Mary Jane Staab

Safety and Immunological Efficacy of a DNA Vaccine Encoding Prostatic Acid Phosphatase in Patients With Stage D0 Prostate Cancer

PURPOSE Prostatic acid phosphatase (PAP) is a prostate tumor antigen. We have previously demonstrated that a DNA vaccine encoding PAP can elicit antigen-specific CD8+ T cells in rodents. We report here the results of a phase I/IIa trial conducted with a DNA vaccine encoding human PAP in patients with stage D0 prostate cancer. PATIENTS AND METHODS Twenty-two patients were treated in a dose-escalation trial with 100 microg, 500 microg, or 1,500 microg plasmid DNA, coadministered intradermally with 200 microg granulocyte-macrophage colony-stimulating factor as a vaccine adjuvant, six times at 14-day intervals. All patients were observed for 1 year after treatment. RESULTS No significant adverse events were observed. Three (14%) of 22 patients developed PAP-specific IFN gamma-secreting CD8+ T-cells immediately after the treatment course, as determined by enzyme-linked immunospot. Nine (41%) of 22 patients developed PAP-specific CD4+ and/or CD8+ T-cell proliferation. Antibody responses to PAP were not detected. Overall, the prostate-specific antigen (PSA) doubling time was observed to increase from a median 6.5 months pretreatment to 8.5 months on-treatment (P = .033), and 9.3 months in the 1-year post-treatment period (P = .054). CONCLUSION The demonstration that a DNA vaccine encoding PAP is safe, elicits an antigen-specific T-cell response, and may be associated with an increased PSA doubling time suggests that a multi-institutional phase II trial designed to evaluate clinical efficacy is warranted.

A Phase II Multicenter, Randomized, Double-Blind, Safety Trial Assessing the Pharmacokinetics, Pharmacodynamics, and Efficacy of Oral 2-Methoxyestradiol Capsules in Hormone-Refractory Prostate Cancer

Purpose: To determine whether the preclinical antitumor and antiangiogenic activity of 2-methoxyestradiol can be translated to the clinic. Experimental Design: Men with hormone-refractory prostate cancer were enrolled into this phase II randomized, double-blind trial of two doses of oral 2-methoxyestradiol capsules (400 and 1,200 mg/d) given in 4-week cycles. Pharmacokinetic sampling was done on day 1 of cycles 1 and 2 and trough samples were obtained weekly. Results: Thirty-three men were accrued between February and September 2001. The notable toxicity related to therapy was one grade 2 and two grade 3 episodes of liver transaminase elevation, which resolved with continued treatment in two patients. There were two cases of deep venous thromboses. The drug had nonlinear pharmacokinetic, rapid conversion to 2-methoxyestrone and ∼85% conjugation. Trough plasma levels of unconjugated 2-methoxyestradiol and 2-methoxyestrone were ∼4 and 40 ng/mL, respectively. Prostate-specific antigen declines between 21% and 40% were seen in seven patients in the 1,200 mg group and in one patient in the 400 mg group. The higher-dose group showed significantly decreased prostate-specific antigen velocity (P = 0.037) and compared with the 400 mg dose had a longer median time to prostate-specific antigen progression (109 versus 67 days; P = 0.094) and time on study (126 versus 61 days; P = 0.024). There was a 2.5- and 4-fold increase in sex hormone-binding globulin for the 400 and 1,200 mg dose levels, respectively, at days 28 and 56. Conclusion: 2-Methoxyestradiol is well tolerated and, despite suboptimal plasma levels and limited oral bioavailability with this capsule formulation, still showed some anticancer activity at 1,200 mg/d.

