A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: An Italian sarcoma group study

G. Grignani, E. Palmerini, P. Dileo, S. D. Asaftei, L. D'ambrosio, Y. Pignochino, M. Mercuri, P. Picci, F. Fagioli, P. G. Casali, S. Ferrari, M. Aglietta

Research output: Contribution to journalArticle

Abstract

Purpose: After standard multimodal therapy, the prognosis of relapsed and unresectable high-grade osteosarcoma is dismal and unchanged over the last decades. Recently, mitogen-activated protein kinases were shown to be activated in osteosarcoma specimens, suggesting, therefore, they are suitable targets for the multikinase inhibitor sorafenib. Thus, we explored sorafenib activity in patients with relapsed and unresectable osteosarcoma. Experimental design: Patients >14 years, progressing after standard treatment, were eligible to receive 400 mg of sorafenib twice daily until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months. Secondary objectives were PFS, overall survival (OS), clinical benefit rate (CBR), defined as no progression at 6 months and safety. This nonrandomized phase II study used a Simon two-stage design. PFS and OS at 95% confidence intervals (95% CIs) were calculated by the Kaplan-Meier method. All tests were two sided. Results: Thirty-five patients were enrolled. PFS at 4 months was 46% (95% CI 28% to 63%). Median PFS and OS were 4 (95% CI 2-5) and 7 (95% CI 7-8) months, respectively. The CBR was 29% (95% CI 13% to 44%). We observed 3 (8%) partial responses (PRs), 2 (6%) minor responses (18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography responses were observed among SD patients. Sorafenib was reduced or briefly interrupted in 16 (46%) patients and permanently discontinued in one (3%) case due to toxicity. Conclusions: Sorafenib demonstrated activity as a second- or third-line treatment in terms of PFS at 4 months with some unprecedented long-lasting responses. Sorafenib, the first targeted therapy showing activity in osteosarcoma patients, deserves further investigations.

Original languageEnglish
Pages (from-to)508-516
Number of pages9
JournalAnnals of Oncology
Volume23
Issue number2
DOIs
Publication statusPublished - Feb 2012

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Osteosarcoma
Sarcoma
Disease-Free Survival
Confidence Intervals
Survival
Therapeutics
Fluorodeoxyglucose F18
Mitogen-Activated Protein Kinases
Positron-Emission Tomography
sorafenib
Research Design
Safety

Keywords

  • Bone neoplasms
  • MAPK
  • Osteosarcoma
  • Relapse
  • Sorafenib
  • Target therapy

ASJC Scopus subject areas

  • Oncology
  • Hematology

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A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy : An Italian sarcoma group study. / Grignani, G.; Palmerini, E.; Dileo, P.; Asaftei, S. D.; D'ambrosio, L.; Pignochino, Y.; Mercuri, M.; Picci, P.; Fagioli, F.; Casali, P. G.; Ferrari, S.; Aglietta, M.

In: Annals of Oncology, Vol. 23, No. 2, 02.2012, p. 508-516.

Research output: Contribution to journalArticle

Grignani, G. ; Palmerini, E. ; Dileo, P. ; Asaftei, S. D. ; D'ambrosio, L. ; Pignochino, Y. ; Mercuri, M. ; Picci, P. ; Fagioli, F. ; Casali, P. G. ; Ferrari, S. ; Aglietta, M. / A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy : An Italian sarcoma group study. In: Annals of Oncology. 2012 ; Vol. 23, No. 2. pp. 508-516.
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abstract = "Purpose: After standard multimodal therapy, the prognosis of relapsed and unresectable high-grade osteosarcoma is dismal and unchanged over the last decades. Recently, mitogen-activated protein kinases were shown to be activated in osteosarcoma specimens, suggesting, therefore, they are suitable targets for the multikinase inhibitor sorafenib. Thus, we explored sorafenib activity in patients with relapsed and unresectable osteosarcoma. Experimental design: Patients >14 years, progressing after standard treatment, were eligible to receive 400 mg of sorafenib twice daily until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months. Secondary objectives were PFS, overall survival (OS), clinical benefit rate (CBR), defined as no progression at 6 months and safety. This nonrandomized phase II study used a Simon two-stage design. PFS and OS at 95{\%} confidence intervals (95{\%} CIs) were calculated by the Kaplan-Meier method. All tests were two sided. Results: Thirty-five patients were enrolled. PFS at 4 months was 46{\%} (95{\%} CI 28{\%} to 63{\%}). Median PFS and OS were 4 (95{\%} CI 2-5) and 7 (95{\%} CI 7-8) months, respectively. The CBR was 29{\%} (95{\%} CI 13{\%} to 44{\%}). We observed 3 (8{\%}) partial responses (PRs), 2 (6{\%}) minor responses (18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography responses were observed among SD patients. Sorafenib was reduced or briefly interrupted in 16 (46{\%}) patients and permanently discontinued in one (3{\%}) case due to toxicity. Conclusions: Sorafenib demonstrated activity as a second- or third-line treatment in terms of PFS at 4 months with some unprecedented long-lasting responses. Sorafenib, the first targeted therapy showing activity in osteosarcoma patients, deserves further investigations.",
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T1 - A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy

T2 - An Italian sarcoma group study

AU - Grignani, G.

AU - Palmerini, E.

AU - Dileo, P.

AU - Asaftei, S. D.

AU - D'ambrosio, L.

AU - Pignochino, Y.

AU - Mercuri, M.

AU - Picci, P.

AU - Fagioli, F.

AU - Casali, P. G.

AU - Ferrari, S.

AU - Aglietta, M.

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N2 - Purpose: After standard multimodal therapy, the prognosis of relapsed and unresectable high-grade osteosarcoma is dismal and unchanged over the last decades. Recently, mitogen-activated protein kinases were shown to be activated in osteosarcoma specimens, suggesting, therefore, they are suitable targets for the multikinase inhibitor sorafenib. Thus, we explored sorafenib activity in patients with relapsed and unresectable osteosarcoma. Experimental design: Patients >14 years, progressing after standard treatment, were eligible to receive 400 mg of sorafenib twice daily until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months. Secondary objectives were PFS, overall survival (OS), clinical benefit rate (CBR), defined as no progression at 6 months and safety. This nonrandomized phase II study used a Simon two-stage design. PFS and OS at 95% confidence intervals (95% CIs) were calculated by the Kaplan-Meier method. All tests were two sided. Results: Thirty-five patients were enrolled. PFS at 4 months was 46% (95% CI 28% to 63%). Median PFS and OS were 4 (95% CI 2-5) and 7 (95% CI 7-8) months, respectively. The CBR was 29% (95% CI 13% to 44%). We observed 3 (8%) partial responses (PRs), 2 (6%) minor responses (18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography responses were observed among SD patients. Sorafenib was reduced or briefly interrupted in 16 (46%) patients and permanently discontinued in one (3%) case due to toxicity. Conclusions: Sorafenib demonstrated activity as a second- or third-line treatment in terms of PFS at 4 months with some unprecedented long-lasting responses. Sorafenib, the first targeted therapy showing activity in osteosarcoma patients, deserves further investigations.

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KW - Sorafenib

KW - Target therapy

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