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

NCT ID: NCT00802841

Last Updated: 2015-11-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 191 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-05-31
• Study Completion Date: 2014-07-31

Brief 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.

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.

Conditions

Chronic Myelogenous Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Nilotinib

Participants received 400 mg nilotinib twice daily (BID).

Group Type: EXPERIMENTAL

nilotinib

Intervention Type: DRUG

Supplied as 200 mg tablets

Imatinib

Participants received 600 mg imatinib once daily (QD).

Group Type: ACTIVE_COMPARATOR

imatinib

Intervention Type: DRUG

Supplied as 100 mg and 400 mg tablets

Interventions

nilotinib

Supplied as 200 mg tablets

Intervention Type: DRUG

imatinib

Supplied as 100 mg and 400 mg tablets

Intervention Type: DRUG

Other Intervention Names

Tasigna; Gleevec/Glivec

Eligibility 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.

• Minimum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Caba, Buenos Aires, Argentina

Novartis Investigative Site

Caba, Buenos Aires, Argentina

Novartis Investigative Site

La Plata, Buenos Aires, Argentina

Novartis Investigative Site

Rio Negro, Viedma, Argentina

Novartis Investigative Site

Belo Horizonte, Minas Gerais, Brazil

Novartis Investigative Site

Cuiaba, Minas Gerais, Brazil

Novartis Investigative Site

Curitiba, Paraná, Brazil

Novartis Investigative Site

Londrina, Paraná, Brazil

Novartis Investigative Site

Rio de Janeiro, Rio de Janeiro, Brazil

Novartis Investigative Site

Rio de Janeiro, Rio de Janeiro, Brazil

Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, Brazil

Novartis Investigative Site

Florianópolis, Santa Catarina, Brazil

Novartis Investigative Site

Campinas, São Paulo, Brazil

Novartis Investigative Site

Jaú, São Paulo, Brazil

Novartis Investigative Site

São Paulo, São Paulo, Brazil

Novartis Investigative Site

São Paulo, São Paulo, Brazil

Novartis Investigative Site

São Paulo, São Paulo, Brazil

Novartis Investigative Site

São Paulo, São Paulo, Brazil

Novartis Investigative Site

Nanjing, Jiangsu, China

Novartis Investigative Site

Chengdu, Sichuan, China

Novartis Investigative Site

Tianjin, Tianjin Municipality, China

Novartis Investigative Site

Beijing, , China

Novartis Investigative Site

Fuzhou, , China

Novartis Investigative Site

Shanghai, , China

Novartis Investigative Site

Bogota, Cundinamarca, Colombia

Novartis Investigative Site

Montería, , Colombia

Novartis Investigative Site

Berlin, , Germany

Novartis Investigative Site

Guatemala City, Departamento de Guatemala, Guatemala

Novartis Investigative Site

Hyderabad, Andhra Pradesh, India

Novartis Investigative Site

Bangalore, Karnataka, India

Novartis Investigative Site

Vellore, Tamil Nadu, India

Novartis Investigative Site

Ahmedabad, , India

Novartis Investigative Site

Mumbai, , India

Novartis Investigative Site

Mumbai 400 020, , India

Novartis Investigative Site

New Delhi, , India

Novartis Investigative Site

Zapopan, Jalisco, Mexico

Novartis Investigative Site

Mexico City, Mexico City, Mexico

Novartis Investigative Site

Mexico City, Mexico City, Mexico

Novartis Investigative Site

Mexico City, Mexico City, Mexico

Novartis Investigative Site

Mexico City, Mexico City, Mexico

Novartis Investigative Site

Monterrey, Nuevo León, Mexico

Novartis Investigative Site

Panama City, Provincia de Panamá, Panama

Novartis Investigative Site

Krakow, , Poland

Novartis Investigative Site

Wroclaw, , Poland

Novartis Investigative Site

Krasnoyarsk, , Russia

Novartis Investigative Site

Moscow, , Russia

Novartis Investigative Site

Moscow, , Russia

Novartis Investigative Site

N.Novgorod, , Russia

Novartis Investigative Site

Perm, , Russia

Novartis Investigative Site

Rostov-on-Don, , Russia

Novartis Investigative Site

Saint Petersburg, , Russia

Novartis Investigative Site

Saint Petersburg, , Russia

Novartis Investigative Site

Volgograd, , Russia

Novartis Investigative Site

Yekaterinburg, , Russia

Novartis Investigative Site

Caracas, Distrito Federal, Venezuela

Novartis Investigative Site

Maracaibo, Zulia, Venezuela

Countries

Argentina; Brazil; China; Colombia; Germany; Guatemala; India; Mexico; Panama; Poland; Russia; Venezuela

References

Cortes JE, De Souza CA, Ayala M, Lopez JL, Bullorsky E, Shah S, Huang X, Babu KG, Abdulkadyrov K, de Oliveira JSR, Shen ZX, Sacha T, Bendit I, Liang Z, Owugah T, Szczudlo T, Khanna S, Fellague-Chebra R, le Coutre PD. Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR): a randomised, open-label trial. Lancet Haematol. 2016 Dec;3(12):e581-e591. doi: 10.1016/S2352-3026(16)30167-3.

Reference Type: DERIVED

PMID: 27890073 (View on PubMed)

Other Identifiers

2008-007054-35

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CAMN107A2404

Identifier Type: -

Identifier Source: org_study_id