Safety and Efficacy Evaluation of Two Year Imatinib Treatment in Adjuvant Gastrointestinal Stromal Tumor (GIST) (INV555)

A Multi-center, Single Arm, Phase II Study of Adjuvant Imatinib (Glivec®) in Patients Following the Resection of Primary Gastrointestinal Stromal Tumor ( GIST)

GISTs are the most common mesenchymal tumors of the gastrointestinal tract. Approximately 95% of GISTs are positive for KIT (CD117)-the receptor for stem cell factor (SCF). GISTs are not responsive to conventional cytotoxic chemotherapy and disease often recurs even after complete resection with wide margins.

Imatinib mesylate (trade names: Glivec® and Gleevec®, imatinib, formerly STI571) is a signal transduction inhibitor targeting several protein-tyrosine kinases that are believed to play a role in the proliferation of tumor cells. In the Phase II study of imatinib [CSTI571B 2222] in 147 patients with recurrent or metastatic GIST, the partial response rates were 67% and 66% in patients treated at 400 mg/d and 600 mg/d, respectively. Skin rash and elevated transaminases were the most common reason for drug discontinuation. The most frequently reported AEs were mild nausea, vomiting, diarrhea, superficial edema (primarily periorbital or lower limb), myalgia and muscle cramps. Grade 3/4 events included fluid retention (pleural or pericardial effusions, ascites, and pulmonary edema), skin rash, liver toxicity and gastrointestinal (GI) hemorrhage. Myelosuppression (neutropenia and thrombocytopenia) was a consistent finding. Also, a tumor lysis-like syndrome occurred in some patients leading to gastrointestinal (GI) and/or intratumoral hemorrhage.

In a Phase 3, American College of Surgeons Oncology Group trial (ACOSOG Z9001) of adjuvant imatinib, imatinib significantly improved 1-year recurrence-free survival (RFS) compared with placebo.

In summary, clinical trials have shown that imatinib produces clinical benefit in most patients with unresectable or metastatic GIST and extends median survival from 19 to 57 months. Imatinib is the standard of care for advanced GIST and has received regulatory approval for the treatment of unresectable or metastatic GIST. Studies suggest that adjuvant imatinib for 1 year prolongs RFS in patients at high risk of recurrent disease and metastases following complete surgical resection of the primary GIST.

Imatinib is an appealing adjuvant therapy for resected GIST because:

1. Patients with primary GIST have a high chance of tumor recurrence
2. Conventional adjuvant treatment modalities are ineffective
3. Imatinib specifically inhibits the Kit receptor which is constitutively activated in most GISTs
4. Imatinib inhibits the growth of Kit positive cells in vitro
5. Imatinib is highly effective in many patients with advanced GIST in a Phase II trial
6. Imatinib has been associated with minimal toxicity in patients with advanced GIST and in patients with chronic myelogenous leukemia (CML)
7. Imatinib may have its greatest impact on survival when there is minimal disease.

Primary

• To assess Recurrence Free Survival Rate in patients with resected primary GIST who are treated with adjuvant imatinib for a duration of 2 years Secondary
• To compare Recurrence Free Survival, Overall Survival, and Time to Recurrence of patients with resected primary GIST who are treated with adjuvant imatinib for a duration of 2 years with historical data To assess the safety of imatinib given as adjuvant therapy for 2 years in patients with resected primary GIST

Study Overview

• Status: Completed
• Conditions: Gastrointestinal Stromal Tumors
• Intervention / Treatment: Drug: imatinib mesylate

• Study Type: Interventional
• Enrollment (Actual): 132
• Phase: Phase 2

Contacts and Locations

Study Locations

• Algeria
  • Alger, Algeria, 016000
    • Novartis Investigative Site
• Egypt
  • Cairo, Egypt
    • Novartis Investigative Site
  • Mansoura, Egypt
    • Novartis Investigative Site
• India
  • Mumbai, India, 400016
    • Novartis Investigative Site
  • New Delhi, India, 110044
    • Novartis Investigative Site
  • Gujrat
    • Ahmedabad, Gujrat, India, 380009
      • Novartis Investigative Site
  • Maharashtra
    • Pune, Maharashtra, India, 411 001
      • Novartis Investigative Site
• Jordan
  • Amman, Jordan
    • Novartis Investigative Site
• Lebanon
  • Beirut, Lebanon, 1107 2020
    • Novartis Investigative Site
• Russian Federation
  • Ekaterinburg, Russian Federation, 620036
    • Novartis Investigative Site
  • Irkutsk, Russian Federation, 664035
    • Novartis Investigative Site
  • Kursk, Russian Federation, 305035
    • Novartis Investigative Site
  • Omsk, Russian Federation, 644013
    • Novartis Investigative Site
  • St. Petersburg, Russian Federation, 198255
    • Novartis Investigative Site
  • Tatarstan Republic
    • Kazan, Tatarstan Republic, Russian Federation, 420029
      • Novartis Investigative Site
• Saudi Arabia
  • Riyadh, Saudi Arabia, 11211
    • Novartis Investigative Site
• South Africa
  • Parktown, South Africa, 2193
    • Novartis Investigative Site
• Taiwan
  • Lin-Ko, Taiwan, 33305
    • Novartis Investigative Site
  • Niaosong Township, Taiwan, 83301
    • Novartis Investigative Site
  • Taichung, Taiwan, 40705
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taiwan ROC
    • Tainan 704, Taiwan ROC, Taiwan
      • Novartis Investigative Site
  • Taiwan, ROC
    • Taipei, Taiwan, ROC, Taiwan, 112
      • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10330
    • Novartis Investigative Site
  • Bangkok, Thailand, 10700
    • Novartis Investigative Site
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site
  • Songkla, Thailand, 90110
    • Novartis Investigative Site
• Tunisia
  • Tunis, Tunisia, 1006
    • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06100
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically proven diagnosis of primary GIST (without peritoneal or distant metastasis) with positive immunostaining for KIT (CD117);
• Undergone complete gross resection of a primary GIST within 70 days prior to enrollment (includes R0 [negative microscopic margins] and R1 [positive microscopic margins]);
• Intermediate or high risk of recurrence based on Corless criteria (Section 5.1):

Exclusion Criteria:

• Patient has received prior therapy with imatinib, or any other molecular targeted or biological therapy.

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: imatinib mesylate	Drug: imatinib mesylate; Other Names: STI571; Gleevec/Glivec

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Recurrence Free Survival Rate	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Adverse Events	2 years
Compare Recurrence Free Survival Rate to historical controls	2 years
Compare Overall Survival to historical controls	2 years
Compare Time To Recurrence to historical controls	2 years
Treatment Compliance - tracking if the patient is coming to visits as per visit schedule in protocol	2 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• J Clin Oncol 30, 2012 (suppl; abstr e20514) (From 2012 ASCO Annual Meeting )

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (ACTUAL): March 1, 2014
• Study Completion (ACTUAL): March 1, 2014

Study Registration Dates

• First Submitted: June 22, 2010
• First Submitted That Met QC Criteria: July 28, 2010
• First Posted (ESTIMATE): July 29, 2010

Study Record Updates

• Last Update Posted (ACTUAL): May 31, 2017
• Last Update Submitted That Met QC Criteria: May 28, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: GIST; tumor recurrence; advanced GIST; Resected GIST; primary GIST; KIT receptor; KIT positive; minimal toxicity
• 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: CSTI571BIC08