CHICAGO, IL USA (UroToday.com) - Presented by Mark W. Frohlich, MD at the American Society of Clinical Oncology (ASCO) Annual Meeting - May 31 - June 4, 2013 - McCormick Place - Chicago, IL USA
A randomized phase II trial of sipuleucel-T with concurrent or sequential abiraterone acetate (AA) plus prednisone (P) in metastatic castrate-resistant prostate cancer (mCRPC)
Eric Jay Small, Raymond S. Lance, Charles H. Redfern, Frederick E. Millard, Thomas A. Gardner, Lawrence Ivan Karsh, Nancy Ann Dawson, Candice McCoy, Andrew Stubbs, Todd DeVries, Corazon P. dela Rosa, Nadeem A. Sheikh, Neal D. Shore
University of California, San Francisco, San Francisco, CA; Eastern Virginia Medical School, Norfolk, VA; Sharp Clinical Oncology Research, San Diego, CA; Moores UCSD Cancer Center, San Diego, CA; Urology Indiana University Health, Indianapolis, IN; The Urology Center of Colorado, Denver, CO; Georgetown University Medical Center, Washington, DC; Dendreon Corporation, Seattle, WA; Carolina Urologic Research Center, Myrtle Beach, SC
Background: Sipuleucel-T and AA+P are FDA-approved for asymptomatic/minimally symptomatic mCRPC. Suppression of the androgen axis can be immunostimulatory and AA suppresses circulating androgen levels; AA plus sipuleucel-T may therefore be synergistic. However P used with AA, which may be immunosuppressive, has not been studied with concurrent sipuleucel-T and could impair sipuleucel-T production and/or immunologic response. P11-3 (NCT01487863) is the first study to evaluate the combination of sipuleucel-T and AA+P
Methods: Patients (pts) with asymptomatic/minimally symptomatic mCRPC were randomized (1:1) to sipuleucel-T (3 infusions at approx 2-wk intervals) with up to 26 wks of AA+P (AA 1000mg QD+P 5mg BID) starting 1 day after the first sipuleucel-T infusion (concurrent, arm A) or at 10 wks following the first sipuleucel-T infusion (sequential, arm B). Endpoints included the effect of AA+P on product (sipuleucel-T) characteristics e.g., antigen presenting cell (APC) activation, measured as CD54 upregulation (primary endpoint), APC (measured as CD54+ cells) and total nucleated cell (TNC) counts, as well as safety and immunologic responses.
Results: 31 pts in arm A and 32 pts in arm B completed sipuleucel-T treatment by the interim analysis (Nov 2012). Baseline characteristics were similar in the 2 arms. 60/63 pts received all 3 infusions of sipuleucel-T. No significant differences in median cumulative APC activation, APC count or TNC count were seen between the arms. Increased CD54 upregulation with the 2nd and 3rd treatments were indicative of a prime boost effect in both arms. Similar profiles of antigen-specific humoral and cellular immune responses were generated with no difference in magnitude of response between the arms (p.0.05). The incidence of adverse events (AEs) and serious AEs was similar in both arms.
Conclusions: These data suggest sipuleucel-T can be successfully manufactured during concurrent AA+P. Product potency and prime boost effect were similar to sipuleucel-T alone. Immune responses and AEs were similar in both arms. It is not known if sipuleucel-T will provide similar efficacy with concurrent or sequential AA 1 P. Clinical trial information: NCT01487863.
A randomized phase II study evaluating the optimal sequencing of sipuleucel-T and androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC): Immune results
Emmanuel S. Antonarakis, Adam S Kibel, George Adams, Lawrence Ivan Karsh, Aymen Elfiky, Neal D. Shore, Nicholas J. Vogelzang, John M. Corman, Robert Claude Tyler, Candice McCoy, Yang Wang, Nadeem A. Sheikh, Charles G. Drake
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; Brigham and Women’s Hospital/Harvard University, Boston, MA; Urology Centers of Alabama, Homewood, AL; The Urology Center of Colorado, Denver, CO; Carolina Urologic Research Center, Myrtle Beach, SC; Comprehensive Cancer Centers of Nevada, The US Oncology Network, Las Vegas, NV; Virginia Mason Medical Center, Seattle, WA; Dendreon Corporation, Seattle, WA
Background: ADT is a standard treatment for men with BRPC after failure of local therapy, and has immunomodulatory effects. Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic/ minimally symptomatic metastatic castrate resistant prostate cancer. The STAND trial (NCT01431391) aimed to evaluate optimal sequencing of sipuleucel-T and ADT in men with BRPC at high risk for metastases (i.e., PSA doubling time ≤ 12 mo).
