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Nilotinib (Tasigna, previously called AMN107)

Nilotinib is a tyrosine kinase inhibitor (like imatinib/Gleevec) designed to bind more tightly than Gleevec to the Bcr-Abl abnormal fusion protein responsible for chronic myeloid leukemia, and the drug is FDA-approved for treatment of CML.  Nilotinib also binds the KIT and PDGFRA proteins that are relevant to GIST.

Manufacturer:  Novartis

Definition from NCI Drug Dictionary: An orally bioavailable aminopyrimidine-derivative Bcr-Abl tyrosine kinase inhibitor with antineoplastic activity. Designed to overcome imatinib resistance, nilotinib binds to and stabilizes the inactive conformation of the kinase domain of the Abl protein of the Bcr-Abl fusion protein, resulting in the inhibition of the Bcr-Abl-mediated proliferation of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) cells. This agent also inhibits the receptor tyrosine kinases platelet-derived growth factor receptor (PDGF-R) and c-kit, a receptor tyrosine kinase mutated and constitutively activated in most gastrointestinal stromal tumors (GISTs). With a binding mode that is energetically more favorable than that of imatinib, nilotinib has been shown to have an approximately 20-fold increased potency in kinase and proliferation assays compared to imatinib.

Available Results for Nilotinib Used in GIST

1.  Very early preliminary results were reported at ASCO 2010 from an ongoing trial of nilotinib as first-line treatment in newly diagnosed GIST patients (link for abstract):

Preliminary data of nilotinib in the first-line treatment of patients with metastatic or unresectable gastrointestinal stromal tumors (GIST). 
Citation: J Clin Oncol 28:15s, 2010 (suppl; abstr TPS332^)
Author(s): P. G. Casali, H. Joensuu, J. Martin Broto, X. Garcia del Muro, J. Blay, C. May, A. Pustowka, P. Reichardt.

The abstract states: "Best overall response included 6 pts with partial responses (42.9%), 6 with stable disease (42.9%), and 2 with progressive disease (14.3%). Rate of progression-free pts at 6 mo is 85.7%"

2.  Results of a completed Phase I nilotinib trial for GIST are published as (link for abstract):

Demetri GD, Casali PG, Blay JY, von Mehren M, Morgan JA, Bertulli R,Ray-Coquard I, Cassier P, Davey M, Borghaei H, Pink D, Debiec-Rychter M, Cheung W, Bailey SM, Veronese ML, Reichardt A, Fumagalli E, Reichardt P.
A phase I study of single-agent nilotinib or in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors.
Clin Cancer Res. 2009 Sep 15;15(18):5910-6. PubMed PMID: 19723647

You can read two abstracts from earlier presentations about this trial:

  • an abstract of a paper presented at ASCO 2006 entitled "A phase I study of AMN107 alone and in combination with imatinib in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST)."  This was a preliminary report.
  • an abstract of a paper presented at ASCO 2007 entitled  "A phase I study of nilotinib alone and in combination with imatinib (IM) in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST) - Study update."  This update indicated that 68% of patients achieved stable disease lasting from 6 weeks to over 6 months, including 2 patients with wild-type GIST (no detected mutations).

3.  Results in patients taking nilotinib outside of trials are described in this paper:

Montemurro M, Schöffski P, Reichardt P, Gelderblom H, Schütte J, Hartmann JT, von Moos R, Seddon B, Joensuu H, Wendtner CM, Weber E, Grünwald V, Roth A, Leyvraz S.
Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib.
Eur J Cancer. 2009 Sep;45(13):2293-7.  PubMed PMID: 19467857 

 

Off-label Nilotinib 

A patient who does not qualify for any of the trials described below may consider having his/her oncologist prescribe nilotinib off-label, although insurance may not cover off-label use.  Alternatively, the patient may apply to obtain nilotinib through the Novartis Patient Assistance Program.  The Novartis Oncology Reimbursement Hotline (1-800-282-7630)  will be able to provide assistance with the reimbursement process for Novartis products.

The NCCN Soft Tissue Sarcoma Guidelines (versions 2.2009 and later) section "SARC-E page, Generally Accepted Systemic Therapy Agents and Regimens" (which is on page 35 of the 69-page pdf) includes nilotinib.  This inclusion indicating NCCN endorsement of the drug for GIST may help patients secure insurance coverage for off-label use.  You can access this guide by going to the NCCN website, completing a free registration and log-in, then clicking on Soft Tissue Sarcoma under the tab for NCCN Clinical Practice Guidelines in Oncology.

