Pharmacodynamics (PD) and pharmacokinetics (PK) of E7389 (eribulin, halichondrin B analog) during a phase i trial in patients with advanced solid tumors

A California Cancer Consortium trial

Robert J. Morgan, Timothy W. Synold, Jeffrey A. Longmate, David I. Quinn, David R Gandara, Heinz Josef Lenz, Christopher Ruel, Bixin Xi, Michael D. Lewis, A. Dimitrios Colevas, James Doroshow, Edward M. Newman

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background: The California Cancer Consortium completed a phase I trial of E7389 (eribulin mesylate), an analog of the marine natural product halichondrin B. This trial was to determine the pharmacodynamics, pharmacokinetics, and MTD of E7389 administered by bolus injection weekly for 3 weeks out of four. Methods: This trial included a rapid titration design. Real-time pharmacokinetics were utilized to guide dose escalation. Initially, single-patient cohorts were enrolled with intra- and inter-patient dose doubling. The second phase was a standard 3 + 3 dose escalation schedule. At the MTD, a cohort of patients was enrolled for target validation studies (separate manuscript). The starting dose was 0.125 mg/m2, and doses were doubled within and between patients in the first phase. Blood and urine sampling for E7389 pharmacokinetics was performed on doses 1 and 3 of cycle 1. Levels were determined using a LC/MS/MS assay. Results: Forty patients were entered. Thirty-eight were evaluable for toxicity and 35 for response. The rapid escalation ended with a grade 3 elevation of alkaline phosphatase at 0.5 mg/m2/week. The second phase ended at 2.0 mg/m2/week with dose-limiting toxicities of grades 3 and 4 febrile neutropenia. Other toxicities included hypoglycemia, hypophosphatemia, and fatigue. The MTD was 1.4 mg/m2/week. Responses included four partial responses (lung cancer [2], urothelial [1], and melanoma [1]). Conclusions: E7389 was well tolerated in this trial with the major toxicity being myelosuppression. PD shows that E7389 induces significant morphologic changes (bundle formation) in the microtubules of peripheral blood mononuclear cells and tumor cells in vivo. The data suggest that lower intra-tumoral levels of β-tubulin III or higher intra-tumoral levels of MAP4 may correlate with response to E7389, while lower intra-tumoral levels of stathmin may be associated with progression. PK data reveal that E7389 exhibits a tri-exponential elimination from the plasma of patients receiving a rapid i.v. infusion. At sub-toxic doses, plasma concentrations of E7389 are maintained well above the levels required for activity in vitro for >72 h.

Original languageEnglish (US)
Pages (from-to)897-907
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume76
Issue number5
DOIs
StatePublished - Sep 11 2015

Fingerprint

eribulin
Pharmacodynamics
Pharmacokinetics
Toxicity
Tumors
Neoplasms
Blood
Stathmin
Plasmas
Poisons
Tubulin
Biological Products
Titration
Alkaline Phosphatase
Assays
Hypophosphatemia
Cells
Febrile Neutropenia
Fatigue of materials
Sampling

Keywords

  • Eribulin
  • Halichondrin B analog
  • Pharmacodynamics
  • Pharmacokinetics
  • Phase I trial

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Pharmacodynamics (PD) and pharmacokinetics (PK) of E7389 (eribulin, halichondrin B analog) during a phase i trial in patients with advanced solid tumors : A California Cancer Consortium trial. / Morgan, Robert J.; Synold, Timothy W.; Longmate, Jeffrey A.; Quinn, David I.; Gandara, David R; Lenz, Heinz Josef; Ruel, Christopher; Xi, Bixin; Lewis, Michael D.; Colevas, A. Dimitrios; Doroshow, James; Newman, Edward M.

In: Cancer Chemotherapy and Pharmacology, Vol. 76, No. 5, 11.09.2015, p. 897-907.

