2.1 Dose

Each dose of PROVENGE contains a minimum of 50 million autologous CD54 + cells activated with PAP-GM-CSF [ see Description ( 11) ].

The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals. In controlled clinical trials, the median dosing interval between infusions was 2 weeks (range 1 to 15 weeks); the maximum dosing interval has not been established.

If, for any reason, the patient is unable to receive a scheduled infusion of PROVENGE, the patient will need to undergo an additional leukapheresis procedure prior to continuing a course of treatment. Advise patients of this possibility prior to initiating treatment.

2.2 Administration

• Do not use PROVENGE until confirmation of product release is received from Dendreon.
• Dendreon will send the Final Product Disposition Notification form containing the patient identifiers, expiration date and time, and the disposition status (approved for infusion or rejected), to the infusion site. Infusion must begin prior to the expiration date and time indicated on the Final Product Disposition Notification form and Product Label. Do not use expired PROVENGE. Keep the sealed, patient-specific PROVENGE infusion bag within the insulated polyurethane container inside the outer cardboard shipping box until the time of administration.
• To minimize potential acute infusion reactions, premedicate the patients orally with acetaminophen and an antihistamine, such as diphenhydramine, approximately 30 minutes prior to administration of PROVENGE.

5.1 Acute Infusion Reactions

Acute infusion reactions (reported within 1 day of infusion) may occur and include nausea, vomiting, fatigue, fever, rigor or chills, respiratory events (dyspnea, hypoxia, and bronchospasm), syncope, hypotension, hypertension, and tachycardia. Acute infusion reactions (reported within 1 day of infusion) may occur and include nausea, vomiting, fatigue, fever, rigor or chills, respiratory events (dyspnea, hypoxia, and bronchospasm), syncope, hypotension, hypertension, and tachycardia.

In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction. The most common events (≥ 20%) were chills, fever, and fatigue. In 95.1% of patients reporting acute infusion reactions, the reactions were mild or moderate. Fevers and chills generally resolved within 2 days (71.9% and 89%, respectively). In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction. The most common events (≥ 20%) were chills, fever, and fatigue. In 95.1% of patients reporting acute infusion reactions, the reactions were mild or moderate. Fevers and chills generally resolved within 2 days (71.9% and 89%, respectively).

In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs. 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs. 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, decrease the infusion rate or stop the infusion, depending on the severity of the reaction. Administer appropriate medical treatment as needed. [ ] Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, decrease the infusion rate or stop the infusion, depending on the severity of the reaction. Administer appropriate medical treatment as needed. [ See Dosage and Administration ( 2.2) ]

5.2 Thromboembolic Events

Thromboembolic events, including deep venous thrombosis and pulmonary embolism, can occur following infusion of PROVENGE. The clinical significance and causal relationship are uncertain. Most patients had multiple risk factors for these events. PROVENGE should be used with caution in patients with risk factors for thromboembolic events. Thromboembolic events, including deep venous thrombosis and pulmonary embolism, can occur following infusion of PROVENGE. The clinical significance and causal relationship are uncertain. Most patients had multiple risk factors for these events. PROVENGE should be used with caution in patients with risk factors for thromboembolic events.

5.3 Vascular Disorders

5.4 Handling Precautions for Control of Infectious Disease

PROVENGE is not tested for transmissible infectious diseases. Therefore, patient leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product. Accordingly, health care professionals should employ universal precautions when handling leukapheresis material or PROVENGE.

5.5 Concomitant Chemotherapy or Immunosuppressive Therapy

Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or PROVENGE has not been studied. PROVENGE is designed to stimulate the immune system, and concurrent use of immune-suppressive agents may alter the efficacy and/or safety of PROVENGE. Therefore, evaluate patients carefully to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE.

5.6 Product Safety Testing

PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after PROVENGE has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety evaluation of PROVENGE is based on 601 prostate cancer patients in the PROVENGE group who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The control group (n = 303) received non-activated autologous peripheral blood mononuclear cells. Patients received 3 infusions of PROVENGE or control every other week over a period of 4 weeks.

Almost all (98.3%) patients in the PROVENGE group and 96% in the control group reported an adverse event. In 67.4% of patients in the PROVENGE group, these adverse events were mild or moderate in severity. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4% of patients in the PROVENGE group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the PROVENGE group compared with 3.6% of patients in the control group. The most common (≥ 2%) Grade 3-5 adverse events reported in the PROVENGE group were back pain and chills.

Serious adverse events were reported in 24% of patients in the PROVENGE group and 25.1% of patients in the control group. Serious adverse events in the PROVENGE group included acute infusion reactions [ see Warnings and Precautions ( 5.1) ], cerebrovascular events [ see Warnings and Precautions ( 5.3) ], and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare.

PROVENGE was discontinued in 1.5% of patients in Study 1 due to adverse events. Some patients who required central venous catheters for treatment with PROVENGE developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended.

