Clinical trial NCT01657604: TKI and Interferon Alpha Evaluation Initiated by the German Chronic Myeloid Leukemia Study Group - the TIGER Study
Official title: Treatment Optimization of Newly Diagnosed Ph/BCR-ABL Positive Patients With Chronic Myeloid Leukemia (CML) in Chronic Phase With Nilotinib vs. Nilotinib Plus Interferon Alpha Induction and Nilotinib or Interferon Alpha Maintenance Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Myeloid Leukemia
Keywords: CML
Tasigna
Nilotinib
Interferon
Lead sponsor: University of Jena
Sponsor class: OTHER
First posted: 2012-08-06
Enrollment: 717
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: Advances in Chronic Myeloid Leukemia (CML) therapy led to an expected survival prolongation of \> 20 years after diagnosis. So far, discontinuation of tyrosine kinase inhibitors led to recurrence of disease in the majority of patients. The trial aims to improve treatment strategies in CML by improving induction therapy and deescalating maintenance therapy using low dose IFN as inducer of immunosurveillance. The trial will provide important data on the duration of active therapy in CML patients. Considering the rapidly increasing prevalence of CML this is of individual but also socioeconomic importance.

Detailed description: Objectives

Primary:

* Evaluation of the major molecular response (MMR) rate at 18 months of nilotinib compared to nilotinib+pegylated Interferon alpha (IFN) in adult patients with newly diagnosed Ph/BCR-ABL CML in chronic phase.
* Evaluation of the feasibility to discontinue drug therapy in stable deep molecular response (MR4) after nilotinib versus IFN maintenance therapy.

Secondary:

* Evaluation of the efficacy and tolerability of IFN added to nilotinib 2x300 mg/day.
* Evaluation of the efficacy and tolerability of a maintenance therapy with nilotinib versus IFN after stable MMR after at least 24 months of nilotinib therapy.

Eligibility criteria: Inclusion Criteria:

* Male or female patients with diagnosis of CP-CML with cytogenetic confirmation of Ph chromosome \[t(9;22)(q34;q11)\]
* Ph negative cases or patients with variant translocations who are BCR-ABL positive in multiplex PCR (Cross, et al 1994) are eligible as well
* ECOG performance status of \< 2
* Pretreatment with hydroxyurea for 6 months and imatinib or nilotinib for a duration of up to 6 weeks is permitted
* Age ≥ 18 years old (no upper age limit given)
* Normal serum levels ≥ LLN (lower limit of normal) of potassium, magnesium, total calcium corrected for serum albumin, or corrected to within normal limits with supplements
* ASAT and ALAT ≤ 2.5 x ULN (upper limit of normal) or ≤ 5.0 x ULN if considered due to leukemia
* Alkaline phosphatase ≤ 2.5 x ULN unless considered due to leukemia
* Total bilirubin ≤ 1.5 x ULN, except known Mb. Gilbert
* Serum lipase and amylase ≤ 1.5 x ULN
* Serum creatinine ≤ 2 x ULN
* Written informed consent prior to any study procedures being performed

Exclusion Criteria:

* Known impaired cardiac function, including any of the following:

  * Left ventricular ejection fraction (LVEF) \< 45%
  * Congenital long QT syndrome
  * History of or presence of clinically significant ventricular or atrial tachyarrhythmias
* Clinically significant resting bradycardia (\< 50 beats per minute)
* QTc \> 450 msec on screening ECG. If QTc \> 450 ms and electrolytes are not within normal ranges before nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTc criterion
* Myocardial infarction within 12 months prior to starting therapy
* Other clinical significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)
* History of acute (i.e., within 1 year of starting study medication) or chronic pancreatitis
* Acute or chronic viral hepatitis with moderate or severe hepatic impairment (Child-Pugh scores \> 6), even if controlled
* Other concurrent uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol
* Impaired gastrointestinal function or disease that may alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting and diarrhea, malabsorption syndrome, small bowel resection or gastric by-pass surgery)
* Concomitant medications with potential QT prolongation
* Concomitant medications known to be strong inducers or inhibitors of the CYP450 isoenzyme CYP3A4
* Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
* Patients who are pregnant or breast feeding, or women of reproductive potential not employing an effective method of birth control. (Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to administration of nilotinib). Post menopausal women must be amenorrheic for at least 12 months in order to be considered of non-childbearing potential. Female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug
* Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)
* Active autoimmune disorder, including autoimmune hepatitis
* Known serious hypersensitivity reactions to peginterferon alfa-2b or interferon alfa-2b or drug excipients
* Known serious hypersensitivity reactions to nilotinib
* Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
* Patients unwilling or unable to comply with the protocol

