Using Paclitaxel for GIST Patients Who Failed Multiple Treatments

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.

This study is testing if the drug paclitaxel can help adults with gastrointestinal stromal tumors (GIST) who haven’t had success with other treatments.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 40 (estimated)
• Ages: 20 Years and up
• Sex: All
• Sponsor: Asan Medical Center (Academic / other)
• Drugs / interventions: imatinib, sunitinib, chemotherapy
• Locations: 1 site (Seoul)
• Trial ID: NCT03944304 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates the efficacy of paclitaxel in patients with gastrointestinal stromal tumors (GIST) who have low P-glycoprotein expression and have previously failed treatment with imatinib, sunitinib, and regorafenib. The study is a single-center, prospective, single-arm, open-label phase II trial aimed at assessing the response of GIST patients to paclitaxel, given the limited options available after standard therapies have failed. The trial will include patients aged 20 years or older with histologically confirmed metastatic or unresectable GIST. The primary focus is to explore the potential of paclitaxel as a viable treatment option for this patient population.

Who should consider this trial

Good fit: Ideal candidates are adults aged 20 and older with metastatic or unresectable GIST who have previously failed at least imatinib, sunitinib, and regorafenib.

Not a fit: Patients who have not been diagnosed with GIST or those who have not failed the aforementioned treatments may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for GIST patients who have exhausted standard treatment options.

How similar studies have performed: While conventional chemotherapy has historically shown limited effectiveness in GIST, recent screening suggests that some chemotherapies, including paclitaxel, may have anti-cancer effects, indicating potential for success in this novel approach.

Eligibility criteria

Inclusion Criteria:

1. Age 20 years or older, at the time of acquisition of informed consent
2. Histologically confirmed metastatic or unresectable GIST with CD117(+), DOG-1(+), or mutation in KIT or PDGFRαgene
3. 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
4. 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).
5. ECOG performance status of 0\~2
6. Toxicity of all previous treatments is recovered to Grade 0 or Grade 1 according to NCI-CTCAE Version 5.0
7. At least one measurable lesion by RECIST Version 1.1.
8. 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
9. Expected life expectancy of ≥12 weeks
10. 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)
11. Patients who signed informed consent

Exclusion Criteria:

1. A pregnant or nursing woman, or a woman of childbearing age
2. A woman or a man who is not willing to use effective contraception during study drug administration or within 3 months following end of study drug administration. Barrier method should be used both in men and women during study drug administration and up to 3 months following end of administration. Oral preparations, implants, or contraceptive injections are not deemed as effective contraceptions in this study since these may be influenced by cytochrome P450 interactions.

   Women of childbearing age are defined as sexually mature women who have not received hysterectomy or do not undergo natural menopause for more than 12 consecutive months, at least (that is, who had the menses within previous 12 months), and must be shown to be negative in serum or urine pregnancy test within 14 days before starting paclitaxel treatment.
3. If a patient falls under one of the followings within 6 months prior to recruitment: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass, NYHA class III or IV congestive heart failure, stroke or transient ischemic attacks, serious cardiac arrhythmia requiring treatment
4. 4) Uncontrolled infection
5. Diabetes with sign of clinically significant peripheral disease
6. Acute or chronic liver disease and all chronic hepatic impairments (a patient with stable chronic hepatitis B is eligible.)
7. Uncontrolled gastrointestinal toxicity (nausea, diarrhea, vomiting) accompanied with toxicity above NCI CTCAE Grade 2
8. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for this study
9. A patient who has hemorrhage that is thought to threaten one's life requiring transfusion or endoscopic or surgical intervention, or Grade 3 or 4 hemorrhage within 3 months prior to treatment with study drug
10. Major surgery ≤ 28 days prior to starting study drug or who have not recovered from side effects of such therapy If diagnosis of HIV infection is known (HIV test is not obligatory)
11. Known diagnosis of HIV infection (HIV testing is not mandatory)
12. History of another primary malignancy that is currently clinically significant or currently requires active intervention
13. A patient with brain metastasis when evaluated by radiological imaging (e.g. CT, MRI) if there is a symptom that is clinically suspected of brain metastasis
14. Alcohol or substance abuse disorder

Where this trial is running

Seoul

• Asan Medical Center — Seoul, Korea, Republic of (Recruiting)

Study contacts

• Principal investigator: Min-Hee Ryu — Asan Medical Center
• Study coordinator: Min-Hee Ryu

Conditions Gastrointestinal Stromal Tumors; Single-center; Prospective; single-arm; open-label; phase II