Phase II trial of perillyl alcohol (NSC 641066) administered daily in patients with metastatic androgen independent prostate cancer

Objective. We conducted a phase II multicenter trial of perillyl alcohol in patients with advanced hormone refractory prostate cancer (HRPC). The primary endpoint was to evaluate the 6-month progression-free survival given the potential cytostatic nature of the drug. Secondary objectives included assessing acute and chronic toxicities, as well as measuring objective response rates. Methods. Patients with metastatic androgen-independent prostate cancer that failed at least one prior chemotherapeutic or experimental regimen were eligible. Perillyl alcohol was administered orally at 1200 mg/m2/dose four times daily and continued until disease progression or development of unacceptable toxicity. Results. Fifteen patients were eligible. Six patients received less than one cycle (4 weeks) of drug, four of which stopped because of drug intolerance. Only six patients received more than two cycles of therapy and were considered evaluable for response. Main toxicity included grade 1–2 gastrointestinal intolerance (nausea/vomiting in 60% of the patients) and fatigue (47%). One patient developed a grade 4 hypokalemia that was felt likely attributable to the drug. No objective responses were seen. All patients either progressed or withdrew from the study secondary to drug intolerance before the 6-month time period. Conclusion. Perillyl alcohol administered at this dose and formulation did not have any objective clinical activity in this patient population.

Randomized, Double-Blinded Phase II Evaluation of Docetaxel with or without Doxercalciferol in Patients with Metastatic, Androgen-Independent Prostate Cancer

Purpose: Docetaxel is standard of care for androgen-independent prostate cancer (AIPC). Doxercalciferol (1α-hydroxyvitamin D2) had modest activity in phase I/II trials. Preclinical data support combining vitamin D analogues with docetaxel to treat AIPC. Experimental Design: Chemotherapy-naive men with metastatic AIPC were randomized 1:1 to receive, on a 4-week cycle, docetaxel (35 mg/m2 i.v., days 1, 8, and 15) with or without doxercalciferol (10 μg orally, days 1-28). The primary end point was prostate-specific antigen (PSA) response. Secondary end points were progression-free survival, overall survival, objective response, and toxicity. Survival was analyzed as intent to treat. Results: Seventy patients were randomized. Median follow-up was 17.6 months (range, 3.3-45.2). PSA response rate was 46.7% [95% confidence interval (95% CI), 30-64] in the doxercalciferol arm and 39.4% (95% CI, 25-56) with placebo (P = 0.560). Median progression-free survival in the doxercalciferol arm was 6.17 months (95% CI, 4.20-10.7) versus 6.20 months (95% CI, 4.83-9.07) with placebo (P = 0.764). Median overall survival in the doxercalciferol arm was 17.8 months (95% CI, 14.9-23.6) versus 16.4 months (95% CI, 11.9-23.8) with placebo (P = 0.383). Twenty-four patients in the doxercalciferol arm and 23 in the placebo arm were evaluable for objective response. No complete responses were observed. Partial objective response rate was 12.5% with doxercalciferol versus 8.7% with placebo (P = 0.672). Rate of grade ≥3 toxicity was 46% with doxercalciferol versus 42% with placebo (P = 0.785). Conclusions: Daily doxercalciferol with weekly docetaxel did not enhance PSA response rate or survival. Toxicity was similar between arms. Despite the disappointing results of this study, other vitamin D analogues remain under active investigation.

Real-time immune monitoring to guide plasmid DNA vaccination schedule targeting prostatic acid phosphatase in patients with castration-resistant prostate cancer

Purpose: We have previously reported that a DNA vaccine encoding prostatic acid phosphatase (PAP) could elicit PAP-specific T cells in patients with early recurrent prostate cancer. In the current pilot trial, we sought to evaluate whether prolonged immunization with regular booster immunizations, or “personalized” schedules of immunization determined using real-time immune monitoring, could elicit persistent, antigen-specific T cells, and whether treatment was associated with changes in PSA doubling time (PSA DT). Experimental Design: Sixteen patients with castration-resistant, nonmetastatic prostate cancer received six immunizations at 2-week intervals and then either quarterly (arm 1) or as determined by multiparameter immune monitoring (arm 2). Results: Patients were on study a median of 16 months; four received 24 vaccinations. Only one event associated with treatment >grade 2 was observed. Six of 16 (38%) remained metastasis-free at 2 years. PAP-specific T cells were elicited in 12 of 16 (75%), predominantly of a Th1 phenotype, which persisted in frequency and phenotype for at least 1 year. IFNγ-secreting T-cell responses measured by ELISPOT were detectable in 5 of 13 individuals at 1 year, and this was not statistically different between study arms. The overall median fold change in PSA DT from pretreatment to posttreatment was 1.6 (range, 0.6–7.0; P = 0.036). Conclusions: Repetitive immunization with a plasmid DNA vaccine was safe and elicited Th1-biased antigen-specific T cells that persisted over time. Modifications in the immunization schedule based on real-time immune monitoring did not increase the frequency of patients developing effector and memory T-cell responses with this DNA vaccine. Clin Cancer Res; 20(14); 3692–704. ©2014 AACR.

A Randomized Phase II Trial Evaluating Different Schedules of Zoledronic Acid on Bone Mineral Density in Patients With Prostate Cancer Beginning Androgen Deprivation Therapy

OBJECTIVE To assess the effects of timing and schedule of zoledronic acid (ZA) administration on bone mineral density (BMD) in patients beginning androgen deprivation therapy (ADT) for the treatment of recurrent prostate cancer. PATIENTS AND METHODS In this randomized, 3-arm trial, we evaluated changes in BMD after 3 different ZA administration schedules in men with recurrent prostate cancer who were beginning ADT. Forty-four patients were enrolled and randomized to receive a single dose of ZA given 1 week before beginning ADT (arm 1), a single dose of ZA given 6 months after beginning ADT (arm 2), or monthly administration of ZA starting 6 months after beginning ADT, for a total of 6 doses (arm 3). RESULTS Patients who received ZA before ADT had a significant improvement in BMD at the total proximal femur and trochanter after 6 months compared with the other groups. In addition, only patients in the arm that received multiple doses improved lumbar spine BMD while on ADT, with these findings persisting to 24 months. However, this group also experienced more grade 1 adverse events. CONCLUSIONS Analysis of these data suggests that ZA administration before initiation of ADT was superior to treatment 6 months after starting ADT in maintaining BMD. In addition, monthly ZA administration can increase BMD above baseline but is associated with more adverse events. Further study is needed to examine whether the timing and frequency of ZA therapy in patients on ADT can reduce fracture risk.

High resolution ultrasound features of prostatic rib metastasis: A prospective feasibility study with implication in the high-risk prostate cancer patient

OBJECTIVE In a prior study, high resolution ultrasound (US) was shown to be accurate for evaluating rib metastasis detected on bone scan. However, that study did not address the specific US appearance typical of osteoblastic rib metastasis. Our objective was to determine the specific US imaging appearance of osteoblastic prostate carcinoma rib metastasis using osteolytic renal cell carcinoma rib metastasis as a comparison group. MATERIALS AND METHODS The Institutional Review Board approval and informed consent were obtained for this prospective feasibility study. We performed high resolution US of 16 rib metastases in 4 patients with prostate carcinoma metastases and compared them to 8 rib metastases in 3 male patients with renal cell carcinoma. All patients had rib metastases proven by radiographs and computed tomography (CT). High resolution US scanning was performed by a musculoskeletal radiologist using a 12-5 MHz linear-array transducer. Transverse and longitudinal scans were obtained of each rib metastasis. RESULTS All 16 prostate carcinoma metastases demonstrated mild cortical irregularity of the superficial surface of the rib without associated soft tissue mass, cortical disruption, or bone destruction. 7 of 8 (88%) renal cell carcinoma rib metastases demonstrated cortical disruption or extensive bone destruction without soft tissue mass. One of 8 (12%) renal cell carcinoma rib metastases demonstrated only minimal superficial cortical irregularity at the site of a healed metastasis. CONCLUSION Osteoblastic prostate carcinoma rib metastases have a distinctive appearance on US. Our success in visualizing these lesions suggests that US may be a useful tool to characterize isolated rib abnormalities seen on a bone scan in high-risk prostate cancer patients who are being evaluated for curative surgery or radiation treatment.