Primary outcomes:
measure: MMR rate at 18 months of nilotinib monotherapy versus nilotinib+pegylated interferon alpha
timeFrame: at least 18 months after start of study treatment
measure: rate of continuous MMR after discontinuation of nilotinib versus pegylated interferon alpha
timeFrame: at least 12 months after stopping all therapy
Secondary outcomes:
measure: rate of CCyR and MMR
timeFrame: at 12, 18 and 24 months after start of treatment
measure: Time to CCyR, MMR, MR4 and MR4.5
timeFrame: date of randomization until time to endpoints or end of study duration (at least 36 months)
measure: rate of MR4 and MR4.5 during maintenance therapy and after discontinuation
timeFrame: start of maintenance therapy (after at least 24 months of treatment) until end of study duration (at least 36 months)
measure: Progression-Free Survival (PFS)
timeFrame: at 12, 24 and 60 months after start of treatment
measure: Rate of patients off treatment for at least 6 months
timeFrame: at 60 months after start of treatment
measure: safety and tolerability profile of nilotinib in comparison with nilotinib+pegylated interferon alpha and pegylated interferon alpha
timeFrame: time of first study treatment until 28 days after stop of study treatment (expected 36 months)
measure: patients compliance to nilotinib based therapies
timeFrame: until stop of study treatment (at least 36 months)
measure: quality of life during induction therapy with ilotinib versus nilotinib+pegylated interferon alpha and during maintenance therapy with nilotinib versus pegylated interferon alpha
timeFrame: during induction therapy (until at least 24 months), during maintenance therapy (until at least 36 months)
measure: pharmacoeconomics of the treatment strategies
timeFrame: after end of study (expected in December 2020) (up to 8 years)
measure: Overall Survival (OS)
timeFrame: at 12, 24 and 60 months after start of treatment
Other outcomes:
Locations:
city: Brno
country: Czechia
facility: University Hospital and Masaryk University Brno
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen Medizinische Klinik IV
city: Amberg
country: Germany
facility: Gesundheitszentrum St. Marien GmbH, Onkologie/ Hämatologie Onkologisches Zentrum
city: Arnsberg
country: Germany
facility: MVZ am Klinikum Arnsberg GmbH, Hämatologie - Internistische Onkologie
city: Aschaffenburg
country: Germany
facility: Studienzentrum Drs. Klausmann
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth GmbH
city: Berlin
country: Germany
facility: Vivantes Netzwerk für Gesundheit GmbH, Klinikum Neukölln, Klinik für Innere Medizin - Hämatologie und Onkologie
city: Berlin
country: Germany
facility: Charité CVK, CC14, Klinik für Hämatologie und Onkologie
city: Bielefeld
country: Germany
facility: Evangelisches Klinikum Bethel
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn Med. Klinik und Poliklinik III, Hämatologie
city: Bonn
country: Germany
facility: Zentrum für Ambulante Hämatologie und Onkologie
city: Braunschweig
country: Germany
facility: Städtisches Klinikum Braunschweig gGmbh, Medizinische Klinik III - Hämatologie
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte gGmbH
city: Bremen
country: Germany
facility: DIAKO Ev. Diakonie-Krankenhaus gGmbH, Medizinische Klinik II
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH Klinik für Innere Medizin III
city: Dresden
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
city: Eisenach
country: Germany
facility: Onkologisch-Hämatologische Schwerpunktpraxis
