Drug Detail

Information about Gleevec

Generic Name
Imatinib
IND
STI571
Brand Name (US)
Gleevec
Manufacturer
Novartis
Drug Type
Tyrosine Kinase Inhibitor
Delivery
Oral
Approval Status
Approved for GIST
Indications
Front-line therapy for GIST and CML
Overall Strategy
KIT Protein Based
Strategy
Block KIT
Drug Category
KIT/PDGFRA inhibitor

Based on the striking results of phase II clinical trials, Gleevec® was filed for registration and received approval from the European Union (EU), the Food and Drug Administration (FDA) in the United States, and several other countries for the treatment of adult patients with c-Kit (CD117)–positive unresectable and/or metastatic malignant GISTs. Gleevec is also approved in the U.S. (Dec. 19th, 2008) for adjuvant treatment (preventative treatment after surgery to remove a primary tumor). It is also approved for adjuvant treatment in other countries.

Gleevec® is known by several different names:

* Gleevec® in the U.S.
* Glivec® outside the U.S.
* Imatinib Mesylate.
* STI571 when it was in clinical trials (STI stands for Signal Transduction Inhibitor).

Gleevec is a pill that is taken either once or twice daily, depending on the dose.

Gleevec is different from traditional chemotherapy in that it is very selective. Traditional chemotherapy kills all cells that are dividing quickly. This is what causes so many of the side effects of traditional chemotherapy. In addition to the cancer cells, this type of chemotherapy also kills many of the bodies normal cells. Gleevec is much more selective and as a result has fewer side effects. It was designed to block the activity of a mutant type of enzyme (an enzyme is a specific type of protein) that causes Chronic Myeloid Leukemia (CML). This enzyme is called Bcr/Abl. In addition to blocking Bcr/Abl, Gleevec also blocks several other enzymes (enzymes are a type of protein). These are:

* KIT.
* Platelet Derived Growth Factor Receptors (PDGFR-alpha and PDGFR-beta).
* Various forms of the Abl enzymes.

The KIT receptor belongs to a class of receptors called the tyrosine kinase family. It is estimated that the human genome will reveal more than 400 tyrosine kinases . Because Gleevec selectively blocks only a few of these tyrosine kinases, it is both effective and has fewer side effects than traditional chemotherapy.

For normal signal transduction to occur in the KIT receptor, a chemical called ATP (adenosine triphosphate) must bind to a site in the kinase domain of the receptor. Gleevec prevents signal transduction of KIT by binding to this ATP binding site. This prevents the transfer of phosphate groups from ATP and blocks signal transduction in normal and mutated forms of KIT.


Links

 

All About Gleevec (LRG website)
   

 

Gleevec prescribing information
   

 

Patient assistance program (insurance, financial help, etc).
   

 

Gleevec blood level monitoring (LRG story/info)
   

 

Gleevec drug interactions (LRG site)
   

 

Gleevec.com website (GIST portion)
   

 

FDA approves adjuvant Gleevec
   

 

Effect of a proton pump inhibitor on the pharmacokinetics of imatinib
   

 

Imatinib Mesylate May Improve Fasting Blood Glucose in Diabetic Ph+ Chronic Myelogenous Leukemia Patients Responsive to Treatment
   

 

European Commission approves new label for Novartis drug Glivec® extending adjuvant therapy to three years for certain GIST patients
   

 

Disintegration of chemotherapy tablets (including imatinib) for oral administration in patients with swallowing difficulties
   

 

Imatinib-induced hyperbilirubinemia with UGT1A1 (*28) promoter polymorphism: first case series in patients with gastrointestinal stromal tumor.
   

Trials of this drug

  

STI571 in Treating Patients With Recurrent or Refractory Soft Tissue Sarcoma
   

  

Comparison of Two Different Doses of STI571 in Treating Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumor (S0033)
   

  

Imatinib Mesylate in Treating Patients With Gastrointestinal Stromal Tumor That Has Been Completely Removed During Surgery (Z9000)
   

  

Imatinib Mesylate in Treating Patients With Advanced Cancer and Liver Dysfunction
   

  

Imatinib Mesylate in Treating Patients With Advanced Cancer and Kidney Failure
   

  

Neoadjuvant and Adjuvant Imatinib Mesylate in Treating Patients With Primary or Recurrent Malignant Gastrointestinal Stromal Tumor (RTOG-S-0132)
   

