Lenvatinib and Eribulin in Advanced Soft Tissue Sarcoma

Phase 1

Active, not recruiting

Conditions: Leiomyosarcoma
Advanced Cancer
Liposarcoma
Soft Tissue Sarcoma Adult

Interventions: Drug: Eribulin
Drug: Lenvatinib

Registration Number: NCT03526679

Lead Sponsor: National Taiwan University Hospital

Brief Summary: This study is designed to test the safety and efficacy of the combination of lenvatinib, a drug that can inhibit the growth of supplying vessels around the tumors, and eribulin, a chemotherapy drug that targets the cancer cell during mitosis, in inoperable or metastatic adipocytic sarcoma and leiomyosarcoma.

Detailed Description: Recently, the US Food and Drug Administration (FDA) granted approval to eribulin for the treatment of adipocytic sarcoma who have received a prior anthracycline-containing regimen based on a Phase III study results of improved overall survival (OS) as compared with the standard treatment dacarbazine. In the leiomyosarcoma cohort of the study, although eribulin did not demonstrate a significant benefit over dacarbazine, still about 5.1% of leiomyosarcoma patients treated with eribulin had a partial response, suggesting that eribulin may have activity against leiomyosarcoma. However, the overall response rate (ORR) and progression-free survival (PFS) remained unsatisfactory in the two most common soft tissue sarcoma (STS) subtypes-adipocytic sarcoma and leiomyosarcoma, prompting new therapeutic options of STS patients.

Anti-angiogenic therapies had shown promising results in soft tissue sarcoma (ST). Pazopanib, an anti-angiogenic multi-kinase inhibitor, has shown clinical benefit with a longer median PFS of 4.6 months versus placebo in STS patients refractory to at least one line of systemic chemotherapy. Another anti-angiogenic targeted therapy, regorafenib, showed significant improvement in PFS as compared with placebo in various STS. In a phase I study of lenvatinib for solid tumors in Japan, 4 out of 6 leiomyosarcoma patients has tumor decreased more than 10%. Moreover, other tyrosine receptor targets of lenvatinib, such as fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR), may also plays a role in treating STS. In high-grade STS patients, about 30% of patients had FGFR1 amplification or overexpression. FGFR1-overexpression STS cell lines are sensitive to FGFR inhibitors such as BGJ398 and AZD45475. Furthermore, a monoclonal antibody of PDGFR alpha, olaratumab, was recently approved by the FDA in combination with doxorubicin for advanced STS based on a median 10-month OS benefit compared to doxorubicin only in a randomized phase II trial.

It has been demonstrated in various cancer types that an increased quantity of tumor infiltrating lymphocyte (TILs) is associated with increased response to chemotherapy or improved prognosis. One of the factors that had been shown to impede the migration and trafficking of TILs into tumor is vascular endothelial growth factor (VEGF). In renal cell carcinoma, treatment with bevacizumab, an anti-VEGF antibody, or in combination with atezolizumab, increased the recognition of tumor antigen, increased expression of major histocompatibility complex (MHC) class I receptor on tumor cells, and the amount of TIL migration into the tumor stroma9. Many of the STS were detected with scarce TILs in the tumor microenvironment, thus it would be interesting to see if anti-angiogenic tyrosine kinase inhibitors could adjust the tumor microenvironment toward a more chemotherapy-friendly milieu.

Thus, we would like to propose a clinical trial to understand the anti-tumor activity of the combination of lenvatinib and eribulin in advanced STS patients.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 30

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Experimental arm	Lenvatinib	The combination of lenvatinib and eribulin
Experimental arm	Eribulin	The combination of lenvatinib and eribulin

Primary Outcome Measures

Name	Time	Method
The Objective Response Rate (ORR) Based on RECIST 1.1	24 weeks	We will measure the radiographic changes of the tumor based on a prespecified criteria called RECIST (Response evaluation criteria in solid tumors). A tumor decreased in the sum of longest diameters of measurable tumors of more than 30% is considered responsive; a growth of tumor more than 20% in the sum of the longest diameter is considered disease progression; and shrinkage or growth between these intervals is considered stable disease (SD).

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS) Rate at 12-months	12 months	The definition of 12-months OS rate is the percentage of patients who had NOT has an event before or at 12 months. An event is defined as follows: Death due to any cause.
The Proportion of Patients Who Are Progression-free and Alive at 24 Weeks	24 weeks	We will measure how many patients (proportion) of the participants that the tumor has progressed in the first 24 weeks of treatment
Overall Survival (OS) Rate at 6 Months	6 months	The definition of 6 months OS rate is the percentage of patients who had NOT has an event before or at 6 months. An event is defined as follows: Death due to any cause.
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	6 months	Toxicities will be assessed according to CTCAE 4.03. The number of all grade toxicities will be recorded