at baseline to 1.26, P =.017). Conclusions: The fact that over 70% of patients receiving placebo experienced lengthened PSADT suggests that, in the absence of a control arm, changes in PSADT from baseline are not a reliable measure of treatment effect in trials in early prostate cancer. PSADT data from trials in this population should be interpreted with caution. [Table: see text]

Randomized trial of active cellular immunotherapy with sipuleucel-T in androgen dependent prostate cancer (ADPC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5059-5059 ◽  
Author(s):  
T. M. Beer ◽  
G. T. Bernstein ◽  
J. M. Corman ◽  
M. L. Glode ◽  
S. Hall ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Distant Metastases ◽  
Prognostic Indicator ◽  
Disease Recurrence ◽  
Hazard Ratio ◽  
Controlled Study ◽  
Cellular Immunotherapy ◽  
Double Blind ◽  
Clinical Endpoints

5059 Background: Sipuleucel-T is an investigational, active cellular immunotherapy product for prostate cancer. To explore the potential benefit in ADPC, sipuleucel-T was studied in a randomized, double blind, multicenter, placebo controlled study, P-11. Methods: ADPC patients with a rise in serum prostate specific antigen (PSA) as the only sign of disease recurrence after prostatectomy were randomized (2:1) to sipuleucel-T or placebo, administered in weeks 0, 2, and 4, following 3-months of hormonal therapy. PSA kinetics were evaluated by time to biochemical failure (BF), defined as any PSA = 3 ng/mL (primary endpoint), as well as PSA doubling time (PSADT). Clinical endpoints included time to distant metastases (DF) and survival. The effect of a single booster infusion of sipuleucel-T on the immune system was also evaluated. Results: 176 patients were randomized (117 sipuleucel-T:59 placebo) and analyzed by intent to treat. Median time to BF was 18.0 months for sipuleucel-T and 15.4 months for placebo (hazard ratio (HR)=0.94 [95% confidence interval (CI): 0.64, 1.38]; p>0.05, log rank). The hazard ratio for BF was 0.80 in favor of sipuleucal-T ([95%CI: 0.53, 1.20], p>0.05) when the analysis was restricted to patients with a confirmed BF. An analysis of PSADT calculated from 90 days following randomization to BF or the initiation of systemic therapy demonstrated that patients randomized to sipuleucel-T had a 35% increase in PSADT (125 vs 91 days; p=0.046, F-test). PSADT calculated after testosterone recovery to baseline levels demonstrated a 48% increase in PSADT for the sipuleucel-T arm (155 vs 105 days; p=0.038). Only 16% of patients developed distant metastases. The hazard ratio for time to DF was 0.78 (95%CI: 0.34, 1.58, p>0.05, log rank). Patients are still being followed for DF and survival. The most common treatment-associated adverse events were chills, fatigue, headache, and pyrexia, which were primarily Grade 1–2. Conclusions: Time to BF was not different between the two study arms. The effect on PSADT, an important prognostic indicator in ADPC, may suggest the biologic activity of sipuleucel-T in this population. Additional follow-up for clinical endpoints of DF and survival is of interest. No significant financial relationships to disclose.

Overall survival (OS) analysis of a phase II randomized controlled trial (RCT) of a poxviral-based PSA targeted immunotherapy in metastatic castration-resistant prostate cancer (mCRPC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5013-5013
Author(s):  
P. W. Kantoff ◽  
T. Schuetz ◽  
B. A. Blumenstein ◽  
M. M. Glode ◽  
D. Bilhartz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Viral Vectors ◽  
Controlled Trial ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Gm Csf