  

Imatinib Mesylate in Treating Patients With Relapsed or Refractory Solid Tumors of Childhood
   

  

Imatinib Mesylate (Gleevec; STI571) in Treating Patients With Primary Gastrointestinal Stromal Tumor That Has Been Completely Removed by Surgery (ACOSOG-Z9001)
   

  

Imatinib Mesylate or Observation Only in Treating Patients Who Have Undergone Surgery for Localized Gastrointestinal Stromal Tumor (EORTC-62024)
   

  

Imatinib Mesylate in Treating Patients With Locally Advanced Gastrointestinal Stromal Tumor
   

  

Study Comparing 12 Months Versus 36 Months of Imatinib in the Treatment of Gastrointestinal Stromal Tumor (GIST) (SSGXVIII/AIO)
   

  

Post-Marketing Clinical Study of Postoperative Adjuvant Therapy With Imatinib Mesylate in Patients With Gastrointestinal Stromal Tumors (GIST) (Japan CSTI571BJP07)
   

  

Phase II Clinical Study of Imatinib Mesylate in Patients With Malignant Gastrointestinal Stromal Tumors (Extension Study) Japan
   

  

A Study of the Efficacy and Safety of Imatinib Mesylate in Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing c-Kit Gene (Extension of US Phase II study, B2222)
   

  

Adjuvant Imatinib in High-Risk GIST With c-Kit Mutation (ROK CSTI571BKR08)
   

  

Gleevec Administered Preoperatively to Reduce Gastrointestinal Stromal Tumor (GIST)
   

  

Open-Label Trial of Glivec With Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumors
   

  

Prospective Multicentric Randomized Study of Glivec® in Advanced Gastrointestinal Stromal Tumors Expressing c-Kit: Interruption After 5 Years vs Maintenance
   

  

Preoperative and Postoperative Imatinib Mesylate Study in Patients With c-Kit Positive GIST (MDACC)
   

  

Effect of Imatinib on Bone Metabolism in Patients With Chronic Myelogenous Leukemia or Gastrointestinal Stromal Tumors
   

  

Imatinib Mesylate in Treating Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumor (EORTC-62005)
   

  

Imatinib Mesylate in Treating Patients With Liver Metastasis From a Gastrointestinal Stromal Tumor
   

  

Five Year Adjuvant Imatinib Mesylate (Gleevec®) in Gastrointestinal Stromal Tumor (GIST) (Novartis CSTI571BUS282)
   

  

Imatinib Mesylate With or Without Surgery in Treating Patients With Metastatic Gastrointestinal Stromal Tumor That is Responding to Imatinib Mesylate
   

  

Study of Dose Escalation Versus no Dose Escalation of Imatinib in Metastatic Gastrointestinal Stromal Tumors (GIST) Patients
   

  

Perioperative Imatinib Mesylate in Treating Patients With Locally Advanced Gastrointestinal Stromal Tumor
   

  

Rechallenge of Imatinib in GIST Having no Effective Treatment (RIGHT)
   

  

A Prospective, Multicenter Study on Best Clinical Use of Imatinib in the Advanced Gastrointestinal Stromal Tumors
   

  

Phase ll Study of Imatinib Mesylate for the Neoadjuvant Treatment of Patients With Gastrointestinal Stromal Tumors (GIST) (CONVERT)
   

  

Safety and Efficacy Evaluation of Two Year Imatinib Treatment in Adjuvant Gastrointestinal Stromal Tumor (GIST) (IMAGE) (Novartis CSTI571BIC08)
   

  

Imatinib Dose Escalation to 800 mg/Day in Korean Patients With Metastatic or Unresectable GIST Harboring KIT Exon 9 Mutation
   

  

Efficiency of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST) (ImadGist)
   

  

Influence of an Acidic Beverage on the Imatinib Exposure After Major Gastrectomy (ABILITY)
   

  

Three Versus Five Years of Adjuvant Imatinib as Treatment of Patients With Operable GIST
   

  

A Study of Intermittent Dosing Schedule of Imatinib in Patients With Tyrosine Kinase Inhibitor Refractory GISTs
   

  

The Stop-GIST Trial: Discontinuation of Imatinib in Patients With Oligo-metastatic GIST
   

  

A Retrospective Pharmacokinetics and Pharmacogenomics Research of Imatinib in Gastrointestinal Stromal Tumor Treatment
   

Trial results

  2011 ASCO - Final Results - Twelve versus 36 months of adjuvant imatinib (IM) as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial (SSGXVIII/AIO)
   
  ASCO 2015 Poster
   
  ASCO 2012 - Effect of five years of imatinib on cure for patients with advanced GIST: Updated survival results from the prospective randomized phase III BFR14 trial.
   