Research output: Contribution to journalArticle

Morgan, Robert J. ; Synold, Timothy W. ; Longmate, Jeffrey A. ; Quinn, David I. ; Gandara, David R ; Lenz, Heinz Josef ; Ruel, Christopher ; Xi, Bixin ; Lewis, Michael D. ; Colevas, A. Dimitrios ; Doroshow, James ; Newman, Edward M. / Pharmacodynamics (PD) and pharmacokinetics (PK) of E7389 (eribulin, halichondrin B analog) during a phase i trial in patients with advanced solid tumors : A California Cancer Consortium trial. In: Cancer Chemotherapy and Pharmacology. 2015 ; Vol. 76, No. 5. pp. 897-907.
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abstract = "Background: The California Cancer Consortium completed a phase I trial of E7389 (eribulin mesylate), an analog of the marine natural product halichondrin B. This trial was to determine the pharmacodynamics, pharmacokinetics, and MTD of E7389 administered by bolus injection weekly for 3 weeks out of four. Methods: This trial included a rapid titration design. Real-time pharmacokinetics were utilized to guide dose escalation. Initially, single-patient cohorts were enrolled with intra- and inter-patient dose doubling. The second phase was a standard 3 + 3 dose escalation schedule. At the MTD, a cohort of patients was enrolled for target validation studies (separate manuscript). The starting dose was 0.125 mg/m2, and doses were doubled within and between patients in the first phase. Blood and urine sampling for E7389 pharmacokinetics was performed on doses 1 and 3 of cycle 1. Levels were determined using a LC/MS/MS assay. Results: Forty patients were entered. Thirty-eight were evaluable for toxicity and 35 for response. The rapid escalation ended with a grade 3 elevation of alkaline phosphatase at 0.5 mg/m2/week. The second phase ended at 2.0 mg/m2/week with dose-limiting toxicities of grades 3 and 4 febrile neutropenia. Other toxicities included hypoglycemia, hypophosphatemia, and fatigue. The MTD was 1.4 mg/m2/week. Responses included four partial responses (lung cancer [2], urothelial [1], and melanoma [1]). Conclusions: E7389 was well tolerated in this trial with the major toxicity being myelosuppression. PD shows that E7389 induces significant morphologic changes (bundle formation) in the microtubules of peripheral blood mononuclear cells and tumor cells in vivo. The data suggest that lower intra-tumoral levels of β-tubulin III or higher intra-tumoral levels of MAP4 may correlate with response to E7389, while lower intra-tumoral levels of stathmin may be associated with progression. PK data reveal that E7389 exhibits a tri-exponential elimination from the plasma of patients receiving a rapid i.v. infusion. At sub-toxic doses, plasma concentrations of E7389 are maintained well above the levels required for activity in vitro for >72 h.",
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T1 - Pharmacodynamics (PD) and pharmacokinetics (PK) of E7389 (eribulin, halichondrin B analog) during a phase i trial in patients with advanced solid tumors

T2 - A California Cancer Consortium trial

AU - Morgan, Robert J.

AU - Synold, Timothy W.

AU - Longmate, Jeffrey A.

AU - Quinn, David I.

AU - Gandara, David R

AU - Lenz, Heinz Josef

AU - Ruel, Christopher

AU - Xi, Bixin

AU - Lewis, Michael D.

AU - Colevas, A. Dimitrios

AU - Doroshow, James

AU - Newman, Edward M.

PY - 2015/9/11

Y1 - 2015/9/11

N2 - Background: The California Cancer Consortium completed a phase I trial of E7389 (eribulin mesylate), an analog of the marine natural product halichondrin B. This trial was to determine the pharmacodynamics, pharmacokinetics, and MTD of E7389 administered by bolus injection weekly for 3 weeks out of four. Methods: This trial included a rapid titration design. Real-time pharmacokinetics were utilized to guide dose escalation. Initially, single-patient cohorts were enrolled with intra- and inter-patient dose doubling. The second phase was a standard 3 + 3 dose escalation schedule. At the MTD, a cohort of patients was enrolled for target validation studies (separate manuscript). The starting dose was 0.125 mg/m2, and doses were doubled within and between patients in the first phase. Blood and urine sampling for E7389 pharmacokinetics was performed on doses 1 and 3 of cycle 1. Levels were determined using a LC/MS/MS assay. Results: Forty patients were entered. Thirty-eight were evaluable for toxicity and 35 for response. The rapid escalation ended with a grade 3 elevation of alkaline phosphatase at 0.5 mg/m2/week. The second phase ended at 2.0 mg/m2/week with dose-limiting toxicities of grades 3 and 4 febrile neutropenia. Other toxicities included hypoglycemia, hypophosphatemia, and fatigue. The MTD was 1.4 mg/m2/week. Responses included four partial responses (lung cancer [2], urothelial [1], and melanoma [1]). Conclusions: E7389 was well tolerated in this trial with the major toxicity being myelosuppression. PD shows that E7389 induces significant morphologic changes (bundle formation) in the microtubules of peripheral blood mononuclear cells and tumor cells in vivo. The data suggest that lower intra-tumoral levels of β-tubulin III or higher intra-tumoral levels of MAP4 may correlate with response to E7389, while lower intra-tumoral levels of stathmin may be associated with progression. PK data reveal that E7389 exhibits a tri-exponential elimination from the plasma of patients receiving a rapid i.v. infusion. At sub-toxic doses, plasma concentrations of E7389 are maintained well above the levels required for activity in vitro for >72 h.

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