[Show abstract][Hide abstract] ABSTRACT: Background:
Sipuleucel-T has demonstrated improved overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This analysis examined the effect of sipuleucel-T on time to disease-related pain (TDRP) and time to first use of opioid analgesics (TFOA) in mCRPC using data pooled from three randomized phase III studies in men with asymptomatic or minimally symptomatic mCRPC (D9901 (NCT00005947), D9902A (NCT01133704), D9902B (IMPACT; NCT00065442)).
Four-hundred and twenty-eight asymptomatic patients were analyzed for TDRP; 737 patients were analyzed for TFOA. Pain status was collected using logs adjudicated by blinded, independent reviewers. Opioid use for cancer-related pain was identified from medically reviewed reports of concomitant medication. Disease-related pain was defined as pain post enrollment. TDRP and TFOA were analyzed using the Kaplan–Meier method and Cox regression.
Treatment with sipuleucel-T was not associated with a significant difference in TDRP (hazard ratio (HR)=0.819; 95% confidence interval (CI): 0.616–1.089; P=0.170; median TDRP 5.6 months for sipuleucel-T and 5.3 months for control, respectively), although 39.3% of sipuleucel-T-treated patients and 18.9% of control patients were pain-free at 12 months. However, there was a significant delay in TFOA with sipuleucel-T (HR=0.755; 95% CI: 0.579–0.985; P=0.038). Median TFOA for sipuleucel-T was 12.6, and 9.7 months for control, with 50.6% and 43.1% opioid-free at 12 months, respectively. Kaplan–Meier curves for both end points began to diverge at 6 months.
Sipuleucel-T was associated with longer TFOA but not significantly longer TDRP. Both end points demonstrated evidence of a delayed treatment effect, consistent with an active immunotherapy.
Preview · Article · Jun 2014 · Prostate Cancer and Prostatic Diseases
[Show abstract][Hide abstract] ABSTRACT: To collect and analyze quality-of-life (QOL) data from PROvenge Treatment and Early Cancer Treatment trial (PROTECT, NCT00779402), a phase III, randomized controlled trial of sipuleucel-T in patients with asymptomatic androgen-dependent prostate cancer.
Patients experiencing prostate-specific antigen relapse after radical prostatectomy entered a 3- to 4-month run-in phase of androgen-deprivation therapy (ADT), followed by 2:1 randomization to sipuleucel-T or control. QOL was assessed throughout the run-in and 26-week post-randomization phases using the Brief Fatigue Inventory (BFI), Linear Analog Self-Assessment (LASA) scale, Global Rating of Change (GRoC) scale, and an elicited symptoms list.
One hundred seventy-six patients were randomized into 2 groups, the sipuleucel-T group (n = 117) or the control group (n = 59). The sample provided 80% power to detect a difference in fatigue interference score between treatment arms of 0.9 points. QOL declined predictably during ADT. At week 26, 26.2% of sipuleucel-T-treated patients and 21.6% of control-treated patients (P = .68) reported fatigue in the previous week, and the mean score for fatigue interference in the past 24 hours was 0.9 for both arms (P = .88). Results were comparable for usual fatigue (P = .91) and worst fatigue (P >.99). Mean LASA scores decreased in both groups (P = .26). The proportion of patients reporting better overall QOL on GRoC was similar (P = .62).
There is no clinically significant negative impact on QOL after sipuleucel-T treatment compared with control after a period of ADT in patients with asymptomatic androgen-dependent prostate cancer.
[Show abstract][Hide abstract] ABSTRACT: Objective:
To explore the prognostic and predictive value of baseline variables in 512 patients with metastatic castration-resistant prostate cancer from the phase III Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial who were randomized to receive sipuleucel-T or control.
The most powerful of these prognostic factors, baseline prostate-specific antigen (PSA), was subdivided into quartiles to evaluate treatment effect patterns. Cox regression analyses were used to assess predictors of overall survival (OS) and sipuleucel-T treatment effect within PSA quartiles. Median OS was estimated by the Kaplan-Meier method.
PSA was the strongest baseline prognostic factor (P <.0001). Furthermore, the sipuleucel-T treatment effect appeared greater with decreasing baseline PSA. The OS hazard ratio for patients in the lowest baseline PSA quartile (≤22.1 ng/mL) was 0.51 (95% confidence interval, 0.31-0.85) compared with 0.84 (95% confidence interval, 0.55-1.29) for patients in the highest PSA quartile (>134 ng/mL). Estimated improvement in median survival varied from 13.0 months in the lowest baseline PSA quartile to 2.8 months in the highest quartile. Estimated 3-year survival in the lowest PSA quartile was 62.6% for sipuleucel-T patients and 41.6% for control patients, representing a 50% relative increase.
The greatest magnitude of benefit with sipuleucel-T treatment in this exploratory analysis was observed among patients with better baseline prognostic factors, particularly those with lower baseline PSA values. These findings suggest that patients with less advanced disease may benefit the most from sipuleucel-T treatment and provide a rationale for immunotherapy as an early treatment strategy in sequencing algorithms for metastatic castration-resistant prostate cancer.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Sipuleucel-T is an autologous cellular immunotherapy. We review the safety of the leukapheresis procedure required for sipuleucel-T preparation and complications related to venous catheter use in the randomized, placebo controlled phase 3 IMPACT (IMmunotherapy for ProstAte Cancer Trial) study (NCT 00065442).
