Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma

A multicentre, open-label, phase 2 trial

Gary K. Schwartz, William D. Tap, Li Xuan Qin, Michael B. Livingston, Samir D. Undevia, Bartosz Chmielowski, Mark Agulnik, Scott M. Schuetze, Damon R. Reed, Scott Heitaka Okuno, Joseph A. Ludwig, Vicki Keedy, Petra Rietschel, Andrew S. Kraft, Douglas Adkins, Brian A. Van Tine, Bruce Brockstein, Vincent Yim, Christiana Bitas, Abdul Abdullah & 8 others Cristina R. Antonescu, Mercedes Condy, Mark A. Dickson, Shyamprasad Deraje Vasudeva, Alan L. Ho, L. Austin Doyle, Helen X. Chen, Robert G. Maki

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

Background: Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry. Methods: We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015. Findings: Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21-43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24-47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28-51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3-4. The most common grade 3-4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%). Interpretation: The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination. Funding: National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center.

Original languageEnglish (US)
Pages (from-to)371-382
Number of pages12
JournalThe Lancet Oncology
Volume14
Issue number4
DOIs
StatePublished - Apr 2013

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Somatomedin Receptors
Sarcoma
Bone and Bones
Immunohistochemistry
temsirolimus
anti-IGF-1R antibody A12
Stomatitis
Lymphopenia
Intention to Treat Analysis
National Cancer Institute (U.S.)
Therapeutics

ASJC Scopus subject areas

  • Oncology

Cite this

Schwartz, G. K., Tap, W. D., Qin, L. X., Livingston, M. B., Undevia, S. D., Chmielowski, B., ... Maki, R. G. (2013). Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: A multicentre, open-label, phase 2 trial. The Lancet Oncology, 14(4), 371-382. https://doi.org/10.1016/S1470-2045(13)70049-4

Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma : A multicentre, open-label, phase 2 trial. / Schwartz, Gary K.; Tap, William D.; Qin, Li Xuan; Livingston, Michael B.; Undevia, Samir D.; Chmielowski, Bartosz; Agulnik, Mark; Schuetze, Scott M.; Reed, Damon R.; Okuno, Scott Heitaka; Ludwig, Joseph A.; Keedy, Vicki; Rietschel, Petra; Kraft, Andrew S.; Adkins, Douglas; Van Tine, Brian A.; Brockstein, Bruce; Yim, Vincent; Bitas, Christiana; Abdullah, Abdul; Antonescu, Cristina R.; Condy, Mercedes; Dickson, Mark A.; Vasudeva, Shyamprasad Deraje; Ho, Alan L.; Doyle, L. Austin; Chen, Helen X.; Maki, Robert G.

In: The Lancet Oncology, Vol. 14, No. 4, 04.2013, p. 371-382.

