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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03944304
Recruitment Status : Recruiting
First Posted : May 9, 2019
Last Update Posted : July 13, 2020
Information provided by (Responsible Party):
Yoon-Koo Kang, Asan Medical Center

Tracking Information
First Submitted Date  ICMJE May 8, 2019
First Posted Date  ICMJE May 9, 2019
Last Update Posted Date July 13, 2020
Actual Study Start Date  ICMJE May 20, 2019
Estimated Primary Completion Date August 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 8, 2019)
Disease control rate [ Time Frame: At week 16 ]
evaluate with RECIST Version 1.1 by dynamic abdomen and pelvis CT scan
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Paclitaxel in Patients With GIST With Low P-glycoprotein Expression After Failure of at Least Imatinib and Sunitinib, and Regorafenib.
Official Title  ICMJE 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.
Brief Summary

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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Gastrointestinal Stromal Tumors
Intervention  ICMJE Drug: Paclitaxel
Paclitaxel will be administered at 80mg/m2/day every four weeks at Day 1, Day 8 and Day 15 per cycle. One cycle consists of 4 weeks (28 days).
Study Arms  ICMJE Experimental: Paclitaxel
Paclitaxel will be administered at 80mg/m2/day every four weeks at Day 1, Day 8 and Day 15 per cycle. One cycle consists of 4 weeks (28 days).
Intervention: Drug: Paclitaxel
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 8, 2019)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 1, 2021
Estimated Primary Completion Date August 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Yoon-Koo Kang 82-2-3010-3230
Listed Location Countries  ICMJE Korea, Republic of
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03944304
Other Study ID Numbers  ICMJE AMC1901
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Yoon-Koo Kang, Asan Medical Center
Study Sponsor  ICMJE Asan Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Yoon-Koo Kang Asan Medical Center
PRS Account Asan Medical Center
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP