A phase 1 and randomized controlled phase 2 trial of the safety and efficacy of the combination of gemcitabine and docetaxel with ontuxizumab (MORAb-004) in metastatic soft-tissue sarcomas

Robin L. Jones, Sant P. Chawla, Steven Attia, Patrick Schöffski, Hans Gelderblom, Bartosz Chmielowski, Axel Le Cesne, Brian A. Van Tine, Jonathan C. Trent, Shreyaskumar Patel, Andrew J. Wagner, Rashmi Chugh, John W. Heyburn, Susan C. Weil, Wenquan Wang, Kert Viele, Robert G. Maki

Research output: Contribution to journalArticle

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Abstract

Background: Ontuxizumab, a humanized monoclonal antibody, targets endosialin (tumor endothelial marker 1 [TEM-1] or CD248), which is expressed on sarcoma cells and is believed to be involved in tumor angiogenesis. This is the first trial to evaluate ontuxizumab in patients with sarcoma. Methods: Part 1 was an open-label, dose-finding, safety lead-in: 4, 6, or 8 mg/kg with gemcitabine and docetaxel (G/D; 900 mg/m 2 gemcitabine on days 1 and 8 and 75 mg/m 2 docetaxel on day 8). In part 2, patients were randomized in a double-blind fashion in 2:1 ratio to ontuxizumab (8 mg/kg) or a placebo with G/D. Randomization was stratified by 4 histological cohorts. Results: In part 2 with 209 patients, no significant difference in progression-free survival between ontuxizumab plus G/D (4.3 months; 95% confidence interval [CI], 2.7-6.3 months) and the placebo plus G/D (5.6 months; 95% CI, 2.6-8.3 months) was observed (P =.67; hazard ratio [HR], 1.07; 95% CI, 0.77-1.49). Similarly, there was no significant difference in median overall survival between the 2 groups: 18.3 months for the ontuxizumab plus G/D group (95% CI, 16.2-21.1 months) and 21.1 months for the placebo plus G/D group (95% CI, 14.2 months to not reached; P =.32; HR, 1.23; 95% CI, 0.82-1.82). No significant differences between the treatment groups occurred for any efficacy parameter by sarcoma cohort. The combination of ontuxizumab plus G/D was generally well tolerated. Conclusions: Ontuxizumab plus G/D showed no enhanced activity over chemotherapy alone in soft-tissue sarcomas, whereas the safety profile of the combination was consistent with G/D alone.

Original languageEnglish (US)
JournalCancer
DOIs
StatePublished - Jan 1 2019

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docetaxel
gemcitabine
Sarcoma
Confidence Intervals
Safety
Placebos
Antibodies, Monoclonal, Humanized
Tumor Biomarkers
Random Allocation
Disease-Free Survival
MORAb-004

Keywords

  • endosialin
  • MORAb-004
  • ontuxizumab
  • sarcomas
  • tumor endothelial marker 1 (TEM-1)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A phase 1 and randomized controlled phase 2 trial of the safety and efficacy of the combination of gemcitabine and docetaxel with ontuxizumab (MORAb-004) in metastatic soft-tissue sarcomas. / Jones, Robin L.; Chawla, Sant P.; Attia, Steven; Schöffski, Patrick; Gelderblom, Hans; Chmielowski, Bartosz; Le Cesne, Axel; Van Tine, Brian A.; Trent, Jonathan C.; Patel, Shreyaskumar; Wagner, Andrew J.; Chugh, Rashmi; Heyburn, John W.; Weil, Susan C.; Wang, Wenquan; Viele, Kert; Maki, Robert G.

In: Cancer, 01.01.2019.

Research output: Contribution to journalArticle

Jones, RL, Chawla, SP, Attia, S, Schöffski, P, Gelderblom, H, Chmielowski, B, Le Cesne, A, Van Tine, BA, Trent, JC, Patel, S, Wagner, AJ, Chugh, R, Heyburn, JW, Weil, SC, Wang, W, Viele, K & Maki, RG 2019, 'A phase 1 and randomized controlled phase 2 trial of the safety and efficacy of the combination of gemcitabine and docetaxel with ontuxizumab (MORAb-004) in metastatic soft-tissue sarcomas', Cancer. https://doi.org/10.1002/cncr.32084
Jones, Robin L. ; Chawla, Sant P. ; Attia, Steven ; Schöffski, Patrick ; Gelderblom, Hans ; Chmielowski, Bartosz ; Le Cesne, Axel ; Van Tine, Brian A. ; Trent, Jonathan C. ; Patel, Shreyaskumar ; Wagner, Andrew J. ; Chugh, Rashmi ; Heyburn, John W. ; Weil, Susan C. ; Wang, Wenquan ; Viele, Kert ; Maki, Robert G. / A phase 1 and randomized controlled phase 2 trial of the safety and efficacy of the combination of gemcitabine and docetaxel with ontuxizumab (MORAb-004) in metastatic soft-tissue sarcomas. In: Cancer. 2019.
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title = "A phase 1 and randomized controlled phase 2 trial of the safety and efficacy of the combination of gemcitabine and docetaxel with ontuxizumab (MORAb-004) in metastatic soft-tissue sarcomas",
abstract = "Background: Ontuxizumab, a humanized monoclonal antibody, targets endosialin (tumor endothelial marker 1 [TEM-1] or CD248), which is expressed on sarcoma cells and is believed to be involved in tumor angiogenesis. This is the first trial to evaluate ontuxizumab in patients with sarcoma. Methods: Part 1 was an open-label, dose-finding, safety lead-in: 4, 6, or 8 mg/kg with gemcitabine and docetaxel (G/D; 900 mg/m 2 gemcitabine on days 1 and 8 and 75 mg/m 2 docetaxel on day 8). In part 2, patients were randomized in a double-blind fashion in 2:1 ratio to ontuxizumab (8 mg/kg) or a placebo with G/D. Randomization was stratified by 4 histological cohorts. Results: In part 2 with 209 patients, no significant difference in progression-free survival between ontuxizumab plus G/D (4.3 months; 95{\%} confidence interval [CI], 2.7-6.3 months) and the placebo plus G/D (5.6 months; 95{\%} CI, 2.6-8.3 months) was observed (P =.67; hazard ratio [HR], 1.07; 95{\%} CI, 0.77-1.49). Similarly, there was no significant difference in median overall survival between the 2 groups: 18.3 months for the ontuxizumab plus G/D group (95{\%} CI, 16.2-21.1 months) and 21.1 months for the placebo plus G/D group (95{\%} CI, 14.2 months to not reached; P =.32; HR, 1.23; 95{\%} CI, 0.82-1.82). No significant differences between the treatment groups occurred for any efficacy parameter by sarcoma cohort. The combination of ontuxizumab plus G/D was generally well tolerated. Conclusions: Ontuxizumab plus G/D showed no enhanced activity over chemotherapy alone in soft-tissue sarcomas, whereas the safety profile of the combination was consistent with G/D alone.",
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T1 - A phase 1 and randomized controlled phase 2 trial of the safety and efficacy of the combination of gemcitabine and docetaxel with ontuxizumab (MORAb-004) in metastatic soft-tissue sarcomas

