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

NCT00802841 | Completed Phase 3 Results DMC

• 2 other identifiers: CAMN107A24042008-007054-35
• Study Type: interventional
• Target: 191
• Locations: 12 countries
• Sites: 56

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.

Conditions

Chronic Myelogenous Leukemia

Keywords

Chronic; Myelogenous; Leukemia; CML; Chronic Phase; Suboptimal Response

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Complete Cytogenetic Response (CCyR)

  CCyR was assessed from bone marrow samples. CCyr was defined as having 0% Philadelphia positive (Ph+) chromosome metaphases in bone marrow.

  6 months

Secondary Outcomes (7)

• Percentage of Participants With Major Molecular Response (MMR)

  12 and 24 months

• Percentage of Participants With CCyr

  12 and 24 months

• Time to CCyR

  24 months

• Duration of CCyR

  24 months

• Progression-Free Survival (PFS)

  24 months

Study Arms (2)

Nilotinib

EXPERIMENTAL

Participants received 400 mg nilotinib twice daily (BID).

Drug: nilotinib

Imatinib

ACTIVE COMPARATOR

Participants received 600 mg imatinib once daily (QD).

Drug: imatinib

Interventions

nilotinib DRUG

Supplied as 200 mg tablets

Also known as: Tasigna

Nilotinib

imatinib DRUG

Supplied as 100 mg and 400 mg tablets

Also known as: Gleevec/Glivec

Imatinib

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female ≥ 18 years old;
• ECOG of 0, 1, or 2;
• 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;
• 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.
• mg/daily imatinib (no higher doses) for at least 3months but no longer than 18 months;
• 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.
• Parameters must be present:

You may not qualify if:

• Prior accelerated phase including clonal evolution or blast crisis CML;
• Prior therapy with imatinib in combination with any other CML drug other than Hydroxyurea and/or Anagrelide;
• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (56)

Novartis Investigative Site

Caba, Buenos Aires, C1221ADC, Argentina

Location

Novartis Investigative Site

Caba, Buenos Aires, C1426ANZ, Argentina

Location

Novartis Investigative Site

La Plata, Buenos Aires, B1900AWT, Argentina

Location

Novartis Investigative Site

Rio Negro, Viedma, 8500, Argentina

Location

Novartis Investigative Site

Belo Horizonte, Minas Gerais, 30130-100, Brazil

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Novartis Investigative Site

Cuiaba, Minas Gerais, 78025-000, Brazil

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Novartis Investigative Site

Curitiba, Paraná, 80060-900, Brazil

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Novartis Investigative Site

Londrina, Paraná, 86015-520, Brazil

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Novartis Investigative Site

Rio de Janeiro, Rio de Janeiro, 20211-030, Brazil

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Novartis Investigative Site

Rio de Janeiro, Rio de Janeiro, 20230-130, Brazil

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Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, 91350-200, Brazil

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Novartis Investigative Site

Florianópolis, Santa Catarina, 88034-000, Brazil

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Novartis Investigative Site

Campinas, São Paulo, 13083-970, Brazil

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Novartis Investigative Site

Jaú, São Paulo, 17210-080, Brazil

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Novartis Investigative Site

São Paulo, São Paulo, 01224-000, Brazil

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Novartis Investigative Site

São Paulo, São Paulo, 05403-000, Brazil

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Novartis Investigative Site

São Paulo, São Paulo, 05651-901, Brazil

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Novartis Investigative Site

São Paulo, São Paulo, 08270-070, Brazil

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Novartis Investigative Site

Nanjing, Jiangsu, 210029, China

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Novartis Investigative Site

Chengdu, Sichuan, 610041, China

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Novartis Investigative Site

Tianjin, Tianjin Municipality, 300020, China

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Novartis Investigative Site

Beijing, 100044, China

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Novartis Investigative Site

Fuzhou, 350001, China

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Novartis Investigative Site

Shanghai, 200025, China

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Novartis Investigative Site

Bogota, Cundinamarca, Colombia

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Novartis Investigative Site

Montería, Colombia

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Novartis Investigative Site

Berlin, 13353, Germany

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Novartis Investigative Site

Guatemala City, Departamento de Guatemala, 01010, Guatemala

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Novartis Investigative Site

Hyderabad, Andhra Pradesh, 500018, India

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Novartis Investigative Site

Bangalore, Karnataka, 560 095, India

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Novartis Investigative Site

Vellore, Tamil Nadu, 632004, India

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Novartis Investigative Site

Ahmedabad, 380016, India

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Novartis Investigative Site

Mumbai, 400 012, India

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Novartis Investigative Site

Mumbai 400 020, 014, India

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Novartis Investigative Site

New Delhi, 110 029, India

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Novartis Investigative Site

Zapopan, Jalisco, 45170, Mexico

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Novartis Investigative Site

Mexico City, Mexico City, 02990, Mexico

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Novartis Investigative Site

Mexico City, Mexico City, 06720, Mexico

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Novartis Investigative Site

Mexico City, Mexico City, 06726, Mexico

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Novartis Investigative Site

Mexico City, Mexico City, 14080, Mexico

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Novartis Investigative Site

Monterrey, Nuevo León, 64020, Mexico

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Novartis Investigative Site

Panama City, Provincia de Panamá, Panama

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Novartis Investigative Site

Krakow, 31-501, Poland

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Novartis Investigative Site

Wroclaw, 50-367, Poland

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Novartis Investigative Site

Krasnoyarsk, 680022, Russia

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Novartis Investigative Site

Moscow, 125167, Russia

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Novartis Investigative Site

Moscow, 129110, Russia

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Novartis Investigative Site

N.Novgorod, 603126, Russia

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Novartis Investigative Site

Perm, 614068, Russia

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Novartis Investigative Site

Rostov-on-Don, 344090, Russia

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Novartis Investigative Site

Saint Petersburg, 191024, Russia

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Novartis Investigative Site

Saint Petersburg, 197341, Russia

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Novartis Investigative Site

Volgograd, 400138, Russia

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Novartis Investigative Site

Yekaterinburg, 620102, Russia

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Novartis Investigative Site

Caracas, Distrito Federal, 1010, Venezuela

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Novartis Investigative Site

Maracaibo, Zulia, 4004, Venezuela

Location

Related Publications (1)

• 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.

  PMID: 27890073 DERIVED

MeSH Terms

Conditions

Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Bronchiolitis Obliterans Syndrome; Leukemia

Interventions

nilotinib; Imatinib Mesylate

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Results Point of Contact

• Title: Study Director
• Organization: Novartis

862-778-1873

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 3, 2008
• First Posted: December 5, 2008
• Study Start: May 1, 2009
• Primary Completion: July 1, 2014
• Study Completion: July 1, 2014
• Last Updated: November 16, 2015
• Results First Posted: November 16, 2015

Record last verified: 2015-10

Locations

BR (14); ME (6); IN (7); PA (1); PL (2); AR (4); DE (1); RU (10); GU (1); CN (6); VE (2); CO (2)