city: Erfurt
country: Germany
facility: Dr. med. Ulrich Hauch
city: Erlangen
country: Germany
facility: Onkologische Schwerpunktpraxis Erlangen, Onkologie, Hämatologie
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen Medizinische Klinik 5 - Hämatologie und int. Onkologie
city: Eschweiler
country: Germany
facility: St.-Antonius-Hospital, Klinik für Hämatologie Onkologie
city: Essen
country: Germany
facility: Klinik für Hämatologie Universitätsklinikum Essen
city: Frankfurt
country: Germany
facility: Klinikum der Goethe Universität
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg Abteilung Innere Medizin I - Hämatologie und Onkologie
city: Fulda
country: Germany
facility: MVZ-Osthessen GmbH Klinikum Fulda Tumorklinik
city: Gerlingen
country: Germany
facility: Praxis Dr. med. Schmitt
city: Goslar
country: Germany
facility: Dr. med. Hans Werner Tessen, Facharzt für Innere Medizin
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald, Klinik und Poliklinik für Innere
city: Göttingen
country: Germany
facility: Georg-August Universität Göttingen Abteilung Hämatologie und Onkologie
city: Güstrow
country: Germany
facility: Internistische Gemeinschaftspraxis
city: Hagen
country: Germany
facility: Katholisches Krankenhaus Hagen gem. GmbH, Klinik für Hämatologie und
city: Halle (Saale)
country: Germany
facility: Universitätsklinikum Halle (Saale)
city: Halle
country: Germany
facility: Gemeinschaftspraxis Hämatologie und internistische
city: Hamburg
country: Germany
facility: Asklepios Klinik St. Georg, Abteilung Hämatologie, Onkologie, Stammzelltransplantation
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg- Eppendorf, Medizinische Klinik 2
city: Hamm
country: Germany
facility: Evangelisches Krankenhaus Hamm
city: Hamm
country: Germany
facility: St. Barbara-Klinik, Standort St. Josef
city: Hannover
country: Germany
facility: Mediprojekt, Gesellschaft für Medizinstatistik und Projektentwicklung
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg Innere Medizin V: Hämatologie, Onkologie und Rheumatologie
city: Heilbronn
country: Germany
facility: Internistische Gemeinschaftspraxis Heilbronn
city: Hildesheim
country: Germany
facility: St. Bernward Krankenhaus Hildesheim
city: Homburg/ Saar
country: Germany
facility: Universitätsklinikum des Saarlandes Klinik für Innere Medizin I
city: Idar-Oberstein
country: Germany
facility: Klinikum Idar-Oberstein GmbH, Innere Medizin I (Hämatologie/Onkologie)
city: Ingolstadt
country: Germany
facility: MVZ Onkologie Ingolstadt
city: Jena
country: Germany
facility: Universitätsklinikum Jena, Klinik für Innere Medizin II, Abt. Hämatologie und internistische Onkologie
city: Kaiserslautern
country: Germany
facility: Westpfalz-Klinikum GmbH Innere 1
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe gGmbH, Medizinische Klinik III: Hämatologie/Onkologie
city: Karlsruhe
country: Germany
facility: St. Vincentius-Kliniken Karlsruhe
city: Kempten
country: Germany
facility: Klinikum Kempten Oberallgäu gGmbH
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, II. Medizinische Klinik und Poliklinik im Städtischen Krankenhaus Kiel
city: Koblenz
country: Germany
facility: InVO, Institut für Versorgungsforschung in der Onkologie
city: Krefeld
country: Germany
facility: Onkologische Gemeinschaftspraxis Dr. M. Neise u. Dr. A. Lollert
city: Kronach
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Köln
country: Germany
facility: Universitätsklinikum Köln
city: Lebach