 

Cardiac Risk

Patients with heart problems should know that nilotinib labeling contains a black box warning regarding the risk of QT prolongation and sudden cardiac death. Five sudden deaths were reported in patients receiving nilotinib therapy; ventricular repolarization abnormalities may have caused the occurrence of these deaths as it is known to prolong QT interval. The manufacturer recommends that nilotinib should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Electrolyte abnormalities should be  corrected prior to initiation of nilotinib. Concomitant use of drugs that prolong the QT interval and CYP3A4 inhibitors should be avoided if possible.  The black box warning is quoted below:

"WARNING: QT PROLONGATION AND SUDDEN DEATHS
See full prescribing information for complete boxed warning.
Tasigna prolongs the QT interval (5.2). Sudden deaths have been reported in patients receiving nilotinib (5.3). Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome (4). Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored (5.2). Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided (5.7). Patients should avoid food 2 hours before and 1 hour after taking dose (5.8). Use with caution in patients with hepatic impairment (5.9). ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments. (5.2, 5.3, 5.6, 5.12)."

See http://www.pharma.us.novartis.com/product/pi/pdf/tasigna.pdf for details at the numbered sections indicated in the warning (such as 5.2, 5.3, etc.)

 

Current Trials for Nilotinib in GIST

July 2008: Currently recruiting, a new trial of nilotinib has opened for GIST patients who have experienced progression on both imatinib and sunitinib.  LINK HERE for the description.  This is a new trial being done only at Fox Chase.   Phone 888 FOX CHASE to inquire about the trial.  Entry criteria are similar to the previous study, but patients can have used other tyrosine kinase inhibitors besides  Gleevec and Sutent.  Patients must have had progression on both Gleevec and Sutent.  This is not a placebo trial; all patients will receive nilotinib. 

Phase III, Open-label Study of Nilotinib Versus Imatinib in GIST Patients, NCT00785785LINK HERE  for details. This trial has been closed because interim results indicated that nilotinib would not be superior to imatinib.  In a news release on April 11, 2011, Novartis announced as follows:

Basel, April 11, 2011- Novartis announced today it is discontinuing a Phase III trial of Tasigna® (nilotinib) for investigational use in the first-line treatment of gastrointestinal stromal tumors (GIST) based on the recommendation of an independent data monitoring committee. Interim results showed Tasigna is unlikely to demonstrate superiority compared to Glivec® (imatinib)*, the current standard of care in this setting.  

The trial was for patients with  GIST which is unresectable and/or metastatic and either:

  1. no prior therapy with imatinib or any investigational therapies (e.g .sunitinib). Note: newly diagnosed patients may have received up to 14 days imatinib treatment for disease management while awaiting study start.
  2. recurrent GIST after stopping adjuvant treatment with imatinib and no subsequent treatment with any other investigational therapies (for example sunitinib).

Treatment of Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumors in First Line With Nilotinib in Gastrointestinal Stromal Tumors, NCT00756509: This Phase II trial will evaluate nilotinib as first line therapy in GIST patients who have not had prior drug treatment.   LINK HERE for NCT00756509.

Nilotinib 800 Mg And Imatinib 800 Mg For The Treatment Of Patients With Gastrointestinal Stromal Tumors (Gist) Refractory To Imatinib 400 Mg (LANGIST) NCT00751036:  This Phase III trial will randomize patients who have had RECIST progression on 400 mg of imatinib (but not doses higher than 400 mg) to an arm for 800 mg imatinib versus an arm for 800 mg nilotinib.  LINK HERE for the description.

Phase II Study Aiming to Evaluate the Efficacy and Safety of Nilotinib Patients With Gastrointestinal Stromal Tumors (GIST) Resistant or Intolerant to Imatinib and or to 2nd Line Tyrosine Kinase (TK) Inhibitors, NCT00633295LINK HERE for details.  This trial is being conducted in Israel.

Nilotinib Pharmacokinetics (PK) in Gastrointestinal Stromal Tumor (GIST), NCT00976612: LINK HERE for details of this study being conducted in South Korea.

 

Links for More Information

For information on this drug from manufacturer Novartis, link to these sites:

www.tasigna.com
(For Non U.S. Health Care Professionals Only)

www.us.tasigna.com
(For U.S. Residents Only)
 

Link for AMN107 nilotinib medical papers in PubMed



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