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

Chronic Myelogenous Leukemia Clinical Trial

— LASOR  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00802841
• Other study ID #: CAMN107A2404
• Secondary ID: 2008-007054-35
• Status: Completed
• Phase: Phase 3
• First received: December 3, 2008
• Last updated: October 15, 2015
• Start date: May 2009
• Est. completion date: July 2014

Study information

• Verified date: October 2015
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationBrazil: Ministry of HealthMexico: Federal Commission for Protection Against Health RisksArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaPanama: Ministry of HealthColombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y AlimentosVenezuela : Ministerio del Poder Popular para la SaludGermany: Federal Institute for Drugs and Medical DevicesPoland: Ministry of HealthGuatemala: Departamento de Regulación de Productos Farmaceuticos y afinesPeru: Instituto Nacional de Salud (INS)Russia: Federal Health MinistryChina: Ministry of Health of The People's Republic of ChinaIndia: Drugs Controller General India
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 191
• Est. completion date: July 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years and older

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Chronic Myelogenous Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Drug:
• nilotinib
Supplied as 200 mg tablets
• imatinib
Supplied as 100 mg and 400 mg tablets

Locations

Country	Name	City	State
Argentina	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
Brazil	Novartis Investigative Site	Belo Horizonte	MG
Brazil	Novartis Investigative Site	Campinas	SP
Brazil	Novartis Investigative Site	Cuiaba	MG
Brazil	Novartis Investigative Site	Curitiba	PR
Brazil	Novartis Investigative Site	Florianopolis	SC
Brazil	Novartis Investigative Site	Jaú	SP
Brazil	Novartis Investigative Site	Londrina	PR
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Chengdu	Sichuan
China	Novartis Investigative Site	Fuzhou
China	Novartis Investigative Site	Nanjing	Jiangsu
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Tianjin	Tianjin
Colombia	Novartis Investigative Site	Bogota	Cundinamarca
Colombia	Novartis Investigative Site	Monteria
Germany	Novartis Investigative Site	Berlin
Guatemala	Novartis Investigative Site	Guatemala City
India	Novartis Investigative Site	Ahmedabad
India	Novartis Investigative Site	Bangalore	Karnataka
India	Novartis Investigative Site	Hyderabad	Andhra Pradesh
India	Novartis Investigative Site	Mumbai
India	Novartis Investigative Site	Mumbai 400 020
India	Novartis Investigative Site	New Delhi
India	Novartis Investigative Site	Vellore	Tamil Nadu
Mexico	Novartis Investigative Site	Mexico	Distrito Federal
Mexico	Novartis Investigative Site	México	Distrito Federal
Mexico	Novartis Investigative Site	México	Distrito Federal
Mexico	Novartis Investigative Site	México	Distrito Federal
Mexico	Novartis Investigative Site	Monterrey	Nuevo León
Mexico	Novartis Investigative Site	Zapopan	Jalisco
Panama	Novartis Investigative Site	Panama City	Panamá
Poland	Novartis Investigative Site	Kraków
Poland	Novartis Investigative Site	Wroclaw
Russian Federation	Novartis Investigative Site	Ekaterinburg
Russian Federation	Novartis Investigative Site	Krasnoyarsk
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	N.Novgorod
Russian Federation	Novartis Investigative Site	Perm
Russian Federation	Novartis Investigative Site	Rostov-on-Don
Russian Federation	Novartis Investigative Site	Saint-Petersburg
Russian Federation	Novartis Investigative Site	St Petersburg
Russian Federation	Novartis Investigative Site	Volgograd
Venezuela	Novartis Investigative Site	Caracas	Distrito Capital
Venezuela	Novartis Investigative Site	Maracaibo	Estado Zulia

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Argentina,  Brazil,  China,  Colombia,  Germany,  Guatemala,  India,  Mexico,  Panama,  Poland,  Russian Federation,  Venezuela, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Percentage of Participants With Major Molecular Response (MMR)	MMR was defined as having a fusion gene of the Bcr and Abl genes of (BCR-ACL) less than or equal to 0.1% on the International Scale (IS).	12 and 24 months	No
Secondary	Percentage of Participants With CCyr	CCyR was assessed from bone marrow samples. CCyr was defined as having 0% Philadelphia positive (Ph+) chromosome metaphases in bone marrow.	12 and 24 months	No
Secondary	Time to CCyR	Time to CCyR was defined as time from date of randomization to date of first documented CCyR.	24 months	No
Secondary	Duration of CCyR	Duration of CCyR was defined as time from the date of ransomization to the date of first loss of CCyR or death, whichever came first.	24 months	No
Secondary	Progression-Free Survival (PFS)	PFS was defined as the time from the date of randomization to the date of documented disease progression to accelerated phase or blast crisis (AP/BC), or death due to any cause.	24 months	No
Secondary	Event-Free Survival (EFS)	EFS was defined as the time from the date of randomization to the date of the first occurrence of any of the following: loss of Complete Hematological Response (CHR), loss of Partial Cytogenetic Response (PCyR), loss of CCyR, death on treatment or progression to AP/BC.	24 months	No
Secondary	Overall Survival (OS)	OS was defined as time from date of randomization to the date of the death.	24 months	No