Concurrent, but not sequential, PD-1 blockade with a DNA vaccine elicits anti-tumor responses in patients with metastatic, castration-resistant prostate cancer

T-cell checkpoint inhibitors have demonstrated dramatic clinical activity against multiple cancer types, however little activity in patients with prostate cancer. Conversely, an anti-tumor vaccine was approved for the treatment of prostate cancer, having demonstrated an improvement in overall survival, despite few objective disease responses. In murine studies, we found that PD-1 expression on CD8+ T cells increased following anti-tumor vaccination, and that PD-1/PD-L1 blockade at the time of immunization elicited greater anti-tumor responses. Based on these data we initiated a pilot trial evaluating the immunological and clinical efficacy of a DNA encoding prostatic acid phosphatase (PAP) when delivered in combination with pembrolizumab. 26 patients were treated for 12 weeks with vaccine and received pembrolizumab either during this time or during the subsequent 12 weeks. Adverse events included grade 2 and 3 fatigue, diarrhea, thyroid dysfunction, and hepatitis. Median time to radiographic progression was not different between study arms. 8/13 (62%) of patients treated concurrently, and 1/12 (8%, p=0.01) of patients treated sequentially, experienced PSA declines from baseline. Of these, two were over 50% and one was a complete PSA response. No confirmed CR or PR were observed, however 4/5 patients treated concurrently had measurable decreases in tumor volume at 12 weeks. PSA declines were associated with the development of PAP-specific Th1-biased T cell immunity and CD8+ T cell infiltration in metastatic tumor biopsy specimens. These data are the first report of a clinical trial demonstrating that the efficacy of an anti-tumor vaccine can be augmented by concurrent PD-1 blockade.

Randomized phase II trial evaluating different schedules of zoledronic acid administration on bone mineral density in patients with stage D prostate cancer beginning androgen deprivation.

4643 Background: Androgen deprivation therapy (ADT), the primary treatment for patients (pts) with metastatic prostate cancer (PC), causes bone loss. Zoledronic acid (ZA) is FDA approved for the treatment of bone metastatic PC, and in that setting is typically used on an every 3-4 week schedule. ZA is also approved for osteoporosis treatment in which setting it is typically used once per year. METHODS In this trial we evaluated changes in bone mineral density (BMD) following 3 different schedules of ZA administration in pts with recurrent PC who were beginning ADT. 44 pts were enrolled and randomized to one of 3 different treatment arms. 14 pts were treated once with 4 mg ZA one week prior to beginning ADT (arm A); 15 pts were treated once with 4 mg ZA 6 mo after beginning ADT (arm B); and 15 pts were treated monthly with 4 mg ZA for six mo beginning six mo after starting ADT (arm C). BMD measurements of the lumbar spine (LS) and femur by dual energy x-ray absorptiometry were assessed at baseline, and after 6, 12, 18 and 24 mo. As of March 2011, all pts will have completed 24 mo of follow up. RESULTS In pts treated on arm A, BMD increased from baseline to 6 mo at the total proximal femur (TPF) (+1.1% +/- 1.9%) that was significantly greater than the loss of BMD observed over the same period in patients in Arm B (-0.2% +/- 1.6%, p=0.05) or Arm C (-0.6% +/- 2.0%, p=0.01). Similar trends were observed at other measured sites. At 24 months, increases in BMD were greatest in pts treated on Arm C (1.5% +/- 3.3% at the TPF), compared with Arm B (0.12% +/- 2.0%) or Arm A (-0.9% +/- 2.6%). AEs believed at least possibly related to ZA consisted of grade 1 constitutional symptoms, grade 1 or 2 musculoskeletal symptoms, and grade 1 insomnia or irritability. CONCLUSIONS Overall, these data demonstrate that BMD loss occurs within months after beginning ADT, and early administration of ZA may prevent significant BMD loss. Consequently the timing of ZA administration may be important for men initiating ADT. Furthermore, ZA administration results in a delayed increase in BMD in patients previously started on ADT.