Imatinib Mesylate (Glivec) as Maintenance Therapy After Cytogenetic Response With Nilotinib (AMN107, Tasigna) First Line in Newly Diagnosed Chronic Myelogenous Leukemia

Condition(s) targeted: Chronic Myelogenous Leukemia

Intervention: Nilotinib (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: American University of Beirut Medical Center

Overall contact:
Ali Bazarbachi, MD, PhD, Phone: 9613612434, Email: bazarbac@aub.edu.lb

The results of the International Randomized Study of Interferon and STI571 (IRIS) trial indicate that in patients with chronic phase CML treated with first line imatinib, achievement of a complete or partial cytogenetic response (CCyR or PCyR) at 12 months is associated with a significantly better progression-free survival (PFS).

Second generation tyrosine kinase inhibitors such as nilotinib can overcome imatinib resistance because of greater potency to bind to BCR-ABL. Recent results indicate that, in patients with previously untreated chronic phase CML, nilotinib results in a faster and higher rate of CCyR or PCyR than imatinib. However, nilotinib use is associated with diet restriction and much higher financial cost.

The primary objective of this study is to evaluate the ability of imatinib to maintain a complete cytogenetic response (CcyR) in patients who achieved a CCyR after 12 months of first-line treatment with nilotinib.

Official title: Imatinib Mesylate (Glivec) as Maintenance Therapy After Cytogenetic Response With Nilotinib (AMN107, Tasigna) First Line in Newly Diagnosed Chronic Myelogenous Leukemia

Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: To test the ability of imatinib to maintain the cytogenetic response in patients who achieved complete cytogenetic response (CCyR) at 12 months with first line nilotinib.

Secondary outcome:

To assess the effects of nilotinib followed by imatinib on molecular response

To assess the effects of nilotinib followed by imatinib on BCR-ABL mutations

Detailed description: Imatinib mesylate selectively targets the causative BCR-ABL oncogene in CML. The results of the IRIS trial indicate that in patients with chronic phase CML treated with first line imatinib, achievement of a complete or partial cytogenetic response (CCyR or PCyR) at 12 months is associated with a significantly better progression free survival (PFS).

Second generation tyrosine kinase inhibitors such as nilotinib can overcome imatinib resistance because of greater potency to bind to BCR-ABL. Recent results indicate that, in patients with previously untreated chronic phase CML, nilotinib results in a faster and higher rate of CCyR or PCyR than imatinib. However, nilotinib use is associated with diet restriction and much higher financial cost. Hence, an appealing strategy is to achieve the high rate of CCyR with first line nilotinib and then to maintain this response with long term imatinib which is user friendly and cost-effective.

The primary objective is to test the ability of imatinib to maintain the cytogenetic response in patients who achieved CCyR or PCyR at 12 months with first line nilotinib. The secondary aims are to assess the effects of this strategy on molecular response, BCR-ABL mutations, and CML progenitors.

Minimum age: 18 Years. Maximum age: 75 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Newly diagnosed untreated Philadelphia chromosome-positive CML (use of hydroxyurea for < 3 months is allowed) in chronic phase defined with the following criteria:

- < 15% blasts in peripheral blood and bone marrow

- < 30% blasts plus promyelocytes in peripheral blood and bone marrow

- < 20% basophils in the peripheral blood

- ≥ 100 x 109/L (≥ 100,000/mm3) platelets

- No evidence of extramedullary leukemic involvement, with the exception of liver

and spleen

2. Males or females ≥18 years of age

3. WHO Performance Status of ≤ 2

4. Patients must have the following laboratory values:

- Potassium within normal limits or corrected to within normal limits with

supplements prior to the first dose of study medication

- Total calcium (corrected for serum albumin) within normal limits or correctable

with supplements

- Magnesium within normal limits or corrected to within normal limits with

supplements prior to the first dose of study medication

- Phosphorus ≥ lower limit of normal (LLN) or correctable with supplements

- ALT and AST ≤ 2. 5 x upper limit of normal (ULN) or ≤ 5. 0 x ULN if considered due

to tumor

- Alkaline phosphatase ≤ 2. 5 x ULN unless considered due to tumor

- Serum bilirubin ≤ 1. 5 x ULN

- Serum creatinine ≤ 1. 5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min

- Serum amylase ≤ 1. 5 x ULN and serum lipase ≤ 1. 5 x ULN

5. Written signed and dated informed consent prior to any study procedures being performed

Exclusion Criteria:

1. Cytopathologically confirmed central nervous system (CNS) infiltration (in absence of suspicion of CNS involvement, lumbar puncture is not required).

