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Open Label Phase II Randomized Trial of Tasigna (Nilotinib) 400 mg Twice Daily Alone or in Combination With Gleevec (Imatinib Mesylate) 400 mg Daily for Patients With Advanced GIST That Have Progressed on High Dose Imatinib

Phase 2
18 Years
Not Enrolling
GIST, Metastatic Disease

Thank you

Trial Information

Open Label Phase II Randomized Trial of Tasigna (Nilotinib) 400 mg Twice Daily Alone or in Combination With Gleevec (Imatinib Mesylate) 400 mg Daily for Patients With Advanced GIST That Have Progressed on High Dose Imatinib

Resistance to imatinib does develop and represents a major clinical challenge. Mechanisms
implicated in imatinib resistance include: target resistance due to new KIT or PDGFRA
mutations or over expression of the KIT protein; target modulation due to activation of an
alternate receptor tyrosine kinase protein with loss of KIT oncoprotein expression;
functional resistance due to KIT or PDGFRA activation without a secondary mutation; and
alterations in imatinib uptake by P-glycoprotein.

This study seeks to test nilotinib alone and nilotinib in combination with imatinib in
patients that have progressed on imatinib.

Nilotinib is a new synthetic second-generation inhibitor of the BCR-ABL tyrosine kinase that
competes for the ATP-bindings sites of BCR-ABL. A completed phase I trial assessed the
activity of nilotinib alone and in combination with imatinib in patients that have
progressed on imatinib in a population of patients with imatinib refractory and intolerant
patients. There were rare responses, but stable disease was observed in grater than 50% of

This study is aiming to treat patients with advanced or metastatic GIST who have disease
progression on imatinib dose escalated up to 600 mg or greater. The rationale for
exploring Nilotinib in this setting is to determine if it has therapeutic efficacy, with
potentially less toxicity than the current standard of care for second line therapy. In
addition, since it is not uncommon to see progression of some metastatic GIST lesions on
imatinib, while others remain controlled, adding nilotinib may treat the progressing lesions
while imatinib continues to control the areas without disease progression.

Inclusion Criteria:

- histologically or cytologically confirmed GIST.

- advanced/metastatic GIST.

- experienced failure of prior treatment with imatinib 600-800 mg per day defined by
progression of disease according to RECIST criteria during treatment. Radiographic
evidence of PD on imatinib must be confirmed by the Investigator prior to enrollment.

- May have focal progression of disease including a new enhancing nodular focus within
a pre-existing tumor nodule; such a nodule should be considered measurable by
standard RECIST criteria.

- measurable disease, defined as at least one lesion that can be accurately measured in
at least one dimension (longest diameter to be recorded) as >20 mm with conventional
techniques or as >10 mm with spiral CT scan.

- At least 4 weeks since prior therapy with imatinib & resolution of all acute toxic
effects of the prior therapy or surgical procedure to grade ≤1.

- Age >18 years.

- ECOG performance status 0-2.

- Normal organ and marrow function as defined below:

- ANC >1,500/mcL

- Platelets >100,000/mcL

- Total bilirubin < or equal to 1.5 X ULN

- AST(SGOT)/ALT(SGPT) < or equal to 2.5 X ULN OR < or equal to 5.0 X ULN if
considered due to tumor

- Amylase/Lipase < or equal to 1.5 X ULN

- Alkaline Phosphatase < or equal to 2.5 X ULN or related.

- Potassium, magnesium, calcium, phosphorus, creatinine WNL prior to randomization

- OR

- Creatinine clearance of > 50 calculated by cockroft-gault formula

- WOCBP must have negative pregnancy test within 7 days of first treatment and use
appropriate contraception.

- Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

- Have received nilotinib or additional tyrosine kinase inhibitors or additional
targeted therapies (except for imatinib).

- May not be receiving any other investigational agents within 4 weeks before

- Prior or concomitant malignancies (with a relapse in the last 5 years or requiring
active treatment) other than GIST and with exception of previous or concomitant basal
cell skin, previous cervical carcinoma in situ.

- Impaired cardiac function, including any one of the following:

Complete left bundle branch block. Ventricular paced cardiac pacemaker. Congenital long QT
syndrome or family history of long QT syndrome. History of or presence of symptomatic
ventricular or atrial tachyarrhythmias. Clinically significant resting bradycardia (< 50
beats per minute). QTc > 480 msec on screening ECG (using the QTcF formula). If QTc > 480
msec and electrolytes are not within normal ranges (electrolytes should be corrected and
then the patient rescreened for QTc).

Right bundle branch block plus left anterior hemiblock, bifascicular block. Myocardial
infarction within 12 months prior to Visit 1. Other clinically significant heart diseases
(e.g., unstable angina, congestive heart failure or uncontrolled hypertension).

Severe and/or uncontrolled concurrent medical disease that could cause unacceptable safety
risks or compromise compliance with protocol e.g. impairment of GI function, or GI disease
that may significantly alter absorption of study drugs; uncontrolled diabetes; active
infections; psychiatric illness/social situation that would limit compliance with study

- Inability to remain laying down in PET scanner for up to one hour.

- Use of any medications that prolong the QT interval and CYP3A4 inhibitors if
treatment cannot be either safely discontinued or switched to a different medication
prior to starting study drug administration.

- Major surgery ≤ 2 weeks prior to Visit 1 or who have not recovered from side effects
of such surgery.

- Known history of noncompliance to medical regimens or inability/unwillingness to
return for scheduled visits, patients who are pregnant or breast feeding, patients
unwilling or unable to comply with the requirements for the protocol.

- Known chronic liver disease (i.e., chronic active, hepatitis, and cirrhosis).

- Known diagnosis of HIV, currently taking combination antiretroviral therapy.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression free survival

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Margaret von Mehren, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fox Chase Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

February 2009

Completion Date:

March 2012

Related Keywords:

  • GIST
  • Metastatic Disease
  • Imatinib Resistance
  • GIST
  • Advanced Disease
  • Nilotinib
  • Neoplasm Metastasis
  • Gastrointestinal Stromal Tumors



Wake Forest University Winston-Salem, North Carolina  27103
Fox Chase Cancer Center Philadelphia, Pennsylvania  19111
Siteman Cancer Center, Washington University School of Mediciine St Louis, Missouri  63110