Research output: Contribution to journalArticle

Schwartz, GK, Tap, WD, Qin, LX, Livingston, MB, Undevia, SD, Chmielowski, B, Agulnik, M, Schuetze, SM, Reed, DR, Okuno, SH, Ludwig, JA, Keedy, V, Rietschel, P, Kraft, AS, Adkins, D, Van Tine, BA, Brockstein, B, Yim, V, Bitas, C, Abdullah, A, Antonescu, CR, Condy, M, Dickson, MA, Vasudeva, SD, Ho, AL, Doyle, LA, Chen, HX & Maki, RG 2013, 'Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: A multicentre, open-label, phase 2 trial', The Lancet Oncology, vol. 14, no. 4, pp. 371-382. https://doi.org/10.1016/S1470-2045(13)70049-4
Schwartz, Gary K. ; Tap, William D. ; Qin, Li Xuan ; Livingston, Michael B. ; Undevia, Samir D. ; Chmielowski, Bartosz ; Agulnik, Mark ; Schuetze, Scott M. ; Reed, Damon R. ; Okuno, Scott Heitaka ; Ludwig, Joseph A. ; Keedy, Vicki ; Rietschel, Petra ; Kraft, Andrew S. ; Adkins, Douglas ; Van Tine, Brian A. ; Brockstein, Bruce ; Yim, Vincent ; Bitas, Christiana ; Abdullah, Abdul ; Antonescu, Cristina R. ; Condy, Mercedes ; Dickson, Mark A. ; Vasudeva, Shyamprasad Deraje ; Ho, Alan L. ; Doyle, L. Austin ; Chen, Helen X. ; Maki, Robert G. / Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma : A multicentre, open-label, phase 2 trial. In: The Lancet Oncology. 2013 ; Vol. 14, No. 4. pp. 371-382.
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title = "Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: A multicentre, open-label, phase 2 trial",
abstract = "Background: Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry. Methods: We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015. Findings: Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31{\%}; one-sided 95{\%} CI lower bound 21{\%}; two-sided 90{\%} CI 21-43), 19 of 54 in IGF-1R-positive bone sarcoma group (35{\%}; one-sided 95{\%} CI lower bound 24{\%}; two-sided 90{\%} CI 24-47), and 21 of 54 in the IGF-1R-negative group (39{\%}, one-sided 95{\%} CI lower bound 28{\%}; two-sided 90{\%} CI 28-51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8{\%}) of which were grade 3-4. The most common grade 3-4 toxicities in the 174 treated patients were anaemia in 16 (9{\%}) patients, hyperglycaemia in 18 (10{\%}), hypophosphataemia in 16 (9{\%}), lymphopenia in 25 (14{\%}), oral mucositis in 19 (11{\%}), and thrombocytopenia in 19 (11{\%}). Interpretation: The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination. Funding: National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center.",
author = "Schwartz, {Gary K.} and Tap, {William D.} and Qin, {Li Xuan} and Livingston, {Michael B.} and Undevia, {Samir D.} and Bartosz Chmielowski and Mark Agulnik and Schuetze, {Scott M.} and Reed, {Damon R.} and Okuno, {Scott Heitaka} and Ludwig, {Joseph A.} and Vicki Keedy and Petra Rietschel and Kraft, {Andrew S.} and Douglas Adkins and {Van Tine}, {Brian A.} and Bruce Brockstein and Vincent Yim and Christiana Bitas and Abdul Abdullah and Antonescu, {Cristina R.} and Mercedes Condy and Dickson, {Mark A.} and Vasudeva, {Shyamprasad Deraje} and Ho, {Alan L.} and Doyle, {L. Austin} and Chen, {Helen X.} and Maki, {Robert G.}",
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TY - JOUR

T1 - Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma

T2 - A multicentre, open-label, phase 2 trial

AU - Schwartz, Gary K.

AU - Tap, William D.

AU - Qin, Li Xuan

AU - Livingston, Michael B.

AU - Undevia, Samir D.

AU - Chmielowski, Bartosz

AU - Agulnik, Mark

AU - Schuetze, Scott M.

AU - Reed, Damon R.

AU - Okuno, Scott Heitaka

AU - Ludwig, Joseph A.

AU - Keedy, Vicki

AU - Rietschel, Petra

AU - Kraft, Andrew S.

AU - Adkins, Douglas

AU - Van Tine, Brian A.

AU - Brockstein, Bruce

AU - Yim, Vincent

AU - Bitas, Christiana

AU - Abdullah, Abdul

AU - Antonescu, Cristina R.

AU - Condy, Mercedes

AU - Dickson, Mark A.

AU - Vasudeva, Shyamprasad Deraje

AU - Ho, Alan L.

AU - Doyle, L. Austin

AU - Chen, Helen X.

AU - Maki, Robert G.

PY - 2013/4

Y1 - 2013/4

N2 - Background: Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry. Methods: We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015. Findings: Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21-43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24-47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28-51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3-4. The most common grade 3-4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%). Interpretation: The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination. Funding: National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center.

AB - Background: Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry. Methods: We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015. Findings: Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21-43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24-47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28-51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3-4. The most common grade 3-4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%). Interpretation: The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination. Funding: National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center.

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