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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.
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2011
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Aa PeptideFirst-in-human PhaseImmunologyPathologyPharmacotherapyAntimicrobial ChemotherapyRedox ProteinTumor BiologyDrug ResistanceNon-hdm2-mediated Peptide InhibitorOncologyMetronomic TherapyAnti-cancer AgentRadiation OncologyCancer ResearchHealth SciencesCancer TreatmentPharmacologyP53+ LesionsP53 UbiquitinationAntibioticsImmune Checkpoint InhibitorMedicine
2511 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 3 X 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 (IgG) 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 (t½ α, 0.1 hr), has a prolonged terminal half-life (t½ γ > 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. Conclusions: p28 may provide a new opportunity to improve overall survival in patients with metastatic, p53+ solid tumors as a single agent without significant toxicity.