A Phase II Study of Flumatinib Versus Imatinib to Treat Philadelphia Chromosome Positive Chronic Myelogenous Leukemia

It is an open-label, randomized, multi-center study. The efficacy and safety of two flumatinib doses, 400 mg once daily and 600 mg once daily, will be compared with imatinib 400 mg once daily in newly diagnosed (within 6 months) patients with Philadelphia chromosome-positive (Ph+) Chronic Myelogenous Leukemia in the chronic phase (CML-CP).

It is an open-label, randomized, multi-center study in comparison of Gleevec and flumatinib in newly diagnosed (within 6 months) CML patients who are Philadelphia chromosome-positive. One hundred and fifty adult patients will be randomized in 1:1:1 ratio. The planned doses are as follows: 400 mg QD (50 patients) of flumatinib, 600 mg QD (50 patients) of flumatinib, and 400 mg QD (50 patients) of imatinib. Flumatinib will be dosed, based on the food effect results, in fasting condition. Imatinib will be dosed with food per the package insert. The study consists of 2 phases: 6 months of core phase and 6 months of extension phase.

• Drug: flumatinib
  Flumatinib was supplied as 100 and 200 mg film-coated tablets for oral administration. Storage condition: 25°C, light proof, sealed.
  Other Name: HHGV678
• Drug: imatinib
  Imatinib was supplied as 100 mg film-coated tablets. Storage condition: 25°C (77°F). Protected from moisture.
  Other Name: Gleevec

• Experimental: flumatinib 400mg qd
  Intervention: Drug: flumatinib
• Experimental: flumatinib 600 mg qd
  Intervention: Drug: flumatinib
• Active Comparator: imatinib
  Intervention: Drug: imatinib

Inclusion Criteria:

1. Male or female patients ≥ 18 years and ≤ 75 years of age.
2. ECOG 0, 1, or 2.
3. Diagnosis of chronic myelogenous leukemia in chronic phase with confirmation of Philadelphia chromosome.
4. Chronic myelogenous leukemia in chronic phase patients within the first 6 months of diagnosis.

5. Adequate end organ function as defined by:

   1. Total bilirubin < 1.5 x ULN,
   2. SGOT and SGPT < 2.5 x ULN,
   3. Creatinine < 1.5 x ULN,
   4. Serum amylase and lipase ≤ 1.5 x ULN,
   5. Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related.

   And 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.
6. Signed informed consent.

Exclusion Criteria:

1. Previously documented T315I mutations.
2. Any medical treatment for CML prior to study entry with the exception of hydroxyurea and/or anagrelide. Treatment with tyrosine kinase inhibitor(s) prior to study entry is not allowed.
3. Treatment with other investigational agents (defined as not used in accordance with the approved indication ) within 4 weeks prior to randomization.
4. Major surgery within 4 weeks prior to randomization or who have not recovered from prior surgery.

5. Impaired cardiac function including any one of the following:

   1. History of unstable angina.
   2. History of clinically documented myocardial infarction (during the last 12 month).
   3. LVEF < 45% or below the institutional lower limit of the normal range (whichever is higher) as determined by locally read echocardiogram.
   4. Inability to determine the QT interval on ECG.
   5. Complete left bundle branch block.
   6. Use of a ventricular-paced pacemaker.
   7. Congenital long QT syndrome or a known family history of long QT syndrome.
   8. History of or presence of clinically significant ventricular, atrial tachyarrhythmias, or QTcF > 450 msec for male or 470 msec for female.
6. Patients with active, uncontrolled psychiatric disorders including: psychosis, major depression, and bipolar disorders.
7. Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection).
8. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery).
9. History of significant congenital or acquired bleeding disorder unrelated to cancer.
10. History of chronic pancreatitis or history of acute pancreatitis within 1 year of study entry.
11. Patients with another primary malignancy.
12. Acute or chronic uncontrolled liver or severe renal disease considered unrelated to disease.
13. Known to be allergic to the study drugs, including crude drug or adjuvant.
14. Patients actively receiving therapy with strong CYP3A4 inhibitors, strong CYP3A4 inducers or any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug.
15. Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test within 7 days prior to Day 1 of study and (d) female of childbearing potential unwilling to use contraceptive precautions throughout the trial (post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential).