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Phase I-II study of ADXS31-142 alone and in combination with pembrolizumab in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC): the KEYNOTE-046 trial
  1. Naomi B Haas1,
  2. Mark N Stein2,
  3. Ronald Tutrone3,
  4. Rodolfo Perini4,
  5. Andrew Denker4,
  6. David Mauro5 and
  7. Lawrence Fong6
  1. Aff1 grid.25879.310000000419368972Abramson Cancer CenterUniversity of Pennsylvania Philadelphia PA USA
  2. Aff2 grid.430387.b0000000419368796Rutgers Cancer Institute of New Jersey New Brunswick NJ USA
  3. Aff3 grid.492712.bChesapeake Urology Research Associates Baltimore MD USA
  4. Aff4 grid.417993.10000000122600793Merck, Sharp & Dohme, Corp North Wales PA USA
  5. Aff5 grid.422071.2Advaxis, Inc. Princeton NJ USA
  6. Aff6 grid.266102.10000000122976811Department of MedicineUniversity of California San Francisco Helen Diller Family Comprehensive Cancer Center San Francisco CA USA

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Meeting abstracts


Activation of tumor antigen-specific T-cell responses and bypass/neutralization of tumor immune tolerance mechanisms are essential for immunotherapeutic efficacy. Listeria monocytogenes (Lm)-listeriolysin O (LLO) immunotherapies have shown to both generate antigen-specific T-cell responses and neutralize cells that protect the tumor microenvironment. ADXS31-142 is a live attenuated Lm-LLO immunotherapy designed to target the prostate-specific antigen (PSA) and bioengineered to secrete an antigen-adjuvant fusion protein, consisting of a truncated fragment of the LLO fused to human PSA. Programmed death receptor 1 (PD-1) is a cell surface protein receptor central to T-cell immunity inhibition. Pembrolizumab is a humanized monoclonal antibody that binds to the PD-1 receptor, blocking interaction with PD-1 ligands and thereby inhibiting tumor immune evasion mechanisms. The combination of an Lm-LLO immunotherapy with an anti-PD-1 antibody has shown synergistic antitumor activity in preclinical studies.


This is a Phase I-II, open-label, multicenter, nonrandomized, 2-part study (NCT02325557) in patients with mCRPC. Part A is a dose escalation of monotherapy ADXS31-142, followed by Part B, a dose escalation of ADXS31-142 plus pembrolizumab; Part B is followed by a dose-expansion cohort. Primary objectives are to evaluate the safety and tolerability of ADXS31-142 alone and in combination with pembrolizumab, and establish the ADXS31-142 recommended Phase II dose (RP2D) for monotherapy and combination therapy. Secondary objectives include evaluation of antitumor activity and progression-free survival. Male patients (≥18 years) with progressive mCRPC (≤3 prior systemic treatment regimens), on androgen deprivation therapy, and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 are eligible. Each dose-determining part will enroll up to 21 patients. ADXS31-142 and pembrolizumab (200 mg) are administered once every 3 weeks in a 12-week treatment cycle, with ADXS31-142 administration limited to weeks 1, 4, and 7. ADXS31-142 dose-escalations (up to a maximum of 1×1010 colony-forming units [CFU]) and de-escalations are done according to predefined dose-limiting toxicity criteria by applying the modified toxicity probability interval design. In Part A, the starting ADXS31-142 dose is 1×109 CFU, and in Part B is either 1 level below the RP2D established for monotherapy or 1×109 CFU, if this was the maximum tolerated dose for monotherapy. Once the ADXS31-142 RP2D for combination with pembrolizumab is determined, the expansion cohort will open for enrollment. A total of 30 patients are planned for treatment at the RP2D. The study is currently open and patient accrual is in progress.

Trial registration identifier NCT02325557.