Glivec® (Imatinib Mesylate, STI571) in Monotherapy Versus Glivec®-Interferon Alpha in the Treatment of Chronic-Phase Chronic Myeloid Leukaemia

Chronic Myeloid Leukaemia Clinical Trial

Official title:

Randomised Multicentre Phase IV Study to Compare Glivec® (Imatinib Mesylate, STI571) in Monotherapy Versus Glivec® in Combination With Interferon Alpha at Low Doses in the Treatment of Newly-Diagnosed Chronic-Phase Chronic Myeloid Leukaemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00390897
• Other study ID #: LMC/PETHEMA
• Secondary ID: 03-0289
• Status: Completed
• Phase: Phase 4
• First received: October 20, 2006
• Last updated: November 26, 2008
• Start date: July 2003
• Est. completion date: December 2007

Study information

• Verified date: November 2008
• Source: PETHEMA Foundation
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

To compare the complete cytogenetic response rate in patients with newly-diagnosed chronic-phase chronic myeloid leukaemia treated with Glivec® alone or in combination with interferon at low doses

Description:

Open, prospective, multicentre, phase IV, comparative and randomised study

Recruitment information / eligibility

• Status: Completed
• Enrollment: 360
• Est. completion date: December 2007
• Est. primary completion date: October 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 72 Years

Eligibility

Inclusion Criteria:

1. Patients with newly-diagnosed chronic-phase Ph-positive chronic myeloid leukaemia (maximum 3 months as of the diagnosis of the disease, with the date of the cytogenetic study regarded as such).

2. Age between 18 and 72 years (both included).

3. Performance status < 2 on the ECOG scale (see Annex 3).

4. Secure written or oral informed consent in the presence of a witness and consent for biological samples (annexes 5 and 6).

Exclusion Criteria:

1. Criteria of acceleration or blastic crisis (see Annex 7).

2. When there is a compatible family donor in patients aged under 40 years or a non-relative donor in patients aged under 30 years (in whom allogenic transplant is still regarded as first-line treatment), the possibility of performing an allogenic transplant as first therapeutic option should be considered. In any case, as this aspect is still a matter of debate, it is left up to each group to take the relevant decision depending on the institution's policy.

3. Administration of other treatments before inclusion in the protocol (a maximum of 3 months of monotherapy with hydroxyurea is permitted).

4. Altered hepatic or renal function (SGOT, SGPT, total bilirubin and creatinine > 1.5 times the upper limit of normality).

5. Uncontrolled diseases, such as thyroidal dysfunction, diabetes mellitus, angina pectoralis, serious heart failure (functional class III/IV of the New York Heart Association classification), neuropsychiatric infection or disease (see annex 15).

