Preoperative Imatinib Mesylate Combined With Rectal-sparing Surgery in Patients With c-KIT Gene-mutant Rectal GIST (PIRKER)

Preoperative Imatinib Mesylate Combined With Rectal-sparing Surgery in Patients With c-KIT Gene-mutant Rectal GIST: an Open-label, Single-arm, Phase III Trial（PIRKER）

Prior to the implementation of preoperative imatinib mesylate therapy, a considerable percentage (ranging from 34.5% to 67.5%) of individuals diagnosed with rectal gastrointestinal stromal tumors (GIST) underwent abdominoperineal resection (APR), a surgical procedure that involved the removal of the anus and necessitated a permanent colostomy.

This study aims to investigate the safety and viability of an organ-preserving approach involving preoperative imatinib mesylate treatment in conjunction with local resection for rectal GIST, specifically targeting patients with c-KIT gene mutations.

Study Overview

• Status: Not yet recruiting
• Conditions: Gastrointestinal Stromal Tumor of Rectum
• Intervention / Treatment: Drug: Imatinib Mesylate; Procedure: Local resection

Detailed Description

Prior to the implementation of preoperative imatinib mesylate therapy, a considerable percentage (ranging from 34.5% to 67.5%) of individuals diagnosed with rectal gastrointestinal stromal tumors (GIST) underwent abdominoperineal resection (APR), a surgical procedure that involved the removal of the anus and necessitated a permanent colostomy.

Previous studies have established that preoperative administration of imatinib mesylate effectively diminishes the size of rectal gastrointestinal stromal tumors (GIST) and enhances the likelihood of sphincter preservation. After initiating preoperative imatinib mesylate treatment, the sphincter preservation rate has notably escalated from 4.2% to 33.0%-94.9%.

In theory, lymph node resection is not required for Gastrointestinal Stromal Tumors (GIST); the local excision of rectal GIST enables sphincter preservation and yields satisfactory anal function and quality of life (QoL). Various surgical techniques are utilized for local excision, including traditional transanal (TA) and transanal minimally invasive surgery (TAMIS) approaches.

This study aims to explore the safety and feasibility of an organ-preservation strategy of preoperative imatinib mesylate combined with local resection in rectal gastrointestinal stromal tumor (GIST), specifically for patients with c-KIT gene mutations.

• Study Type: Interventional
• Enrollment (Estimated): 23
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jiabin Zheng; Phone Number: +8613365910080; Email: xhyykjk@163.com
• Study Contact Backup: Name: Weizhong Jiang, MD; Phone Number: +8613763828825; Email: Jiangwz362100@163.com

Study Locations

• China
  • Fujian
    • Fuzhou, Fujian, China, 350001
      • Weizhong Jiang

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Over the age of 18.
2. Newly pathology-diagnosed rectal GIST
3. Tumor > 2cm; local resection of R0 is not possible in the initial evaluation.
4. The lower margin of the tumor is ≤ 5cm from the anal verge.
5. C-KIT gene mutation.
6. Male or non-pregnant female.
7. ECOG score 0-2.
8. Did not receive targeted therapy before the start of the clinical trial.

9. Sufficient organ functions are defined as follows:

   Total bilirubin < 1.5×ULN (upper limit of normal, ULN), serum AST (SGOT) and ALT (SGPT) < 2. 5 × ULN, creatinine < 1.5×ULN, neutrophil count > 1. 5 ×109 / L, platelet > 100 × 109 / L.

10. The patient's informed consent has been obtained.

Exclusion Criteria:

1. Pathology is non-rectal GIST.
2. Under the age of 18.
3. Patients with distant metastasis.
4. The patient is not permitted to have additional primary malignant tumors within five years unless those tumors are currently deemed clinically insignificant and do not necessitate active intervention, such as basal cell skin cancer or cervical cancer in situ. The presence of any other malignant diseases is strictly prohibited.
5. Individuals diagnosed with stage III or IV cardiac conditions, specifically congestive heart failure and myocardial infarction occurring within six months prior to the commencement of the study.
6. The patient presents with severe and/or uncontrolled medical ailments, such as unmanaged diabetes, advanced chronic kidney disease, or active uncontrolled infection.
7. Co-administration of imatinib with warfarin or acetaminophen is contraindicated, necessitating the substitution of alternative medications (e.g., low molecular weight heparin in place of warfarin).
8. Subjects undergoing radiotherapy, chemotherapy, and/or targeted therapy.
9. Pregnant or lactating female patients.
10. Cognitive or psychiatric disorders.
11. Profound cardiac, hepatic, and renal dysfunction.
12. Non-adherence by the patient or the researchers' assessment of the patient's inability to complete the entire trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Preoperative Imatinib + local excision; Following the attainment of the maximum treatment response through imatinib mesylate administration, typically occurring within 6-12 months, as evidenced by two consecutive imaging evaluations, the tumor exhibited no further reduction in size, thus necessitating the selection of surgical intervention. According to the characteristics of the location of the tumor, the surgeon decides the surgical approach based on the existing literature and the availability of surgical equipment, including: Local transanal resection (TA); Local resection transsacralapproach; Local resection via perineal approach; Local resection transvaginal approach

Drug: Imatinib Mesylate; For patients with c-KIT exon 11 mutation, imatinib mesylate, 400mg, qd.; For patients with c-KIT exon 9 mutation, imatinib mesylate, 600mg or 800mg, qd.; Other Names: Gleevec; Procedure: Local resection; According to the characteristics of the location of the tumor, the surgeon decides the surgical approach based on the existing literature and the availability of surgical equipment, including: Local transanal resection (TA); Local resection transsacralapproach; Local resection via perineal approach; Local resection transvaginal approach

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Organ preservation	Rectum intact, owing to no total mesorectal excision (TME), no locoregional regrowth unless amenable to limited, curative (R0) salvage surgery by local excision (LE) and no permanent stoma (including a never reversed protective stoma, or a stoma owing to toxicities and/or poor functional outcomes)	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-year disease-free survival	The proportion of participants who remain disease-free at 3 years after surgery	36 months
Local recurrence rate	The local recurrence rate is defined as the incidence detection of a tumor involving the bowel wall only that occurs after LE or TME	36 months
Overall survival	The proportion of participants who remain survival at 3 years after surgery	36 months
R0 resection rate	The R0 resection rate is defined as the rate of R0 resection	18 months
Quality of life based on EORTC-QLQs-C30 and EORTC-QLQs-CR29	Quality of life accessed by EORTC-QLQs-C30 and EORTC-QLQs-CR29 questionnaire	Baseline, 3 months, 12 months, 24 months, and 36 months after surgery
Anorectal function	Anorectal function based on LARS score	Baseline, 3 months, 12 months, 24 months, and 36 months after surgery

Collaborators and Investigators

• Sponsor: Fujian Medical University Union Hospital
• Investigators: Principal Investigator: Weizhong Jiang, MD, Fujian Medical University Union Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2023
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2029

Study Registration Dates

• First Submitted: July 23, 2023
• First Submitted That Met QC Criteria: July 23, 2023
• First Posted (Actual): August 1, 2023

Study Record Updates

• Last Update Posted (Actual): August 1, 2023
• Last Update Submitted That Met QC Criteria: July 23, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Imatinib mesylate; Rectum; Gastrointestinal Stromal Tumor; c-KIT gene; Local resection
• 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; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate
• Other Study ID Numbers: 2023XHYG0025-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No