Each dose of PROVENGE requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤ 1 day following a leukapheresis procedure in ≥ 5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%).

Table 1 provides the frequency and severity of adverse events reported in ≥ 5% of patients in the PROVENGE group of randomized, controlled trials of men with prostate cancer. The population included 485 patients with metastatic castrate-resistant prostate cancer and 116 patients with non-metastatic androgen-dependent prostate cancer who were scheduled to receive 3 infusions of PROVENGE at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of PROVENGE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Nervous system disorders: syncope, transient ischemic attack, strokes [see Warnings and Precautions ( 5.1, 5.3)]
• Vascular disorders: hypotension [see Warnings and Precautions ( 5.1)]
• Cardiovascular disorders: myocardial infarction [see Warnings and Precautions ( 5.3)]
• Thromboembolic disorders: deep venous thrombosis and pulmonary embolism [see Warnings and Precautions ( 5.2)]

8.5 Geriatric

In controlled clinical trials, 72.9% of patients (438 of 601) in the PROVENGE group were ≥ 65 years of age. There were no apparent differences in the safety of PROVENGE between patients ≥ 65 years of age and younger patients.

In a survival analysis of the controlled clinical trials of PROVENGE in metastatic castrate-resistant prostate cancer, 78.3% of randomized patients (382 of 488) were ≥ 65 years of age. The median survival of patients in the PROVENGE group ≥ 65 years of age was 23.4 months (95% confidence interval 22.0, 27.1), compared with 17.3 months in the control group (95% confidence interval: 13.5, 21.5).

8.6 Race

In controlled clinical trials, 90.6% of patients were Caucasian, 5.8% were African American, and 3.7% were “Other”. Due to the low numbers of non-Caucasian patients in the trials, no conclusions can be made regarding the safety or efficacy of PROVENGE by race.

12.1 Mechanism of Action

PROVENGE is classified as an autologous cellular immunotherapy. While the precise mechanism of action is unknown, PROVENGE is designed to induce an immune response targeted against PAP, an antigen expressed in most prostate cancers. During ex vivo culture with PAP-GM-CSF, APCs take up and process the recombinant target antigen into small peptides that are then displayed on the APC surface.

In Study 1, 237 out of the 512 patients randomized were evaluated for the development of humoral and T cell immune responses (proliferative and gamma-interferon (γIFN) ELISPOT) to the target antigens at Baseline, and at Weeks 6, 14, and 26. Antibody (IgM and IgG) responses against PAP-GM-CSF and PAP antigen alone were observed through the follow-up period in the PROVENGE group. Neutralizing antibody responses to GM-CSF were transient. T cell proliferative and γIFN ELISPOT responses to PAP-GM-CSF fusion protein were observed in cells collected from peripheral blood of patients through the follow-up period in the PROVENGE treatment group but not in controls. In some patients a response to PAP antigen alone was observed. No conclusions could be made regarding the clinical significance of the observed immune responses.

Study 1

Study 1 was a randomized, double-blind, placebo-controlled, multicenter trial in patients with asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer. Eligible patients had metastatic disease in the soft tissue and/or bone with current or historical evidence of disease progression concomitant with surgical or medical castration, as evidenced by progression of serum Prostate Specific Antigen (PSA) and/or bone or soft tissue disease. Exclusion criteria included visceral (liver, lung, or brain) metastases, moderate to severe prostate cancer-related pain, and use of narcotics for cancer-related pain.

A total of 512 patients were randomized in a 2:1 ratio to receive PROVENGE (n=341) or control (n=171). The median age was 71, and 90% of the patients were Caucasian. Thirty-five percent of patients had undergone radical prostatectomy, 54% had received local radiotherapy, and 82% had received combined androgen blockade. All patients had baseline testosterone levels < 50 ng/mL. Forty-eight percent of patients were receiving bisphosphonates, and 18% had received prior chemotherapy, including docetaxel. Eighty-two percent of patients had an ECOG performance status of 0; 58% had primary Gleason scores of four or more; 44% had bone and soft tissue disease; 48% had bone-only disease; 7% had soft tissue-only disease; and 43% had greater than ten bony metastases.

Supportive Studies

Study 2 was a randomized, double-blind, placebo-controlled, multicenter trial in patients with metastatic castrate-resistant prostate cancer and no cancer-related pain. The primary endpoint was time to disease progression; analysis of the primary endpoint did not reach statistical significance. All patients were to be followed for survival; however, the survival analysis was not pre-specified.

Summary of Study Results

Figure 1 and Table 2 present overall survival results observed in two randomized, Phase 3 studies of PROVENGE in men with metastatic castrate-resistant prostate cancer. The survival findings were consistent across multiple subgroups. Analyses of time to disease progression did not meet statistical significance in any Phase 3 study of PROVENGE.

Figure 1 Kaplan-Meier Overall Survival Curve for Study 1