Robert Claude Tyler

Randomized phase II trial evaluating the optimal sequencing of sipuleucel-T and androgen-deprivation therapy (ADT) in patients (pts) with biochemically recurrent prostate cancer (BRPC).

34 Background: ADT is a standard therapy for pts with BRPC after failure of primary therapy, and has known immunomodulatory effects. Sipuleucel-T is an autologous cellular immunotherapy that targets prostatic acid phosphatase (PAP) and is FDA approved for minimally or asymptomatic metastatic castrate-resistant prostate cancer. Here we report interim data from a phase 2 trial evaluating the optimal sequencing of sipuleucel-T and ADT by examining immune response markers in pts with BRPC at high risk for metastases (i.e., PSA doubling time ≤12 mo). METHODS Men were equally randomized to Arm 1: sipuleucel-T followed by ADT (started 2 wk after the final sipuleucel-T infusion); or Arm 2: ADT followed by sipuleucel-T (started after 3 mo of ADT). In both arms pts received 3 infusions of sipuleucel-T and 12 mo of ADT (2 × 45 mg leuprolide injections at 6 mo intervals). The primary endpoint was antigen-specific immune responses (ELISPOT to PA2024 [PAP-GM-CSF]). Secondary endpoints included safety and product parameters (CD54 upregulation, CD54+ and total nucleated cell counts). RESULTS 68 pts were randomized over 9 mo. Baseline characteristics were balanced across arms. Product parameters, evaluated in 31 and 17 pts in Arms 1 and 2, respectively, were similar between arms at the time of this analysis (26 Sept 2012). Antigen presenting cell activation patterns indicated a prime-boost effect (increased CD54 upregulation at infusions 2 and 3). Analysis of serum samples suggested that there were no differences between the arms in cellular (n=20; n=10) or humoral (n=22; n=13) immune responses to PA2024 or PAP (p>0.05). Similar anti-tetanus titers were seen in both arms, indicating equivalent immunocompetence. To date, the combination of sipuleucel-T and ADT appears to be well tolerated with only 1 serious adverse event seen (vertigo, Arm 2). CONCLUSIONS Preliminary data suggest that in men with BRPC, sipuleucel-T results in a similar prime-boost pattern of immune activation, and antigen-specific cellular and humoral responses, independent of ADT. Sipuleucel-T plus ADT appears to be well tolerated in these pts. Updated results will be presented. CLINICAL TRIAL INFORMATION NCT01431391.

Real-world experience with sipuleucel-T in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who received prior docetaxel (D): Data from PROCEED.

30^ Background: Sipuleucel-T is an autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic mCRPC. The phase III IMPACT trial showed a significant improvement in overall survival with sipuleucel-T treatment (tmt). In IMPACT, D use was prohibited within 3 months prior to registration due to the potential immunosuppressive impact of chemotherapy. PROCEED is an ongoing, multicenter, phase 4 registry enrolling pts receiving sipuleucel-T in the real-world setting. Enrollment has no restrictions on D use; thus, data from PROCEED may help determine whether prior D affects sipuleucel-T manufacture. Here we present preliminary results on baseline demographics and product parameters in PROCEED subjects with and without prior D exposure. METHODS Pts who were treated with sipuleucel-T within the prior 6-months at clinical sites were asked to provide informed consent to participate in PROCEED. RESULTS By September 2012, 560 pts completed sipuleucel-T tmt; 15% previously received D (median 291 days prior to 1st sipuleucel-T infusion). Patients with prior D had higher PSA levels, and those with recent D use tended to have a lower performance status and higher Gleason scores, but product parameters were generally comparable between the groups (see table). CONCLUSIONS Pts enrolled in PROCEED with and without prior D exposure had different baseline demographics and disease characteristics. However, sipuleucel-T product parameters were comparable regardless of prior D exposure. CLINICAL TRIAL INFORMATION NCT01306890. [Table: see text].