5013 Background: Therapeutic poxviral vaccines for prostate cancer are safe with preliminary evidence of clinical benefit in phase I/II studies. PROSTVAC-VF (PV) comprises 2 recombinant viral vectors (Vaccinia and Fowlpox), each encoding transgenes for prostate specific antigen (PSA) and 3 immune costimulatory molecules (B7.1, ICAM-1, and LFA3: TRICOM). PV is administered subcutaneously in a heterologous prime-boost regimen with concurrent low-dose GM-CSF. Methods: 122 patients (pts) were treated in a multi-center, double-blind, RCT of a vaccination series. Pts were randomized 2:1 to PV + GM-CSF vs. placebo empty vector + control saline injections (C). Vaccinia-based vector was used for priming followed by 6 planned Fowlpox-based vector boosts. The trial completed enrollment in July 2005. Eligible pts had metastatic disease, a rising PSA despite castrate testosterone levels, and a Gleason score of ≤7. Pts with a history of prior chemotherapy use, visceral metastasis, or narcotic use were excluded. The 1º endpoint was progression free survival (PFS), with progression defined as 2 new lesions on bone scan or RECIST-defined progression. Vaccination was discontinued after progression. Results: 82 pts received PV and 40 received C. Pt characteristics were similar (means): age (72PV/76C), PSA (134PV/188C), Alk-Phos (142PV/159C), LDH (207PV/218C), Hgb (13PV/13C), and number bone metastatic sites (5.3PV/6.5C). Mean number of vaccinations was 5.4 PV and 5.3 C. PFS was similar in the 2 groups (p = 0.56). However, at 3 years post study, PV patients had a better overall survival than C patients (25 alive, 30%, PV, versus 7 alive, 17%, C) and a longer median survival (24.5 months PV, versus 16 months C); estimated hazard ratio 0.6 (95% CI 0.4–0.9); stratified log rank p = 0.016. Conclusions: In a RCT, PV immunotherapy was associated with an 8.5 month improvement in median OS in men with mCRPC. These data provide evidence of prolonged anti-tumor activity, but need to be confirmed in a larger phase III study. [Table: see text]

Phase II Randomized, Double-Blind, Placebo-Controlled Study of Tasquinimod in Men With Minimally Symptomatic Metastatic Castrate-Resistant Prostate Cancer

2011 ◽  
Vol 29 (30) ◽  
pp. 4022-4028 ◽  
Author(s):  
Roberto Pili ◽  
Michael Häggman ◽  
Walter M. Stadler ◽  
Jeffrey R. Gingrich ◽  
Vasileios J. Assikis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Antitumor Agent ◽  
Controlled Study ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Double Blind Placebo ◽  
The Impact

Purpose The activity of the novel antitumor agent tasquinimod (TASQ) with S100A9 as a molecular target was investigated in men with metastatic castration-resistant prostate cancer (CRPC) and minimal symptoms. Patients and Methods We conducted a randomized, double-blind, placebo-controlled phase II trial in men assigned (at a ratio of two to one) to either oral once-daily TASQ 0.25 mg/d escalating to 1.0 mg/d over 4 weeks or placebo. The primary end point was the proportion of patients without disease progression at 6 months, defined by Response Evaluation Criteria in Solid Tumors Group, Prostate Cancer Working Group (PCWG2), or pain criteria, excluding prostate-specific antigen. Results Two hundred one men (134 assigned to TASQ; 67 to placebo) were evaluable, and baseline characteristics were well balanced. Six-month progression-free proportions for TASQ and placebo groups were 69% and 37%, respectively (P < .001), and median progression-free survival (PFS) was 7.6 versus 3.3 months (P = .0042). In PCWG2 CRPC clinical subgroups, PFS in months was as follows: nodal metastases, 6.1 versus 3.1; bone metastases, 8.8 versus 3.4; and visceral metastases, 6.0 versus 3.0 for patients receiving TASQ versus placebo, respectively. Bone alkaline phosphatase levels were stabilized in the TASQ group, whereas the impact on PSA kinetics was less pronounced. Adverse events (AEs) occurring more frequently in the TASQ arm included GI disorders, fatigue, musculoskeletal pains, and elevations of pancreatic and inflammatory biomarkers. Grade 3 to 4 AEs, including asymptomatic elevations of laboratory parameters, were reported in 40% of patients receiving TASQ versus 10% receiving placebo; deep vein thrombosis (4% v 0%) was more common in the TASQ arm. Conclusion TASQ significantly slowed progression and improved PFS in patients with metastatic CRPC with an acceptable AE profile.

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