6. Positive serology for HIV.

7. Record of cancer in the last 5 years (barring basal cell skin carcinoma and cervical carcinoma in situ).

8. Pregnancy or breastfeeding

Study Design

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• Glivec

• Interferon

Locations

Country	Name	City	State
Spain	Hospital de Alcorcón	Alcorcón	Madrid
Spain	Hospital Ntra. Sra. Sonsoles	Avila
Spain	Hospital Clínic	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Sant pau	Barcelona
Spain	Hospital Universitario "Germans Trias i Pujol"	Barcelona
Spain	Hospital vall d'Hebrón	Barcelona
Spain	Institut Català d'oncología	Barcelona
Spain	Hospital San Pedro de Alcántara	Cáceres
Spain	Complejo Hospitalario Reina Sofía	Córdoba
Spain	Hospital Ruiz de Alda	Granada
Spain	Hospital Juan Ramón Jiménez	Huelva
Spain	Hospital Médico Quirúrgico Ciudad de Jaén	Jaen
Spain	Hospital general de Jerez de la Frontera	Jerez de la Frontera
Spain	Hospital Juan Canalejo	La Coruña
Spain	Hospital Arnau de Vilanova	Lleida
Spain	Clínica La Concepción	Madrid
Spain	Clínica Puerta de Hierro	Madrid
Spain	Hospital Clínico San Carlos de Madrid	Madrid
Spain	Hospital de Fuenlabrada	Madrid
Spain	Hospital Doce de Octubre	Madrid
Spain	Hospital Gregorio Marañón	Madrid
Spain	Hospital Ramón y Cajal	Madrid
Spain	Hospital Universitario Princcipe de Asturias	Madrid
Spain	. Hospital Clínico Universitario Virgen de la Victoria	Málaga
Spain	Hospital Carlos Haya	Málaga
Spain	Hospital de Mataró	Mataró	Barcelona
Spain	Hospital Universitario Morales Meseguer, Murcia	Murcia
Spain	Hospital comarcal de Valdeorras	O'Barco de Valdeorras
Spain	Hospital Central de Asturias	Oviedo	Asturias
Spain	Hospital del Río Carrión	Palencia
Spain	Hospital Son Dureta	Palma de Mallorca	Illes balears
Spain	Hospital Son Llatzer	Palma de Mallorca	Mallorca
Spain	Clínica Universitaria de Navarra	Pamplona	Navarra
Spain	Hospital de Navarra	Pamplona	Navarra
Spain	Corporació Sanitària Parc Taulí	Sabadell	Barcelona
Spain	Hospital Clínico Universitario de Salamanca	Salamanca
Spain	Hospital Universitario Marqués de Valdecilla	Santander
Spain	Hospital General	Segovia
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Spain	Hospital Joan XXIII	Tarragona
Spain	Hospital Universitario de Canarias	Tenerife	Canarias
Spain	Hospital Mútua de Terrassa	Terrassa	Barcelona
Spain	Hospital Verge de la Cinta	Tortosa	Tarragona
Spain	Hospital Clínico Universitario	Valencia
Spain	Hospital dr. Peset	Valencia
Spain	Hospital General Universitario	Valencia
Spain	Hospital Universitario la Fe	Valencia
Spain	Hospital Meixoeiro	Vigo
Spain	Hospital Xeral	Vigo
Spain	Hospital Virgen de la Concha	Zamora

Sponsors (1)

Lead Sponsor	Collaborator
PETHEMA Foundation

Country where clinical trial is conducted

Spain, 

References & Publications (20)

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Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990 Feb 16;247(4944):824-30. — View Citation

Deng M, Daley GQ. Expression of interferon consensus sequence binding protein induces potent immunity against BCR/ABL-induced leukemia. Blood. 2001 Jun 1;97(11):3491-7. — View Citation

Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001 Apr 5;344(14):1031-7. — View Citation

Goldman JM, Szydlo R, Horowitz MM, Gale RP, Ash RC, Atkinson K, Dicke KA, Gluckman E, Herzig RH, Marmont A, et al. Choice of pretransplant treatment and timing of transplants for chronic myelogenous leukemia in chronic phase. Blood. 1993 Oct 1;82(7):2235-8. — View Citation

Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J. Acute leukaemia in bcr/abl transgenic mice. Nature. 1990 Mar 15;344(6263):251-3. — View Citation

Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. N Engl J Med. 1994 Mar 24;330(12):820-5. — View Citation

Kano Y, Akutsu M, Tsunoda S, Mano H, Sato Y, Honma Y, Furukawa Y. In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents. Blood. 2001 Apr 1;97(7):1999-2007. — View Citation

Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M, Druker B, Goldman J, O'Brien SG, Russell N, Fischer T, Ottmann O, Cony-Makhoul P, Facon T, Stone R, Miller C, Tallman M, Brown R, Schuster M, Loughran T, Gratwohl A, Mandelli F, Saglio G, Lazzarino M, Russo D, Baccarani M, Morra E; International STI571 CML Study Group. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002 Feb 28;346(9):645-52. Erratum in: N Engl J Med 2002 Jun 13;346(24):1923. — View Citation

Kantarjian HM, Talpaz M, O'Brien S, Giles F, Garcia-Manero G, Faderl S, Thomas D, Shan J, Rios MB, Cortes J. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood. 2003 Jan 15;101(2):473-5. Epub 2002 Sep 12. — View Citation

Kontsioti F, Pappa V, Papasteriadis C, Economopulos T, Dervenoulas J, Papageorgiou E, Kalantzis D, Valsami S, Pappa M, Raptis S. In vitro effect of STI-571 in combination with A-interferon of the proliferation, differentiation and apoptosis of K562 cells. Hematol J 2002; suppl 1:980.

