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Updated: Feb 5, 2026
Establishment of a Primary Culture of Patient-derived Soft Tissue Sarcoma
Published on: April 11, 2018
Notch pathway inhibition with LY3039478 in soft tissue sarcoma and gastrointestinal stromal tumours
Olivier Mir1, Analia Azaro2, Jaime Merchan3
1Institut Gustave Roussy Cancer Campus, Drug Development Department, Villejuif Cedex, France.
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.
Insights
LY3039478, a Notch inhibitor, showed modest anti-tumour activity in patients with soft tissue sarcoma (STS) and gastrointestinal stromal tumours (GIST). The drug demonstrated a manageable safety profile in this phase 1 trial.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- LY3039478 is an orally bioavailable drug that selectively inhibits Notch signaling.
- This study investigated LY3039478 in patients diagnosed with advanced or metastatic soft tissue sarcoma (STS) and gastrointestinal stromal tumors (GIST).
Purpose of the Study:
- To evaluate the safety, pharmacokinetics (PK), and antitumour activity of LY3039478.
- To determine the recommended phase 2 dose (RP2D) of LY3039478.
- To assess the clinical efficacy of LY3039478 in patients with refractory STS and GIST.
Main Methods:
- A multipart, phase 1 clinical trial design was employed.
- Patients received LY3039478 at doses of 50 mg or 75 mg three times weekly until disease progression.
- Safety was assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.0, and tumour response was evaluated by Response Evaluation Criteria in Solid Tumours (RECIST 1.1) and Choi criteria.
Main Results:
- Sixty-nine patients were enrolled, with 16/37 (43%) evaluable samples showing Notch 1 positivity.
- In leiomyosarcoma (LMS) patients (n=29), 36% had stable disease (SD) and 4% had unconfirmed partial response (PR). In GIST patients (n=13), 31% had SD.
- Median progression-free survival (PFS) ranged from 1.7 to 1.9 months across patient groups. Most common adverse events included diarrhea, nausea, vomiting, and decreased appetite.
Conclusions:
- LY3039478 demonstrated modest clinical activity in patients with STS and GIST.
- The drug exhibited a manageable safety profile, supporting further investigation in phase 2 trials.
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