Treatment of Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumors in First Line With Nilotinib (MACS0276)

• objective tumor response rate based on RECIST criteria (complete response (CR) and partial response PR) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• time to overall response (PR or CR) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• duration of response [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• progression free survival (PFS) during the first 6 months using RECIST criteria [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• overall survival (OS) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• safety and tolerability [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• population pharmacokinetics of Nilotinib [ Time Frame: 6 months ] [ Designated as safety issue: No ]

• objective tumor response rate based on RECIST criteria (complete response (CR) and partial response PR) [ Designated as safety issue: No ]
• time to overall response (PR or CR) [ Designated as safety issue: No ]
• duration of response [ Designated as safety issue: No ]
• progression free survival (PFS) during the first 6 months using RECIST criteria [ Designated as safety issue: No ]
• overall survival (OS) [ Designated as safety issue: No ]
• safety and tolerability [ Designated as safety issue: No ]
• population pharmacokinetics of Nilotinib [ Designated as safety issue: No ]

The purpose of this multicenter, single-arm, exact binomial single-stage, phase II trial is to evaluate the efficacy of Nilotinib in patients with unresectable or metastatic gastrointestinal stromal tumors

Inclusion Criteria:

• Age ≥18 years
• Histologically confirmed diagnosis of GIST that is unresectable and/or metastatic and therefore not amenable to surgery or combined modality with curative intent prior to or at Visit 1
• At least one measurable site of disease on CT/MRI scan at Visit 1, as defined by RECIST criteria (see Post Text Suppl 3 for details) The scans should be at maximum 2 weeks old. New scans are only required as baseline scans if they are older then approx. 2 weeks.
• WHO Performance Status of 0, 1 or 2

• Patients must have the following laboratory values (≥ LLN (lower limit of normal) or corrected to within normal limits with supplements prior to the first dose of study medication.):

  1. Potassium ≥ LLN,
  2. Magnesium ≥ LLN,
  3. Phosphorus ≥ LLN,
  4. Total calcium (corrected for serum albumin) ≥ LLN

• Patients must have normal organ, electrolyte, and marrow function as defined below:

  1. Absolute Neutrophil Count (ANC) ≥ 1.5x 109/L;
  2. Platelets ≥ 100 x 109/L;
  3. ALT and AST ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if considered due to tumor;
  4. Alkaline phosphatase ≤ 2.5 x ULN unless considered due to tumor;
  5. Serum bilirubin ≤ 1.5 x ULN;
  6. Serum lipase and amylase ≤ 1.5 x ULN;
  7. Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min. (calculated creatinine clearance using Cockroft formula is acceptable)
• Ability to understand and willingness to sign a written informed consent

Exclusion Criteria:

• Prior treatment with nilotinib
• Treatment with any cytotoxic and/or investigational cytotoxic drug ≤ 4 weeks (6 weeks for nitrosurea or mitomycin C) prior to Visit 1 with the exception of imatinib targeted therapy as an adjuvant therapy
• Prior or concomitant malignancies requiring active treatment other than GIST with the exception of previous or concomitant basal cell skin cancer, previous cervical carcinoma in situ

• Impaired cardiac function at including any one of the following:

  1. LVEF < 45% or below the institutional LLN range (whichever is higher) as determined by echocardiogram at Visit 1
  2. Complete left bundle branch block
  3. Use of a ventricular paced cardiac pacemaker
  4. Congenital long QT syndrome or family history of long QT syndrome
  5. History of or presence of significant ventricular or atrial tachyarrhythmias
  6. Clinically significant resting bradycardia (< 50 beats per minute)
  7. QTc > 450 msec on screening ECG (using the QTcF formula). If QTc > 450 msec and electrolytes are not within normal ranges (electrolytes should be corrected and then the patient rescreened for QTc.
  8. Right bundle branch block plus left anterior hemiblock, bifascicular block
  9. Myocardial infarction within 12 months prior to Visit 1
  10. Other clinically significant heart disease (e.g., unstable angina, congestive heart failure or uncontrolled hypertension,)
• Patients with severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol e.g. impairment of gastrointestinal (GI) function, or GI disease that may significantly alter the absorption of the study drugs, uncontrolled diabetes