  Long-term Results of Adjuvant Imatinib Mesylate in Localized, High-Risk, Primary Gastrointestinal Stromal Tumor: ACOSOG Z9000 (Alliance) Intergroup Phase 2 Trial.
   
  Phase II Trial of Neoadjuvant/adjuvant Imatinib Mesylate for Advanced Primary and Metastatic/recurrent Operable Gastrointestinal Stromal Tumors: Long-term Follow-up Results of Radiation Therapy Oncology Group 0132
   
  Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial.
   
  Follow-up results after 9 years of the ongoing phase II B2222 trial of imatinib mesylate in patients with metastatic or unresectable KIT+ gastrointestinal stromal tumors (GIST)
   
  Efficacy and Safety of Imatinib Mesylate in Advanced Gastrointestinal Stromal Tumors
   
  Phase II results Poster (PDF)
   
  ASCO 2006 - 4 year follow-up of phase II results
   
  ASCO 2001 - First report of the phase II results
   
  ASCO 2002 - High incidence of durable responses induced by imatinib mesylate (Gleevec) in patients with unresectable and metastatic gastrointestinal stromal tumors (GISTs
   
  Trial results reported in Journal of Surgical Oncology
   
  Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group.
   
  Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study.
   
  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.
   
  Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group.
   
  Efficacy of adjuvant imatinib mesylate following complete resection of localized, primary gastrointestinal stromal tumor (GIST) at high risk of recurrence: The U.S. Intergroup phase II trial ACOSOG Z9000.
   
  Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group.
   
  Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group.
   
  A phase II study of imatinib mesylate in children with refractory or relapsed solid tumors: a Children's Oncology Group study.
   
  Adjuvant imatinib mesylate increases recurrence free survival (RFS) in patients with completely resected localized primary gastrointestinal stromal tumor (GIST): North American Intergroup Phase III trial ACOSOG Z9001.
   
  ASCO 2008 - Imatinib pharmacokinetics (PK) and its correlation with clinical response in patients with unresectable/metastatic gastrointestinal stromal tumor (GIST).
   
  ASCO GI 2008 - Correlation of imatinib plasma levels with clinical benefit in patients (Pts) with unresectable/metastatic gastrointestinal stromal tumors (GIST)
   
  Annals of Surgical Oncology Jan., 2007: Surgical resection of gastrointestinal stromal tumors after treatment with imatinib.
   
  Annals of Surgical Oncology, Oct., 2008: A Randomized, Phase II Study of Preoperative plus Postoperative Imatinib in GIST: Evidence of Rapid Radiographic Response and Temporal Induction of Tumor Cell Apoptosis.
   
  NEJM May, 2006: Altered Bone and Mineral Metabolism in Patients Receiving Imatinib Mesylate
   
  European Journal of Cancer, Sept., 2008: Distribution and prognostic value of histopathologic data and immunohistochemical markers in gastrointestinal stromal tumours (GISTs): An analysis of the EORTC phase III trial of treatment of metastatic GISTs with imatinib mesylate.
   
  ASCO 2007: Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST): A meta-analyis based on 1,640 patients (pts).
   
  ASCO 2004: Outcome of patients with advanced gastro-intestinal stromal tumors (GIST) crossing over to a daily imatinib dose of 800mg (HD) after progression on 400mg (LD) - an international, intergroup study of the EORTC, ISG and AGITG.
   
  Lancet Sept., 2004: Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial.
   
  European Journal of Cancer April, 2007: Imatinib does not induce cardiac left ventricular failure in gastrointestinal stromal tumours patients: analysis of EORTC-ISG-AGITG study 62005.
   
  Update of phase I study of imatinib (STI571) in advanced soft tissue sarcomas and gastrointestinal stromal tumors: a report of the EORTC Soft Tissue and Bone Sarcoma Group.
   
  Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study.
   
  Imatinib does not induce cardiac left ventricular failure in gastrointestinal stromal tumours patients: analysis of EORTC-ISG-AGITG study 62005.
   
  KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours.
   
  Predicting toxicities for patients with advanced gastrointestinal stromal tumours treated with imatinib: a study of the European Organisation for Research and Treatment of Cancer, the Italian Sarcoma Group, and the Australasian Gastro-Intestinal Trials Group (EORTC-ISG-AGITG).
   
  Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group study.
   
  CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: a quantitative analysis correlated with FDG PET findings.
   
  Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial.
   
  Imatinib in advanced gastrointestinal stromal tumour: when is 800 mg the correct dose?
   
  Glivec receives US approval as first treatment to reduce risk of cancer returning in patients with gastrointestinal stromal tumors
   
  Search in ASCO for BFR14 in Title
   
  ASCO 2008 - Does interruption of imatinib (IM) in responding patients after three years of treatment influence outcome of patients with advanced GIST included in the BFR14 trial?
   
  ASCO 2008 - Influence of complete resection of residual disease in responding patients to imatinib (IM) on the outcome of pts with advanced GIST: The experience of the BFR14 trial of the French Sarcoma Group.
   
  ASCO 2006 -Do patients with initially resected metastatic GIST benefit from 'adjuvant' imatinib (IM) treatment? Results of the prospective BFR14 French Sarcoma Group randomized phase III trial.
   
  ASCO 2005 - Prognostic factors for progression free and overall survival in advanced GIST: results from the BFR14 phase III trial of the French Sarcoma Group.
   
  Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group.
   
  Effect of cigarette smoking on imatinib in patients in the soft tissue and bone sarcoma group of the EORTC.
   
  A Prospective, Multicenter, Phase 2 Study of Imatinib Mesylate in Korean Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumor.
   
  Imatinib pharmacokinetics in patients with gastrointestinal stromal tumour: a retrospective population pharmacokinetic study over time. EORTC Soft Tissue and Bone Sarcoma Group.
   
  JCO 2009 Type of progression in patients treated with imatinib for advanced gastrointestinal stromal tumor (GIST): A study based on the EORTC-ISG-AGITG trial 62005.Van Glabbeke, Casali, Verweij et al.
   
  ACRIN 6665/RTOG 0132 phase II trial of neoadjuvant imatinib mesylate (IM) for primary and recurrent operable malignant GIST: imaging findings and correlation with genotype and GLUT4 expression. [Abstract] J Clin Oncol 27 (Suppl 15): A-10552, 2009.
   
  Adjuvant imatinib mesylate in patients with primary high risk gastrointestinal stromal tumor (GIST) following complete resection: Safety results from the U.S. Intergroup Phase II trial ACOSOG Z9000
   
  2008 GI ASCO presentation by Dr. DeMatteo (see the second presentation)
   
  LRG website: Preventative Gleevec for GIST
   
  Glivec approved in the EU (Novartis press release)
   
  Gene expression signatures and response to imatinib mesylate in gastrointestinal stromal tumor.
   
  2010 GI ASCO: Risk assessment for tumor recurrence after surgical resection of GIST:North American intergroup phase III trial ACOSOG Z9001
   
  ASCO 2010 - Risk of relapse with imatinib (IM) discontinuation at 5 years in advanced GIST patients: Results of the prospective BFR14 randomized phase III study comparing interruption versus continuation of IM at 5 years of treatment: A French Sarcoma Group Study.
   
  ASCO 2010 - Time to onset of progression after imatinib interruption and outcome of patients with advanced GIST: Results of the BFR14 prospective French Sarcoma Group randomized phase III trial.
   
  ASCO 2010 - Correlation of the topography of KIT exon 11 mutation with primary GIST location and predictive value for PFS in patients with advanced GIST: Results from the BFR14 randomized phase III trial of the French Sarcoma Group.
   
  Lancet oncology: Discontinuation of Imatinib in Patients With Advanced Gastrointestinal Stromal Tumours After 3 Years of Treatment: An Open-Label Multicentre Randomised Phase 3 Trial
   
  Imatinib: as adjuvant therapy for gastrointestinal stromal tumour.
   

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ClinicalTrials.gov

ASCO

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