Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors

M. A. Dickson, Scott Heitaka Okuno, M. L. Keohan, R. G. Maki, D. R. D'Adamo, T. J. Akhurst, C. R. Antonescu, G. K. Schwartz

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Abstract

Background: HSP90 inhibition leads to proteosomal degradation of activated KIT and has in vitro activity against gastrointestinal stromal tumors (GIST). BIIB021 is an oral non-ansamycin HSP90 inhibitor. We carried out a phase II study of BIIB021 in patients with GIST refractory to imatinib and sunitinib. Patients and methods: The primary end-point was metabolic partial response (mPR) as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET). The secondary end-points were pharmacokinetic assessments of BIIB021 and pharmacodynamic assessments of HSP70. Twenty-three patients were treated on two schedules: 12 pts received 600 mg twice a week (BIW) and 11 patients received 400 mg three times a week (TIW). All had prior imatinib and sunitinib but stopped >14 days before starting BIIB021. Results: The median age was 59 years (33-88 years), 61% male, 44% Eastern Cooperative Oncology Group 1 (ECOG1). The best response was PR by FDG-PET for five patients (3/12 at 600 mg BIW and 2/9 at 400 TIW) for an overall response rate of 22%. The response durationwas 25-138 days. Adverse events (AEs) were mild to moderate. The mean Cmax was 1.5 μmol and the mean AUC was 2.9 μmol h.Cmax >1.5 μmol was associated with a decrease in standardized uptake value (SUVmax). HSP70 increased substantially following treatment. Conclusions: This study met its primary end-point. BIIB021 leads to objective responses in refractory GIST patients. Pharmacodynamic studies confirmed HSP90 inhibition. Further evaluation of BIIB021 in GIST is warranted.

Original languageEnglish (US)
Article numbermds275
Pages (from-to)252-257
Number of pages6
JournalAnnals of Oncology
Volume24
Issue number1
DOIs
StatePublished - Jan 2013

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Gastrointestinal Stromal Tumors
Positron-Emission Tomography
Area Under Curve
6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-ylamine
Appointments and Schedules
Pharmacokinetics

Keywords

  • Gastro-intestinal stromal tumors
  • HSP90 inhibitors
  • Pharmacodynamics
  • Pharmacokinetics
  • Phase II trials
  • Sarcoma/soft-tissue malignancies

ASJC Scopus subject areas

  • Oncology
  • Hematology

Cite this

Dickson, M. A., Okuno, S. H., Keohan, M. L., Maki, R. G., D'Adamo, D. R., Akhurst, T. J., ... Schwartz, G. K. (2013). Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors. Annals of Oncology, 24(1), 252-257. [mds275]. https://doi.org/10.1093/annonc/mds275

Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors. / Dickson, M. A.; Okuno, Scott Heitaka; Keohan, M. L.; Maki, R. G.; D'Adamo, D. R.; Akhurst, T. J.; Antonescu, C. R.; Schwartz, G. K.

In: Annals of Oncology, Vol. 24, No. 1, mds275, 01.2013, p. 252-257.

Research output: Contribution to journalArticle

Dickson, MA, Okuno, SH, Keohan, ML, Maki, RG, D'Adamo, DR, Akhurst, TJ, Antonescu, CR & Schwartz, GK 2013, 'Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors', Annals of Oncology, vol. 24, no. 1, mds275, pp. 252-257. https://doi.org/10.1093/annonc/mds275
Dickson MA, Okuno SH, Keohan ML, Maki RG, D'Adamo DR, Akhurst TJ et al. Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors. Annals of Oncology. 2013 Jan;24(1):252-257. mds275. https://doi.org/10.1093/annonc/mds275
Dickson, M. A. ; Okuno, Scott Heitaka ; Keohan, M. L. ; Maki, R. G. ; D'Adamo, D. R. ; Akhurst, T. J. ; Antonescu, C. R. ; Schwartz, G. K. / Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors. In: Annals of Oncology. 2013 ; Vol. 24, No. 1. pp. 252-257.
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abstract = "Background: HSP90 inhibition leads to proteosomal degradation of activated KIT and has in vitro activity against gastrointestinal stromal tumors (GIST). BIIB021 is an oral non-ansamycin HSP90 inhibitor. We carried out a phase II study of BIIB021 in patients with GIST refractory to imatinib and sunitinib. Patients and methods: The primary end-point was metabolic partial response (mPR) as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET). The secondary end-points were pharmacokinetic assessments of BIIB021 and pharmacodynamic assessments of HSP70. Twenty-three patients were treated on two schedules: 12 pts received 600 mg twice a week (BIW) and 11 patients received 400 mg three times a week (TIW). All had prior imatinib and sunitinib but stopped >14 days before starting BIIB021. Results: The median age was 59 years (33-88 years), 61{\%} male, 44{\%} Eastern Cooperative Oncology Group 1 (ECOG1). The best response was PR by FDG-PET for five patients (3/12 at 600 mg BIW and 2/9 at 400 TIW) for an overall response rate of 22{\%}. The response durationwas 25-138 days. Adverse events (AEs) were mild to moderate. The mean Cmax was 1.5 μmol and the mean AUC was 2.9 μmol h.Cmax >1.5 μmol was associated with a decrease in standardized uptake value (SUVmax). HSP70 increased substantially following treatment. Conclusions: This study met its primary end-point. BIIB021 leads to objective responses in refractory GIST patients. Pharmacodynamic studies confirmed HSP90 inhibition. Further evaluation of BIIB021 in GIST is warranted.",
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AU - Okuno, Scott Heitaka

AU - Keohan, M. L.

AU - Maki, R. G.

AU - D'Adamo, D. R.

AU - Akhurst, T. J.

AU - Antonescu, C. R.

AU - Schwartz, G. K.

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AB - Background: HSP90 inhibition leads to proteosomal degradation of activated KIT and has in vitro activity against gastrointestinal stromal tumors (GIST). BIIB021 is an oral non-ansamycin HSP90 inhibitor. We carried out a phase II study of BIIB021 in patients with GIST refractory to imatinib and sunitinib. Patients and methods: The primary end-point was metabolic partial response (mPR) as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET). The secondary end-points were pharmacokinetic assessments of BIIB021 and pharmacodynamic assessments of HSP70. Twenty-three patients were treated on two schedules: 12 pts received 600 mg twice a week (BIW) and 11 patients received 400 mg three times a week (TIW). All had prior imatinib and sunitinib but stopped >14 days before starting BIIB021. Results: The median age was 59 years (33-88 years), 61% male, 44% Eastern Cooperative Oncology Group 1 (ECOG1). The best response was PR by FDG-PET for five patients (3/12 at 600 mg BIW and 2/9 at 400 TIW) for an overall response rate of 22%. The response durationwas 25-138 days. Adverse events (AEs) were mild to moderate. The mean Cmax was 1.5 μmol and the mean AUC was 2.9 μmol h.Cmax >1.5 μmol was associated with a decrease in standardized uptake value (SUVmax). HSP70 increased substantially following treatment. Conclusions: This study met its primary end-point. BIIB021 leads to objective responses in refractory GIST patients. Pharmacodynamic studies confirmed HSP90 inhibition. Further evaluation of BIIB021 in GIST is warranted.

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