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, Jeremy Cetnar, N. Azad, J. Bruce, M. Kurman, V. E. Allgood, M. Carducci

Research output: Contribution to journalArticle

40 Citations (Scopus)

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
Externally publishedYes

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Thapsigargin
Prodrugs
Clinical Trials
Neoplasms
Exanthema
Creatinine
Pharmacokinetics
Maximum Tolerated Dose
Calcium-Transporting ATPases
Premedication
Sarcoplasmic Reticulum
Acute Kidney Injury
Intravenous Infusions
Endoplasmic Reticulum
Nausea
Fatigue
Disease Progression
Fever
Therapeutics
Safety

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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

In: British Journal of Cancer, Vol. 114, No. 9, 26.04.2016, p. 986-994.

Research output: Contribution to journalArticle

Mahalingam, D, Wilding, G, Denmeade, S, Sarantopoulas, J, Cosgrove, D, Cetnar, J, Azad, N, Bruce, J, Kurman, M, Allgood, VE & Carducci, M 2016, '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', British Journal of Cancer, vol. 114, no. 9, pp. 986-994. https://doi.org/10.1038/bjc.2016.72
Mahalingam, D. ; Wilding, G. ; Denmeade, S. ; Sarantopoulas, J. ; Cosgrove, D. ; Cetnar, Jeremy ; Azad, N. ; Bruce, J. ; Kurman, M. ; Allgood, V. E. ; Carducci, M. / 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. In: British Journal of Cancer. 2016 ; Vol. 114, No. 9. pp. 986-994.
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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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T1 - Mipsagargin, a novel thapsigargin-based PSMA-Activated prodrug

T2 - Results of a first-in-man phase i clinical trial in patients with refractory, advanced or metastatic solid tumours

AU - Mahalingam, D.

AU - Wilding, G.

AU - Denmeade, S.

AU - Sarantopoulas, J.

AU - Cosgrove, D.

AU - Cetnar, Jeremy

AU - Azad, N.

AU - Bruce, J.

AU - Kurman, M.

AU - Allgood, V. E.

AU - Carducci, M.

PY - 2016/4/26

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N2 - 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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