Notch pathway inhibition with LY3039478 in soft tissue sarcoma and gastrointestinal stromal tumours

Olivier Mir, Analia Azaro, Jaime R Merchan, Rashmi Chugh, Jonathan Trent, Jordi Rodon, Ute Ohnmacht, J. T. Diener, Claire Smith, Eunice Yuen, Gerard Joseph Oakley, Axel Le Cesne, Jean Charles Soria, Karim A. Benhadji, Christophe Massard

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: LY3039478 is an orally bioavailable selective Notch inhibitor. This phase 1a/b trial evaluated the safety, pharmacokinetics and antitumour activity of LY3039478 in patients with soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST). Methods: This multipart, phase 1 trial enrolled patients with refractory advanced/metastatic STS and GIST, measurable disease, Eastern Cooperative Oncology Group ≤1 and baseline tumour tissue. Eligible patients received LY3039478 50mg/75 mg three times per week, for 28-day cycle until disease progression. Safety assessments were based on Common Terminology Criteria for Adverse Events, V4.0. Tumour responses were assessed using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) and Choi criteria. Primary objectives were to confirm the recommended phase 2 dose of LY3039478 and document the antitumour activity. Secondary objectives were safety and toxicity, pharmacokinetics (PK), progression-free survival (PFS) and overall survival (OS). Results: Sixty-nine patients were enrolled and received LY3039478 (27 males, 42 females; median age 58, range 31–78). 16/37 (43%) patients with evaluable samples were positive for Notch 1 immunohistochemistry. Per RECIST 1.1, in leiomyosarcoma (LMS) group (n = 29), ten (36%) had stable disease (SD) and one (4%) had unconfirmed partial response (PR). In GIST group (n = 13), four (31%) had SD. Among other STS subtypes (n = 27), one patient with angiosarcoma had unconfirmed PR, six (21%) had SD. Median PFS was 1.9 months (95% confidence interval:1.6–3.3) for LMS, 1.9 months (0.3–6.1) for GIST and 1.7 months (1.4–2.2) for other STS groups. Median OS was 7.4 months (4.3–non-evaluable [NE]) for LMS, 16.5 months (3.9–16.5) for GIST and 5.6 months (3.4-NE) for other STS groups. Most common adverse events were diarrhoea, nausea, vomiting and decreased appetite. Conclusion: LY3039478 suggested a modest clinical activity in patients with STS and GIST and had a manageable safety profile.

Original languageEnglish (US)
Pages (from-to)88-97
Number of pages10
JournalEuropean Journal of Cancer
Volume103
DOIs
StatePublished - Nov 1 2018

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Gastrointestinal Stromal Tumors
Sarcoma
Leiomyosarcoma
Safety
Disease-Free Survival
Pharmacokinetics
Hemangiosarcoma
Survival
Appetite
Terminology
Nausea
Vomiting
Disease Progression
Diarrhea
Neoplasms
Immunohistochemistry
Confidence Intervals
Response Evaluation Criteria in Solid Tumors

Keywords

  • Angiosarcoma
  • Gastrointestinal stromal tumours
  • Leiomyosarcoma
  • Liposarcoma
  • Notch inhibitor
  • Pleomorphic sarcoma
  • Rhabdomyosarcoma
  • Soft tissue sarcoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Notch pathway inhibition with LY3039478 in soft tissue sarcoma and gastrointestinal stromal tumours. / Mir, Olivier; Azaro, Analia; Merchan, Jaime R; Chugh, Rashmi; Trent, Jonathan; Rodon, Jordi; Ohnmacht, Ute; Diener, J. T.; Smith, Claire; Yuen, Eunice; Oakley, Gerard Joseph; Le Cesne, Axel; Soria, Jean Charles; Benhadji, Karim A.; Massard, Christophe.

In: European Journal of Cancer, Vol. 103, 01.11.2018, p. 88-97.

