PMID- 27115568 OWN - NLM STAT- MEDLINE DCOM- 20170518 LR - 20210108 IS - 1532-1827 (Electronic) IS - 0007-0920 (Print) IS - 0007-0920 (Linking) VI - 114 IP - 9 DP - 2016 Apr 26 TI - 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. PG - 986-94 LID - 10.1038/bjc.2016.72 [doi] AB - BACKGROUND: Mipsagargin (G-202; (8-O-(12-aminododecanoyl)-8-O-debutanoyl thapsigargin)-Asp-gamma-Glu-gamma-Glu-gamma-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. FAU - Mahalingam, D AU - Mahalingam D AD - 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. FAU - Wilding, G AU - Wilding G AD - University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA. FAU - Denmeade, S AU - Denmeade S AD - Johns Hopkins University, Baltimore, MD, USA. FAU - Sarantopoulas, J AU - Sarantopoulas J AD - 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. FAU - Cosgrove, D AU - Cosgrove D AD - Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Bunting/Blaustein Building, 1650 Orleans Street, Baltimore, MD 21231-1000, USA. FAU - Cetnar, J AU - Cetnar J AD - University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA. FAU - Azad, N AU - Azad N AD - Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Bunting/Blaustein Building, 1650 Orleans Street, Baltimore, MD 21231-1000, USA. FAU - Bruce, J AU - Bruce J AD - Department of Oncology, University of Wisconsin Carbone Cancer Center, 7057 Wisconsin Institutes for Medical Research, 1111 Highland Avenue, Madison, WI 53705, USA. FAU - Kurman, M AU - Kurman M AD - Genspera Inc., Medical Monitor, 2511 North Loop 1604 W, Suite 204, San Antonio, TX 78258, USA. FAU - Allgood, V E AU - Allgood VE AD - Genspera Inc., Medical Monitor, 2511 North Loop 1604 W, Suite 204, San Antonio, TX 78258, USA. FAU - Carducci, M AU - Carducci M AD - Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Bunting/Blaustein Building, 1650 Orleans Street, Baltimore, MD 21231-1000, USA. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PL - England TA - Br J Cancer JT - British journal of cancer JID - 0370635 RN - 0 (Enzyme Inhibitors) RN - 0 (Prodrugs) RN - 67526-95-8 (Thapsigargin) SB - IM MH - Aged MH - Aged, 80 and over MH - Enzyme Inhibitors/administration & dosage/pharmacokinetics/*therapeutic use MH - Humans MH - Male MH - Middle Aged MH - Neoplasms/*drug therapy MH - Prodrugs/*therapeutic use MH - Thapsigargin/administration & dosage/pharmacokinetics/*therapeutic use PMC - PMC4984914 COIS- M Kurman is a paid consultant to GenSpera, Inc. The other authors declare no conflict of interest. EDAT- 2016/04/27 06:00 MHDA- 2017/05/19 06:00 PMCR- 2016/04/26 CRDT- 2016/04/27 06:00 PHST- 2015/10/13 00:00 [received] PHST- 2016/02/03 00:00 [revised] PHST- 2016/02/16 00:00 [accepted] PHST- 2016/04/27 06:00 [entrez] PHST- 2016/04/27 06:00 [pubmed] PHST- 2017/05/19 06:00 [medline] PHST- 2016/04/26 00:00 [pmc-release] AID - bjc201672 [pii] AID - 10.1038/bjc.2016.72 [doi] PST - ppublish SO - Br J Cancer. 2016 Apr 26;114(9):986-94. doi: 10.1038/bjc.2016.72.