Surgery for Locally Unresectable Advanced GISTs Without Metastasis After Imatinib Therapy

A Trial for Surgical Treatment in Patients With Initially Locally Unresectable Advanced GIST Without Metastasis During Therapy With Imatinib

Gastrointestinal stromal tumors (GISTs) are a form of sarcoma and the most common sarcoma tumors of the gastrointestinal tract. The limited clinical experience suggests that GIST patients may benefit from neo-adjuvant therapy from primary GIST. This is a prospective, multicenter, open, observational study in evaluation of safety and efficacy of imatinib compared with that of historical data for locally unresectable advanced GIST without metastasis. The study will include an up to 28-day screening period, followed by receiving imatinib mesylate (400 mg/day) for at least 6-12 months and followed up for 3 years after surgery.

Study Overview

• Status: Completed
• Conditions: Gastrointestinal Stromal Tumor

Detailed Description

Primary Objective

• To observe the safety of imatinib compared with that of historical data for locally unresectable advanced GIST without metastasis.

Secondary Objective

• Progression-free survival (PFS) in resected patients during follow up
• R0 resection rate
• objective response rate, tumor shrinkage rate
• Correlation of mutation status with response
• Correlation of PK with response
• Surgical morbidity and mortality and safety follow up
• Quality of life
• Overall survival (OS)

• Study Type: Observational
• Enrollment (Actual): 51

Contacts and Locations

Study Locations

• Taiwan
  • Taoyuan, Taiwan, 333
    • Chang Gung Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The study will be conducted in four branch hospitals of Chang Gung Memorial Hospital, Taiwan including Keelung, Linkou, Cha-Yi, and Kaoshung, respectively. To target 50 patients; 90% patients with response after imatinib treatment; 10% patients without response; compare the result with historical data.

Description

Inclusion Criteria

• Locally advanced unresectable GIST without metastasis at

  • EC junction requiring total gastrectomy,
  • Duodenum requiring Whipple operation;
  • Large GIST requiring multiviceral resection;
  • Rectum: requiring APR.
• Histologically documentation with positive immunostaining for KIT (CD117)
• Patient age ≥ 18 years old
• ECOG performance status 0 or 1

• Patient must have the following post-operative laboratory values confirmed within 14 days prior to registration:

  • Creatinine ≤ 1.5 times the institution ULN (upper limit of normal)
  • WBC ≥ 3,000/mm3
  • Platelets ≥ 100,000/mm3
  • Total Bilirubin ≤ 1.5 times the institution ULN. NOTE: Patients with elevated bilirubin secondary to Gilbert's disease are eligible to participate in the study.
  • AST ≤ 2.5 times the institution ULN
  • ALT ≤ 2.5 times the institution ULN
  • Female of childbearing potential must have negative serum pregnancy test. -- -NOTE: Post-menopausal women must be amenorrheic for at least 12 months to be deemed not of reproductive potential.
• Patient is willing to sign informed consent.

Exclusion Criteria

• Patient has received post-operative chemotherapy.
• Patient has received post-operative radiation therapy.
• Patient has received post-operative investigational treatment.
• Patient has received prior therapy with imatinib, or any other molecular targeted or biological therapy.
• Patient has had an active infection requiring antibiotics within 14 days prior to registration.
• any prior malignancies for at least 5 years with potential evidence of recurrence (except for effectively treated basal cell or squamous carcinoma of the skin, carcinoma in-situ of the cervix that has been effectively treated by surgery alone, or lobular carcinoma in-situ of the ipsilateral or contralateral breast treated by surgery alone).
• Patient is deemed by their treating physician to be at risk for recurrence from prior malignancies.New York Heart Association Class 3 or 4 cardiac diseases.
• Patient is taking full dose warfarin. NOTE: The use of mini-dose warfarin (1 mg orally per day) for prevention of central line-associated deep venous thrombosis is permitted.
• Presence of severe and/or uncontrolled concurrent medical disease (e.g., uncontrolled diabetes, uncontrolled chronic renal disease, uncontrolled liver disease, including chronic viral hepatitis judged at risk of reactivation, uncontrolled active infection, such as HIV infection, etc.).
• Patient, if female and breastfeeding. NOTE: It is not known whether imatinib or its metabolites are excreted in human milk.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Imatinib treat; • Locally advanced unresectable GIST without metastasis at; EC junction requiring total gastrectomy,; Duodenum requiring Whipple operation;; Large GIST requiring multiviceral resection;; Rectum: requiring APR.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
progression free survival	Evidence of measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines with CT scan.	five years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
R0 resection rate	all the participants	three years
Objective response rate, tumor shrinkage rate	all the participants	three years
Correlation of PK with response	check PK (trough level of imatinib)of all the participants at first month and every three months later to correlate with the response and check PK (peak level of imatinib) of all the participants who had adverse events	three years
Surgical morbidity and mortality and safety follow up	surgical morbidity: morbidity related to surgical procedure surgical mortality: mortality related to surgical procedure safety: adverse events related imatinib according to NIH toxicity evaluation criteria	five years
Overall survival (OS)	Overall survival (OS) will be measured from after administration of imatinib mesylate and death as the end point of the study, whatever the cause. Alive patients will be censored at the date of last follow-up. Causes of death will be recorded.	five years

Collaborators and Investigators

• Sponsor: Chang Gung Memorial Hospital
• Investigators: Study Chair: Chun-Nan Yeh, MD, Chang Gung Memorial Hospital, Linkou, Taiwan.; Principal Investigator: Jen-Shi Chen, MD., Chang Gung Memorial Hospital, Linkou, Taiwan.; Principal Investigator: Yen-Yang Chen, MD., Chang Gung Memorial Hospital, Kaoshung, Taiwan.; Principal Investigator: Kun-Chun Chiang, MD., Chang Gung Memorial Hospital, Keelung, Taiwan.; Principal Investigator: Liang-Mou Kuo, MD., Chang Gung Memorial Hospital, Cha-Yi, Taiwan.

Publications and helpful links

General Publications

• Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002 Aug 15;347(7):472-80. doi: 10.1056/NEJMoa020461.
• Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, Raymond AK, Bramwell VH, Baker LH, Maki RG, Tanaka M, Hecht JR, Heinrich MC, Fletcher CD, Crowley JJ, Borden EC. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008 Feb 1;26(4):626-32. doi: 10.1200/JCO.2007.13.4452.
• Pawlik TM, Vauthey JN, Abdalla EK, Pollock RE, Ellis LM, Curley SA. Results of a single-center experience with resection and ablation for sarcoma metastatic to the liver. Arch Surg. 2006 Jun;141(6):537-43; discussion 543-4. doi: 10.1001/archsurg.141.6.537.
• Dagher R, Cohen M, Williams G, Rothmann M, Gobburu J, Robbie G, Rahman A, Chen G, Staten A, Griebel D, Pazdur R. Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res. 2002 Oct;8(10):3034-8.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2013
• Primary Completion (Actual): December 31, 2016
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: May 22, 2013
• First Submitted That Met QC Criteria: May 28, 2013
• First Posted (Estimate): May 31, 2013

Study Record Updates

• Last Update Posted (Actual): August 9, 2018
• Last Update Submitted That Met QC Criteria: August 7, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: neoadjuvant; gastrointestinal stromal tumor; GIST; imatinib
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Neoplasms, Connective Tissue; Gastrointestinal Stromal Tumors
• Other Study ID Numbers: Yeh CN001