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Randomized ph Lll Study of Imatinib Dose Optimization vs Nilotinib in CML Patients With Suboptimal Response to Imatinib

Information source: Novartis
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Chronic Myelogenous Leukemia

Intervention: nilotinib (Drug); imatinib (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Novartis Pharmaceuticals

Official(s) and/or principal investigator(s):
Novartis Pharmaceuticals, Study Director, Affiliation: Novartis Pharmaceuticals

Summary

There is no available data on the clinical benefit of dose escalation for patients with suboptimal response to imatinib, and patients may still improve their response with continuation of therapy at the standard dose as shown in the IRIS trial after 5 years of follow-up. However, there is no data yet regarding the potential benefit of using nilotinib in the group of patients with suboptimal response. In this study, the efficacy of nilotinib 400mg BID will be compared to imatinib 600mg QD.

Clinical Details

Official title: A Randomized Phase Lll Study of Imatinib Dose Optimization Compared With Nilotinib in Patients With Chronic Myelogenous Leukemia and Suboptimal Response to Standard-dose Imatinib

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

Primary outcome: to determine the comparative efficacy between imatinib dose escalation and nilotinib, in terms of CCyR) after 6 months of treatment, for patients with CML in chronic phase with suboptimal response to imatinib standard dose

Secondary outcome:

to compare the rate of major molecular response (MMR) between 2 arms at 12 months

to evaluate safety and tolerability of imatinib 600mg/daily and nilotinib 400mg twice a day

to evaluate the rate of CCyR at 12, 18 and 24 months on study

time to CCyR

duration of CCyR

Progression-Free Survival

Event-Free Survival (EFS)

Overall survival (OS)

Detailed description: The comparative efficacy between imatinib dose escalation (600 mg QD) and nilotinib (400 mg BID), in terms of CCyR after 6 months, for patients with CML in chronic phase with suboptimal response to imatinib standard dose will be determined.

Eligibility

Minimum age: 16 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion criteria: 1. Male or female ≥ 18 years old; 2. ECOG of 0, 1, or 2; 3. Ph+ CML in CP defined as:

- <15% blasts in peripheral blood or bone marrow;

- <30% blasts + promyelocytes in peripheral blood or bone marrow;

- <20% basophils in the peripheral blood;

•≥100x109/L (≥ 100,000/mm3) platelets;

- no evidence of extramedullary leukemia involvement, with the exception of

hepatosplenomegaly; 4. SoR to 400 mg imatinib, defined as (min of 20 metaphases):

- No cytogenetic response at ≥ 3 to <6 months (> 95% Ph+ metaphases);or

- No PCyR at ≥ 6 to <12 months (36 to 95% Ph+ metaphases on bone marrow); or

- No CCyR at ≥ 12 to <18 months (1 to 35% Ph+ metaphases on bone marrow);

Confirmation of SoR by FISH is allowed if BMK is done outside the screening window up to 4 wks. 5. 400mg/daily imatinib (no higher doses) for at least 3months but no longer than 18 months; 6. Previous use of IFN, taken prior to imatinib treatment, is allowed at a maximum of 90 days unless reason for switch from IFN to imatinib was intolerance. 7. Parameters must be present:

- Creatinine <2. 0 X ULN

- Total bilirubin <1. 5 X ULN (< 3. 0 X ULN if related to disease);

- SGOT and SGPT < 2. 5 X ULN;

- Serum lipase ≤1. 5 X ULN;

- Alkaline phosphatase ≤2. 5 X ULN

- Serum potassium, phosphorus, magnesium and calcium ≥ LLN or corrected to WNL

with supplements prior to first dose of study drug; 8. Written informed consent prior to any study procedures being performed. Exclusion criteria: 1. Prior accelerated phase including clonal evolution or blast crisis CML; 2. Prior therapy with imatinib in combination with any other CML drug other than Hydroxyurea and/or Anagrelide; 4. Imatinib therapy started more than 12 months after the date of the original diagnosis; 5. Unable to tolerate imatinib at 400mg; 6. Previous treatment with any other tyrosine kinase inhibitor except Glivec and/or CML therapy other than IFN, hydroxyurea, and /or anagrelide; 7. Myelotoxicity ≥ Grade 2 present at the time of randomization, 8. Previously documented T315I mutations; 9. Impaired cardiac function including one of these:

- Long QT syndrome or family history of long QT syndrome

- Clinically significant resting brachycardia (<50 bpm)

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

electrolytes are not with normal ranges, electrolytes should be corrected and then the patient rescreened for QTc to certify QTc <450 msec;

- Myocardial infarction ≤ 12 months prior to the first dose of study drug;

