Paclitaxel in Patients With GIST With Low P-glycoprotein Expression After Failure of at Least Imatinib and Sunitinib, and Regorafenib.

Paclitaxel in Patients With GIST With Low P-glycoprotein Expression After Failure of at Least Imatinib and Sunitinib, and Regorafenib.

Gastrointestinal Stromal Tumor

Recruiting

2

Start Date 05/20/2019

Age of Trial (yrs) 5.5

Gleevec-resistant

Tubulin inhibitor

Cell cycle arrest

Specifically GIST and only GIST

AMC1901

Asan Medical Center

Yoon-Koo Kang 82-2-3010-3230 ykkang@amc.seoul.kr

Intravenous

From Brief Description:

Historic data suggest that GISTs do not respond to conventional cytotoxic chemotherapy, but systematic unbiased screening has not been performed. A recent large-scaled chemotherapy susceptibility screening with GIST cells showed that among a total of 89 chemotherapies, 37 have anti-cancer effect in at least one type of GIST cells. It was suggested that of these agents, transcriptional inhibitors and chemotherapies such as topoisomerase II, paclitaxel, and bortezomib would be effective.

Based on this study result, Asan Medical Center has recently performed a phase II study for efficacy and safety evaluation of paclitaxel in patients with advanced and/or metastatic GIST after failure of at least imatinib and sunitinib. Although paclitaxel showed limited anti-tumor efficacy, it was more effective in patients with low P-glycoprotein expression.

The objective of this study is to evaluate the safety and efficacy of paclitaxel in patients with metastatic or advanced GIST with low P-glycoprotein expression after failure of at least imatinib, sunitinib and regorafenib.

Inclusion Criteria:

Age 20 years or older, at the time of acquisition of informed consent
Histologically confirmed metastatic or unresectable GIST with CD117(+), DOG-1(+), or mutation in KIT or PDGFRαgene

Patients who failed to at least imatinib, sunitinib, and regorafenib (disease progression and/or intolerance) (Note: The number of previous treatment is not limited. Previous use of other chemotherapies such as tyrosine kinase inhibitor (TKI), or any other chemotherapeutic agents concurrently used with imatinib, sunitinib, and regorafenib is permitted.)

Disease progression is defined as follows:
Increase of tumor size by more than 20% according to RECIST version 1.1,
Appearance of a definite new lesion (excluding small cystic new lesions in the liver within 6 months of starting TKIs)
A new solid nodule with in a cystic mass, or
Increase of the size (> 20%) of previously existing solid nodule within a cystic mass

Intolerability to previous TKI is defined as follows:
Less than 75% of medication compliance due to non-hematological toxicity of grade 2 or above despite dose reduction to a one-step lower level (300 mg/day for imatinib; 37.5 mg/day for 4-week on/2-week off schedule or 25 mg/day with continuous schedule for sunitinib; and 120 mg/day for regorafenib)
Febrile neutropenia, Grade 4 neutropenia lasting >6 days, Grade 4 thrombocytopenia, Grade 3 thrombocytopenia accompanied with clinically significant hemorrhage, Grade 3-4 or intolerable continuous Grade 2 non-hematologic toxicity despite dose reduction to one-step lower level as described above

P-glycoprotein immunohistochemistry (IHC) H-score ≤250 in tumor tissue obtained after failure of previous treatment for GIST, including imatinib, sunitinib, and regorafenib
H-score is a sum of the multiplications of each intensity score (0-3) measured by the IHC and its corresponding proportion (0-100) of tumor cells (a score of 0-300).
Intensity is evaluated as 0 (negative), 1 (weak), 2 (moderate), or 3 (strong).
e.g.) If a proportion with an intensity of 3 is 40%, proportion with an intensity of 2 is 30%, proportion with an intensity of 1 is 20%, and proportion with an intensity of 0 is 10%, H-score is 200 (3x40 + 2x30 + 1x20).