A Phase II Study of Oral Paclitaxel (Liporaxel) in GIST Patients With a Low P-glycoprotein Expression After Failure With Imatinib, Sunitinib and Regorafenib

A Phase II Study of Oral Paclitaxel (Liporaxel) in GIST Patients With a Low P-glycoprotein Expression After Failure With Imatinib, Sunitinib and Regorafenib

Gastrointestinal Stromal Tumor

Not yet recruiting

2

Start Date 08/01/2024

Age of Trial (yrs) .3

Gleevec-resistant

Tubulin inhibitor

Cell cycle arrest

Specifically GIST and only GIST

AMC2401

Asan Medical Center

Min-Hee Ryu, MD, PhD 82-2-3010-5936 miniryu@amc.seoul.kr

Oral

Brief Summary
The purpose of this study is to evaluate safety and efficacy of Liporaxel for patients with GIST who failed on prior standard treatments, including imatinib, sunitinib, and regorafenib, and with low P-glycoprotein expression.
Detailed Description

The survival outcomes of patients with advanced and/or metastatic gastrointestinal stromal tumors (GIST) have markedly improved with application of imatinib, the KIT tyrosine kinase inhibitor (GlivecTM, Novartis) for the treatment. Recently, sunitinib (SuteneTM, Pfizer) and regorafenib (StivargaTM, Bayer) have shown efficacy in patients with disease progression on imatinib as second- and third-line treatment, respectively. However, most patients develop acquired resistance to KIT tyrosine kinase inhibitors and show disease progression.

While cytotoxic chemotherapeutic agents were expected to have minimal antitumor effect on GIST, recent preclinical studies have shown that 37 out of 89 different chemotherapeutic agents have shown antitumor effects on at least one or more GIST cell lines. Especially, topoisomerase II inhibitors, paclitaxel, bortezomib have shown promising results. Based on the results, the investigators conducted a single center, single arm phase II study to evaluate efficacy and safety of paclitaxel for patients with GIST who failed to prior imatinib and sunitinib. Overall efficacy was modest, although patients with low P-glycoprotein expression showed better efficacy compared to those with high P-glycoprotein expression. Subsequently, the investigators performed another phase 2 trial to evaluate efficacy of paclitaxel for previously treated GIST patients with low P-glycoprotein expression and have met the primary endpoint.

Liporaxel is an oral formulation of paclitaxel, and showed high bioavailability, safety, and antitumor effect from non-clinical studies. From a phase 1 clinical trial for metastatic solid tumor patients, Liporaxel showed adequate PK/PD profiles. Compared to intravenous paclitaxel, administration is relatively easier and has better safety in terms of hypersensitivity reaction which is caused by the admixture of intravenous formulation of paclitaxel. From a multicenter phase 3 trial conducted in South Korea for patients with advanced gastric adenocarcinoma who failed on first-line palliative chemotherapy (DREAM trial), Liporaxel showed non-inferiority compared to intravenous paclitaxel in terms of both safety and efficacy, and it is currently approved for the second-line treatment in advanced gastric cancer. Also, Liporaxel proved safety and potential efficacy in patients with HER2 negative metastatic breast cancer as first-line chemotherapy, and currently multicenter phase 3 trial in ongoing (OPTIMAL3 trial).

The purpose of this study is to evaluate safety and efficacy of Liporaxel for patients with GIST who failed on prior standard treatments, including imatinib, sunitinib, and regorafenib, and with low P-glycoprotein expression.

Eligibility Criteria: (Partial: For full criteria go to NCT listing)

Inclusion Criteria:

Age 20 years or older, at the time of acquisition of informed consent
Histologically confirmed metastatic and/or advanced GIST with CD117(+), DOG-1(+), or mutation in KIT or PDGFRα gene
Failed (progressed and/or intolerable) after prior treatments for GIST, including at least imatinib and sunitinib, regorafenib.
Adequate tissue obtained after treatment failure to imatinib, sunitinib, and regorafenib for P-glycoprotein immunohistochemistry (IHC) analysis, and showed P-glycoprotein expression of less than 6. (For patients with PDGFRα D842V mutation or other subtypes with poor response to tyrosine kinase inhibitors, tumor tissue obtained at any period can be used.)