O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ; IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003 Mar 13;348(11):994-1004. — View Citation

O´Brien SG, Vallance SE, Craddock C, Holyoake TL, Goldman JM. PEGIntron and STI571 combination evaluation study (PISCES) in chronic phase chronic myeloid leukaemia. Blood 2001; suppl.:3512.

O´Dwyer ME, Mauro MJ, Aust S, Kuyl J, PaquetteR, Sawyers C, Druker BJ. Ongoing evaluation of the combination of imatinib mesylate (Glivectm) with low dose interferon-alpha for the treatment of chronic phase CML. Hematol J 2002; suppl. : 990

Rea D, Legros L, Raffoux E, Thomas X, Turlure P, Maury S, Dupriez B, Pigneux A, Choufi B, Reman O, Stéphane D, Royer B, Vigier M, Ojeda-Uribe M, Recher C, Dombret H, Huguet F, Rousselot P; Intergroupe Français des Leucémies Myéloïdes Chronique; Group for Research in Adult Acute Lymphoblastic Leukemia. High-dose imatinib mesylate combined with vincristine and dexamethasone (DIV regimen) as induction therapy in patients with resistant Philadelphia-positive acute lymphoblastic leukemia and lymphoid blast crisis of chronic myeloid leukemia. Leukemia. 2006 Mar;20(3):400-3. — View Citation

Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973 Jun 1;243(5405):290-3. — View Citation

RUDKIN CT, HUNGERFORD DA, NOWELL PC. DNA CONTENTS OF CHROMOSOME PH1 AND CHROMOSOME 21 IN HUMAN CHRONIC GRANULOCYTIC LEUKEMIA. Science. 1964 Jun 5;144(3623):1229-31. — View Citation

Savage DG, Antman KH. Imatinib mesylate--a new oral targeted therapy. N Engl J Med. 2002 Feb 28;346(9):683-93. Review. — View Citation

Thiesing JT, Ohno-Jones S, Kolibaba KS, Druker BJ. Efficacy of STI571, an abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against bcr-abl-positive cells. Blood. 2000 Nov 1;96(9):3195-9. — View Citation

Trabacchi E, Bassi S, Saglio G, Rege-cambrin G, Bonifazi F, De Vivo A, Testoni N, Martinelli G, Ruggeri D, Amabile M, Giannini B, Alberti D, Fincato GL, Tura S, Rosti G, Baccarani M. Pegylated recombinant interferon alfa 2b (PEGIntron) associated with imatinib mesylate (Glivec) in Ph chronic myeloid leukaemia (CML) in early chronic phase: a phase II study of the ICSG on CML. Hematol J 2002, suppl. :586

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The fundamental objective of this study is to compare the therapeutic efficacy of Glivec® given in monotherapy (providing for dose scaling according to the response obtained at different periods of time from the beginning) in combination with standard in
Primary	The median survival of patients with CML is close to 7 years.
Primary	One year and a half after diagnosis, the rate of progression to the acceleration phase and blastic crisis is very low (3.3%) in patients treated with Glivec® as first line.
Primary	With the treatments available hitherto, the achievement of a major cytogenetic response and above all cytogenetic response translates into a prolongation of survival.
Primary	Therefore, taking into account that the rate of complete cytogenetic responses to Glivec® in newly-diagnosed CML is 76% after 18 months of treatment (see table I), the fundamental objective of the study will be to compare the rate of complete cytogenetic
Secondary	The time until complete cytogenetic responses are obtained
Secondary	Rate of major cytogenetic responses
Secondary	Rate of molecular responses
Secondary	Time to the loss of cytogenetic, haematological or molecular response
Secondary	Time to the progression of the disease to the phases of acceleration and blastic crisis (analysed according to intention to treat)
Secondary	Survival (analysed according to intention to treat)
Secondary	Haematological and non haematological tolerance and safety

External Links

•   Pethema Foundation web
•   Spanish association of Haematology