775PA RANDOMIZED PHASE 2 STUDY EVALUATING OPTIMAL SEQUENCING OF SIPULEUCEL-T (SIP-T) AND ANDROGEN DEPRIVATION THERAPY (ADT) IN BIOCHEMICALLY-RECURRENT PROSTATE CANCER (BRPC): VARIABLES THAT CORRELATE WITH IMMUNE RESPONSE

ABSTRACT Aim: Sip-T is an autologous cellular immunotherapy targeting prostatic acid phosphatase (PAP) approved by the US FDA and EMA for treatment of certain patients with asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer based on a 22% reduction in risk of death in the IMPACT trial. Predictive markers of survival benefit from immunotherapy are needed. Eosinophil counts correlated with humoral response and survival in previous trials of sip-T; here we assess T cell proliferation and variables correlating with immune response in the STAND trial. Methods: STAND evaluates optimal sequencing of sip-T and ADT in men with BRPC at high risk for metastases. Men (N = 68) were randomized 1:1 to Arm 1: sip-T followed by ADT (2 wks after 3rd infusion) or Arm 2: ADT (3 mo lead-in) followed by sip-T. All men had 3 doses of sip-T and 12 mos of ADT. Primary endpoint: cellular immune response. Secondary endpoints: humoral/cytokine responses, product parameters, safety. Spearmans correlations (r) were used to assess the relationship between maximal humoral response, cumulative product parameters, and maximal post-baseline eosinophil count. Results: 65 men have been followed for ≥9 mos post-ADT. Sip-T induced robust immune responses to PA2024 and PAP (T cell memory responses and ELISA antibody responses to PAP and PA2024, a recombinant protein comprising PAP fused to granulocyte-macrophage colony-stimulating factor) in both arms. Variables that correlated with antibody responses included cumulative total nucleated cell (TNC) count (PA2024, P = 0.03; PAP, P = 0.08) and maximum eosinophil count after sip-T treatment (PA2024, P = 0.06; PAP, P = 0.02). Antigen-specific T cell proliferation increased after the 2nd sip-T infusion and persisted to 26 wks. Conclusions: Consistent with other studies, sip-T induced a robust, long-term cellular immune response. Although not different between arms, cumulative TNC count and maximum eosinophil count after sip-T may be markers associated with humoral response, and warrant further study. Disclosure: C.G. Drake: Research funding: Aduro, Bristol Myers Squibb Consultant/advisory role: Bristol Myers Squibb, Dendreon, Janssen, Pfizer, Roche; A.S. Kibel: Advisory Board for Dendreon, Sanofi, and Myraid; G.W. Adams: Speakers bureau for Dendreon & Amgen; L.I. Karsh: Consultant/advisor: Dendreon Investigator: Dendreon Meeting participant/lecturer: Dendreon Scientific study/trial: Dendreon; N.D. Shore: Research/consultant for Algeta, Astellas, Bayer, Pfizer, Millenium, Janssen, Medivation, Sanofi N.J. Vogelzang: Dendreon speakers bureau and research funding from Dendreon; J.M. Corman: Honoraria and Research Funding for Dendreon; R.C. Tyler, C. McCoy, T. Devries and N. Sheikh: Dendreon Corporation: Employee and Stock Holder; E.S. Antonarakis: Dendreon advisory board and Dendreon research funding. All other authors have declared no conflicts of interest.

Real-world experience with sipuleucel-T in patients (pts) ≥80 years old with metastatic castration-resistant prostate cancer (mCRPC): Data from PROCEED.

131^ Background: Sipuleucel-T is an autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic mCRPC based on data from the phase III IMPACT pivotal trial that showed a significant improvement in overall survival (OS) compared to control (HR: 0.78 [95% CI: 0.61, 0.98]; P=0.03; median OS difference 4.1 mos). Analysis of IMPACT demonstrated evidence of a positive sipuleucel-T treatment effect in men above and below the median age of 71. We sought to understand the disease characteristics and product parameters in pts ≥80 years (yrs) given the high prevalence of older men in the mCRPC pt population. METHODS PROCEED is an ongoing, multicenter (>190 sites), phase 4 registry enrolling pts receiving sipuleucel-T. Information on antigen presenting cell (APC) activation and total nucleated cell (TNC) count were obtained during product manufacture. RESULTS Of 560 subjects who completed sipuleucel-T treatment to date: 110 (20%) pts were ≥80 yrs-old. Disease characteristics in pts ≥80 yrs vs <80 yrs are detailed in the table below. Product parameters were similar between groups. CONCLUSIONS Pts ≥80 exhibit similar product parameters compared with their younger counterparts. Future follow-up will explore OS and correlations with immune parameters in both groups. CLINICAL TRIAL INFORMATION NCT01306890. [Table: see text].