A phase 1 study of the Janus kinase 2 (JAK2)V617F inhibitor, gandotinib (LY2784544), in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemia

Srdan Verstovsek, Ruben Mesa, Mohamed E. Salama, Li Li, Celine Pitou, Fabio P. Nunes, Gregory L. Price, Jennifer L. Giles, Deborah N. D'Souza, Richard A. Walgren, Josef T. Prchal

Research output: Contribution to journalArticle

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Abstract

Mutations in Janus kinase 2 (JAK2) are implicated in the pathogenesis of Philadelphia-chromosome negative myeloproliferative neoplasms, including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Gandotinib (LY2784544), a potent inhibitor of JAK2 activity, shows increased potency for the JAK2V617F mutation. The study had a standard 3 + 3 dose-escalation design to define the maximum-tolerated dose. Primary objectives were to determine safety, tolerability, and recommended oral daily dose of gandotinib for patients with JAK2V617F-positive myelofibrosis, essential thrombocythemia, or polycythemia vera. Secondary objectives included estimating pharmacokinetic parameters and documenting evidence of efficacy by measuring clinical improvement. Thirty-eight patients were enrolled and treated (31 myelofibrosis, 6 polycythemia vera, 1 essential thrombocythemia). The maximum-tolerated dose of gandotinib was 120 mg daily, based on dose-limiting toxicities of blood creatinine increase or hyperuricemia at higher doses. Maximum plasma concentration was reached 4 h after single and multiple doses, and mean half-life on day 1 was approximately 6 h. Most common treatment-emergent adverse events were diarrhea (55.3%) and nausea (42.1%), a majority of which were of grade 1 severity. Best response of clinical improvement was achieved by 29% of myelofibrosis patients. A ≥50% palpable spleen length reduction was observed at any time during therapy in 20/32 evaluable patients. Additionally, ≥50% reduction in the Total Symptom Myeloproliferative Neoplasm Symptom Assessment Form Score was seen in 11/21 (52%) and 6/14 patients (43%) receiving ≥120 mg at 12 and 24 weeks respectively. Gandotinib demonstrated an acceptable safety and tolerability profile, and findings at the maximum-tolerated dose of 120 mg supported further clinical testing. Clinicaltrials.gov identifier: NCT01134120.

Original languageEnglish (US)
Pages (from-to)89-95
Number of pages7
JournalLeukemia Research
Volume61
DOIs
StatePublished - Oct 1 2017

Fingerprint

LY2784544
Janus Kinase 2
Essential Thrombocythemia
Polycythemia Vera
Primary Myelofibrosis
Maximum Tolerated Dose
Safety
Philadelphia Chromosome
Hyperuricemia
Mutation
Symptom Assessment
Nausea
Half-Life
Diarrhea
Creatinine
Neoplasms
Spleen
Pharmacokinetics

Keywords

  • Dosage
  • Gandotinib
  • JAK-2
  • Myeloproliferative
  • Neoplasm

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

A phase 1 study of the Janus kinase 2 (JAK2)V617F inhibitor, gandotinib (LY2784544), in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemia. / Verstovsek, Srdan; Mesa, Ruben; Salama, Mohamed E.; Li, Li; Pitou, Celine; Nunes, Fabio P.; Price, Gregory L.; Giles, Jennifer L.; D'Souza, Deborah N.; Walgren, Richard A.; Prchal, Josef T.

In: Leukemia Research, Vol. 61, 01.10.2017, p. 89-95.

Research output: Contribution to journalArticle

Verstovsek, Srdan ; Mesa, Ruben ; Salama, Mohamed E. ; Li, Li ; Pitou, Celine ; Nunes, Fabio P. ; Price, Gregory L. ; Giles, Jennifer L. ; D'Souza, Deborah N. ; Walgren, Richard A. ; Prchal, Josef T. / A phase 1 study of the Janus kinase 2 (JAK2)V617F inhibitor, gandotinib (LY2784544), in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemia. In: Leukemia Research. 2017 ; Vol. 61. pp. 89-95.
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abstract = "Mutations in Janus kinase 2 (JAK2) are implicated in the pathogenesis of Philadelphia-chromosome negative myeloproliferative neoplasms, including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Gandotinib (LY2784544), a potent inhibitor of JAK2 activity, shows increased potency for the JAK2V617F mutation. The study had a standard 3 + 3 dose-escalation design to define the maximum-tolerated dose. Primary objectives were to determine safety, tolerability, and recommended oral daily dose of gandotinib for patients with JAK2V617F-positive myelofibrosis, essential thrombocythemia, or polycythemia vera. Secondary objectives included estimating pharmacokinetic parameters and documenting evidence of efficacy by measuring clinical improvement. Thirty-eight patients were enrolled and treated (31 myelofibrosis, 6 polycythemia vera, 1 essential thrombocythemia). The maximum-tolerated dose of gandotinib was 120 mg daily, based on dose-limiting toxicities of blood creatinine increase or hyperuricemia at higher doses. Maximum plasma concentration was reached 4 h after single and multiple doses, and mean half-life on day 1 was approximately 6 h. Most common treatment-emergent adverse events were diarrhea (55.3{\%}) and nausea (42.1{\%}), a majority of which were of grade 1 severity. Best response of clinical improvement was achieved by 29{\%} of myelofibrosis patients. A ≥50{\%} palpable spleen length reduction was observed at any time during therapy in 20/32 evaluable patients. Additionally, ≥50{\%} reduction in the Total Symptom Myeloproliferative Neoplasm Symptom Assessment Form Score was seen in 11/21 (52{\%}) and 6/14 patients (43{\%}) receiving ≥120 mg at 12 and 24 weeks respectively. Gandotinib demonstrated an acceptable safety and tolerability profile, and findings at the maximum-tolerated dose of 120 mg supported further clinical testing. Clinicaltrials.gov identifier: NCT01134120.",
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