A first in class, first in human, phase I trial of p28, a non-HDM2 mediated peptide inhibitor of p53 ubiquitination in patients with metastatic refractory solid tumors
J.M. Richards, M.A. Warso, D. Mehta, K.T. Christov, C.M. Schaeffer, T. Yamada, L.R. Bressler, C.W. Beattie, T.K. Das Gupta. Oncology Specialists, Park Ridge, IL; University of Illinois COM, Chicago, IL; University of Illinois Medical Center, Chicago, IL.
Background: A 28 aa peptide (p28) derived from azurin, a redox protein secreted from the opportunistic pathogen Pseudomonas aeruginosa, preferentially enters a wide variety of cancer cells and inhibits their proliferation at G2/M through a non HDM2 mediated post translational increase in the level of wild type and mutated p53.
Methods: Refractory (Stage IV) solid tumor patients (15) with p53+ lesions (>10% cells; IHC) were enrolled in an escalating, 5 dose level (.83, 1.66, 2.5, 3.33 and 4.16 mg/kg) Phase I trial to evaluate safety, tolerability, immunogenicity, pharmacokinetics and pharmacodynamics (PK/PD) of p28 as a single agent. p28 was administered 3X per week for 4 weeks as an iv bolus with a two week PK break before the next, higher dose. Serum and tumor specimens were assessed for levels of p28.
Results: To date, none of the 14 patients evaluated exhibited an immune (lgG) response or toxicity grade > 1. This group consisted of 7 melanoma, 4 colon, 1 pancreatic, 1 prostate and 1 sarcoma patient(s), with a median age of 61, age range of 51-71, and ECOG performance status of 0-2 including those receiving the highest dose level. Consequently, the NAOEL and MTD were above the highest dose studied. p28 distributes rapidly (t1/2, 0.1 hr), has a prolonged terminal half-life (t1/2y > 1.7 hr above 2.5 mg/kg) where distribution (Vdss) is maximal. Tumor levels mirrored serum concentrations. Objective responses were observed in target lesions of 8 of 14 patients evaluated to date (1 CR, 7 PR). Patient survival paralleled objective response. The current range in overall survival for patients initially receiving dose levels 1-5 was 2-4, 5-13.5, 3.5-11, 1.5-6 and 2.5-4.5 months, respectively. Currently, 6 of 11 patients receiving dose levels 2-5 remain alive; one with a CR.
Conclusion: p28 may provide a new opportunity to improve overall survival in patients with metastatic, p53+ solid tumors as a single agent without significant toxicity.