AU - Jones, Robin L.

AU - Chawla, Sant P.

AU - Attia, Steven

AU - Schöffski, Patrick

AU - Gelderblom, Hans

AU - Chmielowski, Bartosz

AU - Le Cesne, Axel

AU - Van Tine, Brian A.

AU - Trent, Jonathan C.

AU - Patel, Shreyaskumar

AU - Wagner, Andrew J.

AU - Chugh, Rashmi

AU - Heyburn, John W.

AU - Weil, Susan C.

AU - Wang, Wenquan

AU - Viele, Kert

AU - Maki, Robert G.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Ontuxizumab, a humanized monoclonal antibody, targets endosialin (tumor endothelial marker 1 [TEM-1] or CD248), which is expressed on sarcoma cells and is believed to be involved in tumor angiogenesis. This is the first trial to evaluate ontuxizumab in patients with sarcoma. Methods: Part 1 was an open-label, dose-finding, safety lead-in: 4, 6, or 8 mg/kg with gemcitabine and docetaxel (G/D; 900 mg/m 2 gemcitabine on days 1 and 8 and 75 mg/m 2 docetaxel on day 8). In part 2, patients were randomized in a double-blind fashion in 2:1 ratio to ontuxizumab (8 mg/kg) or a placebo with G/D. Randomization was stratified by 4 histological cohorts. Results: In part 2 with 209 patients, no significant difference in progression-free survival between ontuxizumab plus G/D (4.3 months; 95% confidence interval [CI], 2.7-6.3 months) and the placebo plus G/D (5.6 months; 95% CI, 2.6-8.3 months) was observed (P =.67; hazard ratio [HR], 1.07; 95% CI, 0.77-1.49). Similarly, there was no significant difference in median overall survival between the 2 groups: 18.3 months for the ontuxizumab plus G/D group (95% CI, 16.2-21.1 months) and 21.1 months for the placebo plus G/D group (95% CI, 14.2 months to not reached; P =.32; HR, 1.23; 95% CI, 0.82-1.82). No significant differences between the treatment groups occurred for any efficacy parameter by sarcoma cohort. The combination of ontuxizumab plus G/D was generally well tolerated. Conclusions: Ontuxizumab plus G/D showed no enhanced activity over chemotherapy alone in soft-tissue sarcomas, whereas the safety profile of the combination was consistent with G/D alone.

AB - Background: Ontuxizumab, a humanized monoclonal antibody, targets endosialin (tumor endothelial marker 1 [TEM-1] or CD248), which is expressed on sarcoma cells and is believed to be involved in tumor angiogenesis. This is the first trial to evaluate ontuxizumab in patients with sarcoma. Methods: Part 1 was an open-label, dose-finding, safety lead-in: 4, 6, or 8 mg/kg with gemcitabine and docetaxel (G/D; 900 mg/m 2 gemcitabine on days 1 and 8 and 75 mg/m 2 docetaxel on day 8). In part 2, patients were randomized in a double-blind fashion in 2:1 ratio to ontuxizumab (8 mg/kg) or a placebo with G/D. Randomization was stratified by 4 histological cohorts. Results: In part 2 with 209 patients, no significant difference in progression-free survival between ontuxizumab plus G/D (4.3 months; 95% confidence interval [CI], 2.7-6.3 months) and the placebo plus G/D (5.6 months; 95% CI, 2.6-8.3 months) was observed (P =.67; hazard ratio [HR], 1.07; 95% CI, 0.77-1.49). Similarly, there was no significant difference in median overall survival between the 2 groups: 18.3 months for the ontuxizumab plus G/D group (95% CI, 16.2-21.1 months) and 21.1 months for the placebo plus G/D group (95% CI, 14.2 months to not reached; P =.32; HR, 1.23; 95% CI, 0.82-1.82). No significant differences between the treatment groups occurred for any efficacy parameter by sarcoma cohort. The combination of ontuxizumab plus G/D was generally well tolerated. Conclusions: Ontuxizumab plus G/D showed no enhanced activity over chemotherapy alone in soft-tissue sarcomas, whereas the safety profile of the combination was consistent with G/D alone.

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KW - MORAb-004

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KW - sarcomas

KW - tumor endothelial marker 1 (TEM-1)

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