Clinical trial NCT00802841: Randomized Phase Lll Study of Imatinib Dose Optimization vs Nilotinib in CML Patients With Suboptimal Response to Imatinib
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Myelogenous Leukemia
Keywords: Chronic
Myelogenous
Leukemia
CML
Chronic Phase
Suboptimal Response
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2008-12-05
Enrollment: 191
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Percentage of Participants With Complete Cytogenetic Response (CCyR)
timeFrame: 6 months
Secondary outcomes:
measure: Percentage of Participants With Major Molecular Response (MMR)
timeFrame: 12 and 24 months
measure: Percentage of Participants With CCyr
timeFrame: 12 and 24 months
measure: Time to CCyR
timeFrame: 24 months
measure: Duration of CCyR
timeFrame: 24 months
measure: Progression-Free Survival (PFS)
timeFrame: 24 months
measure: Event-Free Survival (EFS)
timeFrame: 24 months
measure: Overall Survival (OS)
timeFrame: 24 months
Other outcomes:
Locations:
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: La Plata
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Rio Negro
country: Argentina
facility: Novartis Investigative Site
state: Viedma
city: Belo Horizonte
country: Brazil
facility: Novartis Investigative Site
state: MG
city: Cuiaba
country: Brazil
facility: Novartis Investigative Site
state: MG
city: Curitiba
country: Brazil
facility: Novartis Investigative Site
state: PR
city: Londrina
country: Brazil
facility: Novartis Investigative Site
state: PR
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Florianopolis
country: Brazil
facility: Novartis Investigative Site
state: SC
city: Campinas
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Jaú
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: São Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: São Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: São Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Tianjin
country: China
facility: Novartis Investigative Site
state: Tianjin
city: Beijing
country: China
facility: Novartis Investigative Site
city: Fuzhou
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Bogota
country: Colombia
facility: Novartis Investigative Site
state: Cundinamarca
city: Monteria
country: Colombia
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Guatemala City
country: Guatemala
facility: Novartis Investigative Site
city: Hyderabad
country: India
facility: Novartis Investigative Site
state: Andhra Pradesh
city: Bangalore
country: India
facility: Novartis Investigative Site
state: Karnataka
city: Vellore
country: India
facility: Novartis Investigative Site
state: Tamil Nadu
city: Ahmedabad
country: India
facility: Novartis Investigative Site
city: Mumbai 400 020
country: India
facility: Novartis Investigative Site
city: Mumbai
country: India
facility: Novartis Investigative Site
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Mexico
country: Mexico
facility: Novartis Investigative Site
state: Distrito Federal
city: México
country: Mexico
facility: Novartis Investigative Site
state: Distrito Federal
city: México
country: Mexico
facility: Novartis Investigative Site
state: Distrito Federal
city: México
country: Mexico
facility: Novartis Investigative Site
state: Distrito Federal
city: Zapopan
country: Mexico
facility: Novartis Investigative Site
state: Jalisco
city: Monterrey
country: Mexico
facility: Novartis Investigative Site
state: Nuevo León
city: Panama City
country: Panama
facility: Novartis Investigative Site
state: Panamá
city: Kraków
country: Poland
facility: Novartis Investigative Site
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Ekaterinburg
country: Russian Federation
facility: Novartis Investigative Site
city: Krasnoyarsk
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: N.Novgorod
country: Russian Federation
facility: Novartis Investigative Site
city: Perm
country: Russian Federation
facility: Novartis Investigative Site
city: Rostov-on-Don
country: Russian Federation
facility: Novartis Investigative Site
city: Saint-Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Volgograd
country: Russian Federation
facility: Novartis Investigative Site
city: Caracas
country: Venezuela
facility: Novartis Investigative Site
state: Distrito Capital
city: Maracaibo
country: Venezuela
facility: Novartis Investigative Site
state: Estado Zulia
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.