Methods: Men were randomized (1:1) to Arm 1: sipuleucel-T followed by ADT (2 wks after 3rd infusion); or Arm 2: ADT (3 mo lead in) followed by sipuleucel-T. All men had 3 doses of sipuleucel-T and 12 mo of ADT (45 mg leuprolide SQ at 6 mo intervals). The primary endpoint is cellular immune response (ELISPOT to PA2024 [PAP-GMCSF]). Secondary endpoints are humoral and cytokine responses, product parameters and safety.
Results: 68 men were randomized. Preliminary data show higher levels of serum cytokines in Arm 2 vs Arm 1, with a pattern suggesting a mixed TH1/TH2 cellular immune response; elevations were seen in TH1 (IFNγ, IL 12), TH2 (IL 4, 5, 10, 13) and TH17 (IL 17) subsets (all P,<05). The increase in TH1 cytokines was consistent with a trend toward higher PA2024-specific ELISPOT responses 2 wk after the 3rd sipuleucel-T infusion in Arm 2 vs Arm 1 (40.5 vs 12.8 spots; P=.086), suggesting increased T cell activation in Arm 2. Antigen-specific humoral responses were induced in both arms with no differences yet observed between arms. Sipuleucel-T product parameters were roughly equivalent in both arms with APC activation data indicating a robust prime-boost effect.
Conclusions: While confirmation is required, these preliminary data suggest that tumor-specific T cell responses and broad based immune responses are augmented when sipuleucel-T is given after rather than before ADT initiation. These data are consistent with preclinical studies showing that ADT enhances T cell activity, and provide preliminary evidence that combining ADT with sipuleucel-T may augment adaptive immunity. Further follow up will determine whether augmented immune responses correlate with clinical parameters (eg PSA recurrence). Clinical trial information: NCT01431391.
Open-label, multicenter study of sipuleucel-T in men with metastatic castrateresistant prostate cancer (mCRPC) previously treated with sipuleucel-T: Evaluation of antigen presenting cell (APC) activation and ELISPOT data
Tomasz M. Beer, L. Michael Glode, Raymond S. Lance, Richard H. Greengold, Corazon P. dela Rosa, Robert Brownell Sims, Yang Wang, Nadeem A. Sheikh, John M. Corman
Oregon Health & Science University Knight Cancer Institute, Portland, OR; University of Colorado Denver, Aurora, CO; Eastern Virginia Medical School, Norfolk, VA; South Orange County Medical Research Center, Laguna Hills, CA; University of Washington, Seattle, WA; Dendreon Corporation, Seattle, WA; Virginia Mason Medical Center, Seattle, WA
Background: P10-1 (NCT01338012) is a study of sipuleucel-T, an autologous cellular immunotherapy, in men with mCRPC previously treated with sipuleucel-T in PROTECT (NCT00779402). This preliminary analysis of P10-1 evaluates APC activation (a measure of product potency) and immune responses in men retreated with sipuleucelET.
Methods: Men who received ≥ 1 infusion of sipuleucel-T in PROTECT and progressed to mCRPC were retreated with 3 infusions of sipuleucel-T. APC activation was assessed by CD54 upregulation. T cell responses to prostatic acid phosphatase (PAP) and PA2024 (PAP-GM-CSF) antigens were assessed by IFN-γELISPOT assay.
