A Phase II Study of Paclitaxel in Patients With Metastatic or Advanced Gastrointestinal Stromal Tumor (GIST) With Low P-glycoprotein Expression After Failure of at Least Imatinib, Sunitinib, and Regorafenib.
With the development of KIT mutation and KIT tyrosine kinase inhibitor imatinib (GlivecTM, Novartis), survival of patients with advanced and/or metastatic gastrointestinal stromal tumor (GIST) has significantly improved. Recently, sunitinib (SuteneTM, Pfizer) and regorafenib (StivargaTM, Bayer) have been proven to be effective as second- and third-line treatment, respectively in GIST patients who failed to imatinib treatment. However, almost all patients eventually experience disease progression due to the development of drug resistance to first-line imatinib, second-line sunitinib treatment, and third-line regorafenib. 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.
• 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).
• ECOG performance status of 0\
∙ 2
• Toxicity of all previous treatments is recovered to Grade 0 or Grade 1 according to NCI-CTCAE Version 5.0
• At least one measurable lesion by RECIST Version 1.1.
• Adequate bone marrow, hepatic, renal, and other organ functions
‣ Neutrophil ≥ 1,500/mm3
⁃ Platelet ≥ 100,000/mm3
⁃ Hemoglobin ≥ 8.0 g/dL
⁃ Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
⁃ AST/ALT \< 3 x ULN without liver metastases or AST/ALT \< 5 x ULN with liver metastases
⁃ Creatinine ≤1.5 x ULN
• Expected life expectancy of ≥12 weeks
⁃ Washout period of previous TKIs or chemotherapy for more than 4 times the half life (Seven days of washout period is enough for imatinib, sunitinib, and regorafenib)
⁃ Patients who signed informed consent