Phase 3 Studies
The FDA approval for sipuleucel-T was based on three pivotal phase 3 studies (). Overall survival rates were consistent across multiple subgroups. An analysis showed that the time to disease progression (TTP) did not meet statistical significance in any of these phase 3 studies.
Summary of Overall Survival and Time to Disease Progression in Various Clinical Trials
In the first reported phase 3, double-blind, placebo-controlled clinical trial, D9901, immune response data were collected from men with androgen-independent prostate cancer. A total of 127 patients were randomly assigned, in a 2:1 ratio, to receive sipuleucel-T (n = 82) or placebo (n = 45) every two weeks. The placebo patients who were observed to have disease progression were switched to sipuleucel-T. Survival for all patients was evaluated for 36 months. At the time of the data analysis, 115 patients were found to have progressive disease.
The median TTP for sipuleucel-T was 11.7 weeks, compared with 10 weeks for placebo (P = 0.052). The hazard ratio (HR) was 1.45, with a 95% confidence interval (CI) of 0.99 to 2.11. There was no significant delay in TTP for the sipuleucel-T group as a whole (P = 0.061), but a significant difference in TTP was seen in patients with a Gleason score of 7 or less.
Median survival differed significantly for sipuleucel-T (25.9 months), compared with placebo (21.4 months), for a difference of 4.5 months (P = 0.01). Treatment remained a strong independent predictor of overall survival after adjustments were made for prognostic factors (P = 0.002; HR, 2.12; 95% CI, 1.31–3.44). An eightfold increase in T-cell proliferation was shown for the sipuleucel-T patients, compared with the placebo group (16.9 vs. 1.99, respectively; P = 0.001).
At 36 months, 34% of sipuleucel-T patients were alive, compared with 11% of placebo patients, for a significant threefold improvement in overall survival fraction (P = 0.001). Sipuleucel-T therapy was well tolerated. This study suggested that sipuleucel-T might provide survival advantages to patients with asymptomatic hormone-refractory prostate cancer.
Higano et al. (D9901/D9902A)14
An integrated analysis of D9901 and D9902A studies was performed. D9902A was part one of a two-stage phase 3 trial (D9902), which was started concurrently with D9901. D9902 was a double-blind, placebo-controlled study of patients with metastatic, asymptomatic, hormone-refractory prostate cancer. The men were randomly assigned to receive three doses of either sipuleucel-T or placebo.
After 98 patients were recruited, the study was stopped because findings from the previous study (D9901) did not reveal any statistically significant benefit of sipuleucel-T over placebo in TTP (P = 0.033). However, a benefit was noted in a subgroup of patients with a Gleason score of 7 or less. This first part of the study, without regard to the Gleason score, was designated D9902A. The study protocol was amended to focus on patients with a Gleason score of 7 or less and was continued as D9902B. This decision was again reversed after about two years to include patients with a Gleason score greater than 7.
In an integrated analysis of D9901 and D9902A, 225 patients were randomly assigned to receive sipuleucel-T (n = 147) or placebo (n = 78). The treated patients experienced a significant 33% reduction in the risk of death (P = 0.011), compared with a reduction of 15% in the placebo group.
Treatment also resulted in a 21% reduction in the risk of disease progression (P = 0.111). Only seven of the 147 patients (4.8%) in the sipuleucel-T arm had a reduction of 25% or greater in prostate-specific antigen (PSA) levels; however, none of the 78 patients in the placebo group did.
After adjustments were made for imbalances in baseline prognostic factors, post-study treatment chemotherapy use, and non-prostate cancer–related deaths, the treatment effect remained strong. The correlation between a measure of potency, CD54 up-regulation, and overall survival was supported by evidence of sipuleucel-T’s activity.
Adverse drug effects (AEs) were similar in men receiving sipuleucel-T (98.6%) and placebo (96.1%). These AEs, which were well tolerated, minimal, and short-lived, included chills, pyrexia, headache, asthenia, dyspnea, vomiting, and tremor. The study demonstrated a favorable risk–benefit ratio for sipuleucel-T.
Kantoff et al. (D9902B, IMPACT)18
D9902B, also called IMPACT (Immunotherapy for Prostate AdenoCarcinoma Treatment), was a randomized, double-blind, placebo-controlled study of 512 men with metastatic, hormone-refractory prostate cancer. Initially, the targeted patients were those with a Gleason score of 7 or less. Later this criterion was changed to include patients with a Gleason score higher than 7. Patients received intravenous (IV) sipuleucel-T (n = 341) or placebo (n = 171) at two-week intervals, for a total of three doses.
At 36 months, a survival benefit of 4.1 months was noted with sipuleucel-T; median survival was 25.8 months with sipuleucel-T and 21.7 months with placebo. Overall survival was significantly prolonged for sipuleucel-T patients (P = 0.032; HR = 0.775) at the time of cutoff. Results were consistent in multiple patient groups.
An updated analysis performed after the death of 349 patients at an estimated follow-up of 36.5 months showed that sipuleucel-T’s treatment effect remained significant (HR = 0.751; P = 0.012).
AEs that were noted in other studies were also commonly observed in IMPACT, including chills, pyrexia, headache, influenza-like illness, and myalgia. These effects were generally mild, occurring within one day of the infusion and resolving within one to two days. The authors concluded that sipuleucel-T was effective in prolonging survival.
Supportive Phase 1 and 2 Studies
Burch et al.7 and Small et al.12
Phase 1 and 2 clinical trials of sipuleucel-T (APC 8015), designed to assess safety, dosing and immunological response, showed short-lived fever, chills, myalgia, pain, fatigue, urinary incontinence urgency, and nocturia. The studies also revealed a drop in circulating PSA levels after sipuleucel-T was received. T cells drawn from patients after infusions of sipuleucel-T, but not before, could be stimulated in vitro
by GM–CSF (P
= 0.0004) and by PAP (P
= 0.0001), demonstrating broken tolerance against the two normal proteins. However, injections of placebo did not influence the reactivity of T cells against GM–CSF or PAP.7
In a phase 2 study, TTP correlated with development of an immune response to PAP and with the dose of dendritic cells received.12
Small et al. concluded that sipuleucel-T was safe, breaking tolerance to the tissue antigen PAP, and they recommended further research on clinical efficacy data.
Of 601 prostate cancer patients who underwent leukapheresis at least once and who were evaluated for AEs, 98.3% of those in the sipuleucel-T group and 96% in the placebo group reported an AE. The most common AEs in the sipuleucel-T group that occurred more than 10% of the time included chills, fatigue, fever, back pain, nausea, joint aches, headaches, citrate toxicity, paresthesia, vomiting, anemia, constipation, oral paresthesia, pain in the extremities, dizziness, muscle aches, asthenia, and diarrhea (). These AEs occurred within the first few days of treatment and dissipated within one or two days. About 67.4% of AEs were mild to moderate in severity and were related to the infusion. Severe or life-threatening AEs occurred in 27.6% of sipuleucel-T patients and in 28.4% of the placebo group.
Incidence of Adverse Events Occurring in 10% or More of Patients Receiving Sipuleucel-T (Provenge)
Fatalities occurred in 3.3% of treated men and in 3.5% of controls. Back pain and chills were the most common severe or fatal AEs reported with sipuleucel-T. Other serious AEs reported in 24% of sipuleucel-T patients and in 25% of placebo patients included infusion reactions, cerebrovascular events, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare. Overall, there was no increased risk of AEs with sipuleucel-T compared with placebo.