- Other clinically significant heart disease (e. g., CHF, uncontrolled hypertension,

unstable angina, significant ventricular or atrial tachyarrhythmias) 10. Impairment of GI function or disease that may significantly alter the absorption of study drug; 11. Treated with strong CYP3A4 inhibitors that cannot be either discontinued or switched to a different medication prior to starting study drug; 12. Currently receiving treatment with 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; 13. History of previous acute pancreatitis within one year of study entry or medical history of chronic pancreatitis; 14. Known cytopathologically confirmed CNS 15. Women who are pregnant, breast feeding or of a childbearing potential without a negative urine pregnancy test at screening. Female patients of childbearing potential unwilling to use effective contraceptive precautions throughout the trial and for 3 months post trial end. Post-menopausal women must be ammenorrheic for at least 12 months to be considered of non-childbearing potential; 16. History of another primary malignancy that is currently clinically significant or currently requires active intervention; 17. Any other clinically significant medical or surgical condition which, according to investigators' discretion, should preclude participation; 18. Use of investigational agent within 28 days prior to enrollment; 19. Patients unwilling or unable to comply with the protocol.

Locations and Contacts

Novartis Investigative Site, Beijing 100044, China

Novartis Investigative Site, Fuzhou 350001, China

Novartis Investigative Site, Shanghai 200025, China

Novartis Investigative Site, Monteria, Colombia

Novartis Investigative Site, Berlin 13353, Germany

Novartis Investigative Site, Guatemala City 01010, Guatemala

Novartis Investigative Site, Ahmedabad 380016, India

Novartis Investigative Site, Mumbai 400 020 014, India

Novartis Investigative Site, Mumbai 400 012, India

Novartis Investigative Site, New Delhi 110 029, India

Novartis Investigative Site, Wroclaw 50-367, Poland

Novartis Investigative Site, Ekaterinburg 620102, Russian Federation

Novartis Investigative Site, Krasnoyarsk 680022, Russian Federation

Novartis Investigative Site, Moscow 125167, Russian Federation

Novartis Investigative Site, Moscow 129110, Russian Federation

Novartis Investigative Site, N.Novgorod 603126, Russian Federation

Novartis Investigative Site, Perm 614068, Russian Federation

Novartis Investigative Site, Rostov-on-Don 344090, Russian Federation

Novartis Investigative Site, Saint-Petersburg 197341, Russian Federation

Novartis Investigative Site, St Petersburg 191024, Russian Federation

Novartis Investigative Site, Volgograd 400138, Russian Federation

Novartis Investigative Site, Hyderabad, Andhra Pradesh 500018, India

Novartis Investigative Site, Caba, Buenos Aires C1221ADC, Argentina

Novartis Investigative Site, Caba, Buenos Aires C1426ANZ, Argentina

Novartis Investigative Site, La Plata, Buenos Aires B1900AWT, Argentina

Novartis Investigative Site, Bogota, Cundinamarca, Colombia

Novartis Investigative Site, Caracas, Distrito Capital 1010, Venezuela

Novartis Investigative Site, Mexico, Distrito Federal 06726, Mexico

Novartis Investigative Site, México, Distrito Federal 02990, Mexico

Novartis Investigative Site, México, Distrito Federal 06720, Mexico

Novartis Investigative Site, México, Distrito Federal 14080, Mexico

Novartis Investigative Site, Maracaibo, Estado Zulia 4004, Venezuela

Novartis Investigative Site, Zapopan, Jalisco 45170, Mexico

Novartis Investigative Site, Nanjing, Jiangsu 210029, China

Novartis Investigative Site, Bangalore, Karnataka 560 095, India

Novartis Investigative Site, Belo Horizonte, MG 30130-100, Brazil

Novartis Investigative Site, Cuiaba, MG 78025-000, Brazil

Novartis Investigative Site, Monterrey, Nuevo León 64460, Mexico

Novartis Investigative Site, Curitiba, PR 80060-900, Brazil

Novartis Investigative Site, Londrina, PR 86015-520, Brazil

Novartis Investigative Site, Panama City, Panamá, Panama

Novartis Investigative Site, Rio de Janeiro, RJ 20211-030, Brazil

Novartis Investigative Site, Porto Alegre, RS 91350-200, Brazil

Novartis Investigative Site, Florianopolis, SC 88034-000, Brazil

Novartis Investigative Site, Campinas, SP 13083-970, Brazil

Novartis Investigative Site, Jaú, SP 17210-080, Brazil

Novartis Investigative Site, Sao Paulo, SP 05403-000, Brazil

Novartis Investigative Site, São Paulo, SP 01224-000, Brazil

Novartis Investigative Site, São Paulo, SP 05651-901, Brazil

Novartis Investigative Site, São Paulo, SP 08270-070, Brazil

Novartis Investigative Site, Chengdu, Sichuan 610041, China

Novartis Investigative Site, Vellore, Tamil Nadu 632004, India

Novartis Investigative Site, Tianjin, Tianjin 300020, China

Novartis Investigative Site, Rio Negro, Viedma 8500, Argentina

Additional Information

Starting date: May 2009
Last updated: June 3, 2015

Page last updated: August 23, 2015

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