2. Impaired cardiac function, including any one of the following:

- Left ventricle ejection fraction (LVEF) < 45% or below the institutional lower

limit of the normal range (whichever is higher) as determined by MUGA scan or echocardiogram

- Complete left bundle branch block

- Use of a cardiac pacemaker

- ST depression of > 1mm in 2 or more leads and/or T wave inversions in 2 or more

contiguous leads

- Congenital long QT syndrome

- History of or presence of significant ventricular or atrial tachyarrhythmias

- Clinically significant resting bradycardia (< 50 beats per minute)

- QTc > 450 msec on screening ECG (using the QTcF formula)

- Right bundle branch block plus left anterior hemiblock, bifascicular block

- Myocardial infarction within 12 months prior to starting nilotinib

- Unstable angina diagnosed or treated during the past 12 months

- Other clinically significant heart disease (e. g., congestive heart failure,

uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)

3. Use of therapeutic coumarin derivatives (i. e., warfarin, acenocoumarol, phenprocoumon) up to the day before study drug administration

4. Acute or chronic liver or renal disease considered unrelated to tumor such as active Hepatitis A, B, or C.

5. Other concurrent severe and/or uncontrolled medical conditions (e. g., uncontrolled diabetes, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol

6. Patients who are currently receiving treatment with any of the medications that have the potential to prolong the QT interval.

7. Patients who have received any investigational drug ≤ 4 weeks or investigational cytotoxic agent within 1 week (or who are within 5 half-lives of a previous investigational cytotoxic agent) prior to starting study drug or who have not recovered from side effects of such therapy

8. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation < 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy

9. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy

10. Known diagnosis of human deficiency virus (HIV) infection (HIV testing is not mandatory)

11. Patient with a history of another malignancy that is currently clinically significant or currently requires active intervention.

12. Patients who are pregnant or breast feeding, or adults of reproductive potential not employing an effective method of birth control (women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of nilotinib). Post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective method of birth control throughout the study and for 3 months following discontinuation of study drug.

13. Patients unwilling or unable to comply with the protocol

Ali Bazarbachi, MD, PhD, Phone: 9613612434, Email: bazarbac@aub.edu.lb

American University of Beirut Medical Center, Beirut, Lebanon; Recruiting
Ali Bazarbachi, MD, PhD, Phone: 9613612434, Email: bazarbac@aub.edu.lb
Ali Bazarbachi, MD, PhD, Principal Investigator

Related publications:

Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ, Lydon NB. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther. 2000 Oct;295(1):139-45.

Rosti G, Palandri F, Castagnetti F, Breccia M, Levato L, Gugliotta G, Capucci A, Cedrone M, Fava C, Intermesoli T, Cambrin GR, Stagno F, Tiribelli M, Amabile M, Luatti S, Poerio A, Soverini S, Testoni N, Martinelli G, Alimena G, Pane F, Saglio G, Baccarani M; GIMEMA CML Working Party. Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood. 2009 Dec 3;114(24):4933-8. Epub 2009 Oct 12.

Cortes JE, Jones D, O'Brien S, Jabbour E, Konopleva M, Ferrajoli A, Kadia T, Borthakur G, Stigliano D, Shan J, Kantarjian H. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol. 2010 Jan 20;28(3):392-7. Epub 2009 Dec 14.

Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA; IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006 Dec 7;355(23):2408-17.

Starting date: August 2010
Last updated: March 5, 2012