Olivier Mir1, Analia Azaro2, Jaime Merchan3, Rashmi Chugh4, Jonathan Trent3, Jordi Rodon5, Ute Ohnmacht6, J T Diener6, Claire Smith7, Eunice Yuen7, Gerard Joseph Oakley6, Axel Le Cesne1, Jean-Charles Soria1, Karim A Benhadji6, Christophe Massard8. 1. Institut Gustave Roussy Cancer Campus, Drug Development Department, Villejuif Cedex, France. 2. Molecular Therapeutics Research Unit, Department of Medical Oncology, Vall D'Hebron University Hospital, and Pharmacology Department, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. 3. University of Miami, Sylvester Comprehensive Cancer Center, United States. 4. University of Michigan, United States. 5. MD Anderson Cancer Center, United States. 6. Eli Lilly and Company, United States. 7. Eli Lilly and Company, United Kingdom. 8. Institut Gustave Roussy Cancer Campus, Drug Development Department, Villejuif Cedex, France. Electronic address: christophe.massard@gustaveroussy.fr.
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.
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.
Authors: C Even; U Lassen; J Merchan; C Le Tourneau; J-C Soria; C Ferte; F Ricci; J T Diener; E Yuen; C Smith; G J Oakley; K A Benhadji; Christophe Massard Journal: Invest New Drugs Date: 2019-04-06 Impact factor: 3.850