Materials and methods:
A total of 512 patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer were enrolled in the study. All patients were scheduled to undergo 3 standard 1.5 to 2.0 blood volume leukapheresis procedures at 2-week intervals. Leukapheresis related adverse events and those related to venous catheter use were reviewed. Immune cell counts were examined throughout the treatment course.
Of 512 enrolled patients 506 underwent 1 or more leukapheresis procedures and were included in this analysis. Adverse events were comparable between the sipuleucel-T and control arms. Leukapheresis related adverse events were primarily associated with transient hypocalcemia (39.3%). Most leukapheresis related adverse events (97%) were of mild/moderate intensity. Median white blood cell count and absolute monocyte and lymphocyte counts were stable and within normal ranges throughout the treatment course. Of all patients 23.3% had a central venous catheter placed primarily for leukapheresis. Patients with vs without a central venous catheter had a higher risk of infection potentially related to catheter use (11.9% vs 1.3%, p <0.0001) and a trend toward a higher incidence of venous vascular events potentially related to catheter use, excluding the central nervous system (5.9% vs 2.1%, p = 0.06).
Adverse events related to leukapheresis are manageable and quickly reversible. The majority of patients can undergo leukapheresis without a central venous catheter. Central venous catheters are associated with an increased risk of infections and venous vascular events. Peripheral intravenous access should be used when feasible.
No preview · Article · Dec 2012 · The Journal of urology
[Show abstract][Hide abstract] ABSTRACT: Purpose
Sipuleucel-T, the first FDA-approved autologous cellular immunotherapy for treatment of advanced prostate cancer, is manufactured by activating peripheral blood mononuclear cells, including antigen presenting cells (APCs), with a fusion protein containing prostatic acid phosphatase. Analysis of data from three phase 3 trials was performed to immunologically characterize this therapy during the course of the three doses, and to relate the immunological responses to overall survival (OS).
Sipuleucel-T product characteristics [APC numbers, APC activation (CD54 upregulation), and total nucleated cell (TNC) numbers] were assessed in three randomized, controlled phase 3 studies (N = 737). Antigen-specific cellular and humoral responses were assessed in a subset of subjects. The relationships between these parameters and OS were assessed.
APC activation occurred in the first dose preparation [6.2-fold, (4.65, 7.70); median (25th, 75th percentile)] and increased in the second [10.6-fold (7.83, 13.65)] and third [10.5-fold (7.89, 13.65)] dose preparations. Cytokines and chemokines associated with activated APCs were produced during the manufacture of each dose; T-cell activation-associated cytokines were detected in the second and third dose preparations. Antigen-specific T cells were detectable after administration of the first sipuleucel-T dose. Cumulative APC activation, APC number, and TNC number correlated with OS (P
Full-text · Article · Aug 2012 · Cancer Immunology and Immunotherapy
[Show abstract][Hide abstract] ABSTRACT: Sipuleucel-T, the first autologous active cellular immunotherapy approved by the United States Food and Drug Administration, is designed to stimulate an immune response to prostate cancer. Sipuleucel-T is manufactured by culturing a patient's peripheral blood mononuclear cells (including antigen presenting cells) with a recombinant protein comprising a tumor-associated antigen (prostatic acid phosphatase) and granulocyte-macrophage colony stimulating factor. Treatment consists of 3 infusions at approximately 2-week intervals, resulting in a prime-boost pattern of immune activation, a robust antigen-specific cellular and humoral immune response, and, consequently, a survival benefit in subjects with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer. Adverse events are generally mild to moderate and resolve within 2 d. Serious adverse events occur at a low rate. As the first autologous cellular immunotherapy to demonstrate a survival benefit, sipuleucel-T is a novel oncologic therapeutic that warrants the reassessment of the current prostate cancer treatment paradigm.
[Show abstract][Hide abstract] ABSTRACT: We describe the safety of sipuleucel-T using an integrated analysis of 4 randomized, controlled studies in patients with prostate cancer.
Adverse events, survival data and laboratory evaluations were examined for common, rare and latent events.
In 5% or more of sipuleucel-T cases some adverse events were reported at a rate at least twice that in controls, including chills in 53.1%, pyrexia in 31.3%, headache in 18.1%, myalgia in 11.8%, influenza-like illness in 9.7% and hyperhidrosis in 5.0%. These events generally occurred within 1 day of infusion, were grade 1 or 2 in severity and resolved in 2 days or less. The incidence of serious adverse events reported was 24.0% in sipuleucel-T cases and 25.1% in controls. Grade 3 or greater adverse events were reported within 1 day of infusion in 40 of 601 sipuleucel-T cases (6.7%) and 7 of 303 controls (2.3%). The incidence rate of reported cerebrovascular events was 3.5% for sipuleucel-T cases and 2.6% in controls.
Sipuleucel-T therapy in patients with prostate cancer has a side effect profile that is characterized by mild to moderate, short-term, reversible adverse events. There was no evidence of a treatment related increase in autoimmune complications or secondary malignancies after treatment with sipuleucel-T. Sipuleucel-T can be administered safely in the outpatient setting.
No preview · Article · Sep 2011 · The Journal of urology