Research output: Contribution to journalArticle

Mir, O, Azaro, A, Merchan, JR, Chugh, R, Trent, J, Rodon, J, Ohnmacht, U, Diener, JT, Smith, C, Yuen, E, Oakley, GJ, Le Cesne, A, Soria, JC, Benhadji, KA & Massard, C 2018, 'Notch pathway inhibition with LY3039478 in soft tissue sarcoma and gastrointestinal stromal tumours', European Journal of Cancer, vol. 103, pp. 88-97. https://doi.org/10.1016/j.ejca.2018.08.012
Mir, Olivier ; Azaro, Analia ; Merchan, Jaime R ; Chugh, Rashmi ; Trent, Jonathan ; Rodon, Jordi ; Ohnmacht, Ute ; Diener, J. T. ; Smith, Claire ; Yuen, Eunice ; Oakley, Gerard Joseph ; Le Cesne, Axel ; Soria, Jean Charles ; Benhadji, Karim A. ; Massard, Christophe. / Notch pathway inhibition with LY3039478 in soft tissue sarcoma and gastrointestinal stromal tumours. In: European Journal of Cancer. 2018 ; Vol. 103. pp. 88-97.
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abstract = "Background: LY3039478 is an orally bioavailable selective Notch inhibitor. This phase 1a/b trial evaluated the safety, pharmacokinetics and antitumour activity of LY3039478 in patients with soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST). Methods: This multipart, phase 1 trial enrolled patients with refractory advanced/metastatic STS and GIST, measurable disease, Eastern Cooperative Oncology Group ≤1 and baseline tumour tissue. Eligible patients received LY3039478 50mg/75 mg three times per week, for 28-day cycle until disease progression. Safety assessments were based on Common Terminology Criteria for Adverse Events, V4.0. Tumour responses were assessed using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) and Choi criteria. Primary objectives were to confirm the recommended phase 2 dose of LY3039478 and document the antitumour activity. Secondary objectives were safety and toxicity, pharmacokinetics (PK), progression-free survival (PFS) and overall survival (OS). Results: Sixty-nine patients were enrolled and received LY3039478 (27 males, 42 females; median age 58, range 31–78). 16/37 (43{\%}) patients with evaluable samples were positive for Notch 1 immunohistochemistry. Per RECIST 1.1, in leiomyosarcoma (LMS) group (n = 29), ten (36{\%}) had stable disease (SD) and one (4{\%}) had unconfirmed partial response (PR). In GIST group (n = 13), four (31{\%}) had SD. Among other STS subtypes (n = 27), one patient with angiosarcoma had unconfirmed PR, six (21{\%}) had SD. Median PFS was 1.9 months (95{\%} confidence interval:1.6–3.3) for LMS, 1.9 months (0.3–6.1) for GIST and 1.7 months (1.4–2.2) for other STS groups. Median OS was 7.4 months (4.3–non-evaluable [NE]) for LMS, 16.5 months (3.9–16.5) for GIST and 5.6 months (3.4-NE) for other STS groups. Most common adverse events were diarrhoea, nausea, vomiting and decreased appetite. Conclusion: LY3039478 suggested a modest clinical activity in patients with STS and GIST and had a manageable safety profile.",
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T1 - Notch pathway inhibition with LY3039478 in soft tissue sarcoma and gastrointestinal stromal tumours

AU - Mir, Olivier

AU - Azaro, Analia

AU - Merchan, Jaime R

AU - Chugh, Rashmi

AU - Trent, Jonathan

AU - Rodon, Jordi

AU - Ohnmacht, Ute

AU - Diener, J. T.

AU - Smith, Claire

AU - Yuen, Eunice

AU - Oakley, Gerard Joseph

AU - Le Cesne, Axel

AU - Soria, Jean Charles

AU - Benhadji, Karim A.

AU - Massard, Christophe

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Background: LY3039478 is an orally bioavailable selective Notch inhibitor. This phase 1a/b trial evaluated the safety, pharmacokinetics and antitumour activity of LY3039478 in patients with soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST). Methods: This multipart, phase 1 trial enrolled patients with refractory advanced/metastatic STS and GIST, measurable disease, Eastern Cooperative Oncology Group ≤1 and baseline tumour tissue. Eligible patients received LY3039478 50mg/75 mg three times per week, for 28-day cycle until disease progression. Safety assessments were based on Common Terminology Criteria for Adverse Events, V4.0. Tumour responses were assessed using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) and Choi criteria. Primary objectives were to confirm the recommended phase 2 dose of LY3039478 and document the antitumour activity. Secondary objectives were safety and toxicity, pharmacokinetics (PK), progression-free survival (PFS) and overall survival (OS). Results: Sixty-nine patients were enrolled and received LY3039478 (27 males, 42 females; median age 58, range 31–78). 16/37 (43%) patients with evaluable samples were positive for Notch 1 immunohistochemistry. Per RECIST 1.1, in leiomyosarcoma (LMS) group (n = 29), ten (36%) had stable disease (SD) and one (4%) had unconfirmed partial response (PR). In GIST group (n = 13), four (31%) had SD. Among other STS subtypes (n = 27), one patient with angiosarcoma had unconfirmed PR, six (21%) had SD. Median PFS was 1.9 months (95% confidence interval:1.6–3.3) for LMS, 1.9 months (0.3–6.1) for GIST and 1.7 months (1.4–2.2) for other STS groups. Median OS was 7.4 months (4.3–non-evaluable [NE]) for LMS, 16.5 months (3.9–16.5) for GIST and 5.6 months (3.4-NE) for other STS groups. Most common adverse events were diarrhoea, nausea, vomiting and decreased appetite. Conclusion: LY3039478 suggested a modest clinical activity in patients with STS and GIST and had a manageable safety profile.

AB - Background: LY3039478 is an orally bioavailable selective Notch inhibitor. This phase 1a/b trial evaluated the safety, pharmacokinetics and antitumour activity of LY3039478 in patients with soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST). Methods: This multipart, phase 1 trial enrolled patients with refractory advanced/metastatic STS and GIST, measurable disease, Eastern Cooperative Oncology Group ≤1 and baseline tumour tissue. Eligible patients received LY3039478 50mg/75 mg three times per week, for 28-day cycle until disease progression. Safety assessments were based on Common Terminology Criteria for Adverse Events, V4.0. Tumour responses were assessed using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) and Choi criteria. Primary objectives were to confirm the recommended phase 2 dose of LY3039478 and document the antitumour activity. Secondary objectives were safety and toxicity, pharmacokinetics (PK), progression-free survival (PFS) and overall survival (OS). Results: Sixty-nine patients were enrolled and received LY3039478 (27 males, 42 females; median age 58, range 31–78). 16/37 (43%) patients with evaluable samples were positive for Notch 1 immunohistochemistry. Per RECIST 1.1, in leiomyosarcoma (LMS) group (n = 29), ten (36%) had stable disease (SD) and one (4%) had unconfirmed partial response (PR). In GIST group (n = 13), four (31%) had SD. Among other STS subtypes (n = 27), one patient with angiosarcoma had unconfirmed PR, six (21%) had SD. Median PFS was 1.9 months (95% confidence interval:1.6–3.3) for LMS, 1.9 months (0.3–6.1) for GIST and 1.7 months (1.4–2.2) for other STS groups. Median OS was 7.4 months (4.3–non-evaluable [NE]) for LMS, 16.5 months (3.9–16.5) for GIST and 5.6 months (3.4-NE) for other STS groups. Most common adverse events were diarrhoea, nausea, vomiting and decreased appetite. Conclusion: LY3039478 suggested a modest clinical activity in patients with STS and GIST and had a manageable safety profile.

KW - Angiosarcoma

KW - Gastrointestinal stromal tumours

KW - Leiomyosarcoma

KW - Liposarcoma

KW - Notch inhibitor

KW - Pleomorphic sarcoma

KW - Rhabdomyosarcoma

KW - Soft tissue sarcoma

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