2. Academic Validation
  3. 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

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

  • Br J Cancer. 2016 Apr 26;114(9):986-94. doi: 10.1038/bjc.2016.72.
D Mahalingam 1,  G Wilding 2,  S Denmeade 3,  J Sarantopoulas 1,  D Cosgrove 4,  J Cetnar 2,  N Azad 4,  J Bruce 5,  M Kurman 6,  V E Allgood 6,  M Carducci 4
Affiliations

Affiliations

  • 1 University of Texas Health Science Center San Antonio, Cancer Therapy and Research Center, 7979 Wurzbach Road, U639, Mail Code 8232, San Antonio, TX 78229, USA.
  • 2 University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA.
  • 3 Johns Hopkins University, Baltimore, MD, USA.
  • 4 Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Bunting/Blaustein Building, 1650 Orleans Street, Baltimore, MD 21231-1000, USA.
  • 5 Department of Oncology, University of Wisconsin Carbone Cancer Center, 7057 Wisconsin Institutes for Medical Research, 1111 Highland Avenue, Madison, WI 53705, USA.
  • 6 Genspera Inc., Medical Monitor, 2511 North Loop 1604 W, Suite 204, San Antonio, TX 78258, USA.
PMID: 27115568 DOI: 10.1038/bjc.2016.72
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.

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