Mipsagargin, a novel thapsigargin-based PSMA-Activated prodrug: Results of a first-in-man phase i clinical trial in patients with refractory, advanced or metastatic solid tumours

D. Mahalingam*, G. Wilding, S. Denmeade, J. Sarantopoulas, D. Cosgrove, J. Cetnar, N. Azad, J. Bruce, M. Kurman, V. E. Allgood, M. Carducci

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

Background:Mipsagargin (G-202; (8-O-(12-Aminododecanoyl)-8-O-debutanoyl thapsigargin)-Asp-γ-Glu-γ-Glu-γ-GluGluOH)) is a novel thapsigargin-based targeted prodrug that is activated by PSMA-mediated cleavage of an inert masking peptide. The active moiety is an inhibitor of the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump protein that is necessary for cellular viability. We evaluated the safety of mipsagargin in patients with advanced solid tumours and established a recommended phase II dosing (RP2D) regimen.Methods:Patients with advanced solid tumours received mipsagargin by intravenous infusion on days 1, 2 and 3 of 28-day cycles and were allowed to continue participation in the absence of disease progression or unacceptable toxicity. The dosing began at 1.2 mg m-2 and was escalated using a modified Fibonacci schema to determine maximally tolerated dose (MTD) with an expansion cohort at the RP2D. Plasma was analysed for mipsagargin pharmacokinetics and response was assessed using RECIST criteria.Results:A total of 44 patients were treated at doses ranging from 1.2 to 88 mg m-2, including 28 patients in the dose escalation phase and 16 patients in an expansion cohort. One dose-limiting toxicity (DLT; Grade 3 rash) was observed in the dose escalation portion of the study. At 88 mg m-2, observations of Grade 2 infusion-related reaction (IRR, 2 patients) and Grade 2 creatinine elevation (1 patient) led to declaration of 66.8 mg m-2 as the recommended phase II dose (RP2D). Across the study, the most common treatment-related adverse events (AEs) were fatigue, rash, nausea, pyrexia and IRR. Two patients developed treatment-related Grade 3 acute renal failure that was reversible during the treatment-free portion of the cycle. To help ameliorate the IRR and creatinine elevations, a RP2D of 40 mg m-2 on day 1 and 66.8 mg m-2 on days 2 and 3 with prophylactic premedications and hydration on each day of infusion was established. Clinical response was not observed, but prolonged disease stabilisation was observed in a subset of patients.Conclusions:Mipsagargin demonstrated an acceptable tolerability and favourable pharmacokinetic profile in patients with solid tumours.

Original languageEnglish (US)
Pages (from-to)986-994
Number of pages9
JournalBritish Journal of Cancer
Volume114
Issue number9
DOIs
StatePublished - Apr 26 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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