Results: As of October 23, 2012, 7 men were enrolled and received ≥ 1 infusion. Median time between the third PROTECT infusion and first P10-1 infusion was 9.2 (range: 7.8 –10.0) years. APC activation was greater at the first P10-1 treatment vs the last PROTECT treatment. PA2024 and PAP ELISPOT responses were present prior to retreatment, indicating long-term memory; based on other studies of sipuleucel-T, ELISPOT responses are not generally present prior to the first treatment (Beer. Clin Cancer Res 2011; Sheikh. Cancer Immunol Immunother 2013).
Conclusions: This is the first trial to report the feasibility of sipuleucel-T retreatment following treatment in an earlier stage of prostate cancer. These data indicate the presence of existing immunological memory to the immunizing antigen several years after initial treatment. In addition, retreatment with sipuleucel-T appeared to boost product potency compared with prior treatment. Clinical trial information: NCT01338012.
Impact of prior docetaxel (D) on sipuleucel-T (sip-T) product parameters in PROCEED patients (pts)
Celestia S. Higano, Andrew J. Armstrong, Matthew R. Cooperberg, Philip W. Kantoff, James Bailen, Raoul S. Concepcion, Vahan Kassabian, Shaker R. Dakhil, Steven E. Finkelstein, Jeffrey L. Vacirca, Robert M. Rifkin, Andrew Sandler, Candice McCoy, James Boyd Whitmore, Robert Claude Tyler, A. Oliver Sartor
University of Washington/Seattle Cancer Care Alliance, Seattle, WA; Duke Cancer Institute, Durham, NC; University of California, San Francisco, San Francisco, CA; Dana-Farber Cancer Institute, Boston, MA; First Urology, PSC, Jeffersonville, IN; Urology Associates, Nashville, TN; Georgia Urology, Atlanta, GA; Cancer Center of Kansas, Wichita, KS; 21st Century Oncology, Translational Research Consortium (TRC), Scottsdale, AZ; North Shore Hematology Oncology Associates, PC, East Setauket, NY; Rocky Mountain Cancer Centers, US Oncology Research, Denver, CO; Dendreon Corporation, Seattle, WA; Tulane Cancer Center, New Orleans, LA
Background: Sip-T is an autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic mCRPC. The IMPACT trial excluded pts who received D ≤ 3 months prior to registration. PROCEED is an ongoing, phase IV registry, enrolling pts treated with commercial sip-T. Use of D prior to sip-T is not restricted, so prior D affect on sip-T immune manufacturing parameters can be evaluated.
Methods: Pts treated with sip-T ≤ 6 mo were eligible to provide informed consent. Sip-T parameters assessed included: total nucleated cell (TNC) count, antigen presenting cell (APC) count (CD54+large cells) and APC activation (upregulation of CD54).
Results: By Nov. 2012, 108/761 (14%) received D prior to sip-T and had similar median cumulative APC counts (1.83 (Q1, Q3: 1.16, 2.71) vs. 1.82 (1.27, 2.70) x 109) and TNC counts (10.16 (7.30, 13.69) vs. 11.47 (8.56, 15.31) x 109) vs. D naïve, whereas median cumulative APC activation appeared slightly lower (32.39 (25.05, 41.02) vs. 34.84 (28.71, 42.83)), but was well above the release criterion for each infusion (2.6 fold). The group was then split by Eastern Cooperative Oncology Group Performance Status (ECOG PS) and Gleason scores.
Conclusions: Pts with D prior to sip-T appeared to have product parameters comparable to pts without prior D, albeit with a slightly lower APC activation. Further analysis showed that pts receiving D within 3 months of sip-T had higher Gleason and ECOG scores. The clinical significance of these findings is unclear, but suggests that APC activation is not impaired following docetaxel. Clinical trial information: NCT01306890.
Mark W. Frohlich, MD serves as executive vice president of research and development and chief medical officer at Dendreon. Prior to that, Dr. Frohlich was an assistant professor in the Division of Hematology/Oncology at the University of California, San Francisco, where he specialized in urologic oncology and was active in laboratory, translational and clinical research.
Dr. Frohlich did his post-doctoral training in oncology at the University of California, San Francisco. He received his BS from Yale University in electrical engineering and economics and his MD from Harvard Medical School.