country: Germany
facility: Onkologisches Zentrum Gemeinschaftspraxis für Hämato-/ Onkologie, Abt. für Hämato-/ Onkologie im Caritas Krankenhaus
city: Leer
country: Germany
facility: Onkologisches Schwerpunktpraxis
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig, Department für Innere Medizin
city: Leipzig
country: Germany
facility: Dr. Aldaoud - Dr. Schwarzer Forschungsgesellschaft mbH
city: Limburg An Der Lahn
country: Germany
facility: Krankenhausgesellschaft St. Vincenz mbH Limburg
city: Magdeburg
country: Germany
facility: Gemeinschaftspraxis Uhle, Müller, Kröning, Jentsch-Ullrich
city: Mainz
country: Germany
facility: Internistische Gemeinschaftspraxis Onkologie/Hämatologie
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes- Gutenberg Universität Mainz, III. Medizinische Klinik und Poliklinik, Hämatologie, internistische Onkologie und Pneumologie
city: Mannheim
country: Germany
facility: Mannheimer Onkologie Praxis
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim III. Medizinische Klinik
city: Marburg
country: Germany
facility: Klinikum der Philipps-Universität Marburg, Klinik für Innere Medizin, Schwerpunkt Hämatologie, Onkologie und Immunologie
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden, Mühlenkreikliniken (AöR), Hämatologie/Onkologie
city: Muhr am See
country: Germany
facility: Drs. Schmidt/Schauenberg Onkologie
city: Mutlangen
country: Germany
facility: Stauferklinikum Schwäbisch Gmünd, Zentrum Innere Medizin
city: München
country: Germany
facility: Hämatologisch-Onkologische Gemeinschaftspraxis
city: München
country: Germany
facility: Gemeinschaftspraxis Hämatologie/ Onkologie
city: München
country: Germany
facility: MHP Münchener Hämatologie Praxis
city: München
country: Germany
facility: Universitätsklinikum Grosshadern LMU München
city: München
country: Germany
facility: Klinikum rechts der Isar, III. Medizinische Klinik und Poliklinik
city: München
country: Germany
facility: Hämatologisch-Onkologische Schwerpunktpraxis
city: Neumarkt
country: Germany
facility: Onkologische und hämatologische Schwerpunktpraxis
city: Nürnberg
country: Germany
facility: MVZ I des Klinikums Nürnberg
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg Klinik für Onkologie und Hämatologie / Innere Medizin II
city: Paderborn
country: Germany
facility: Brüderkrankenhaus St. Josef Paderborn
city: Passau
country: Germany
facility: Klinikum Passau, II. Medizinische Klinik
city: Potsdam
country: Germany
facility: MVZ für Blut- und Krebserkrankungen
city: Recklinghausen
country: Germany
facility: Klinikum Vest, Behandlungszentrum Recklinghausen, Medizinische Klinik III
city: Regensburg
country: Germany
facility: Krankenhaus Barmherzige Brüder Regensburg, Klinik für Onkologie und Hämatologie
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg Abteilung für Hämatologie und internistische Onkologie
city: Reutlingen
country: Germany
facility: Kreiskliniken Reutlingen GmbH, Klinikum am Steinenberg, Medizinische Klinik I
city: Rostock
country: Germany
facility: Universitätsmedizin Rostock, ZIM II Klinik für Hämatologie, Onkologie und
city: Rotenburg
country: Germany
facility: Agaplesion Diakonieklinikum Rotenburg
city: Schweinfurt
country: Germany
facility: Leopoldina-Krankenhaus
city: Schwäbisch Hall
country: Germany
facility: Diakonie-Klinikum Schwäbisch Hall gGmbH, Innere Medizin III: Sektion für Onkologie und Hämatologie
city: Sindelfingen
country: Germany
facility: Klinikverbund Südwest, Kliniken Sindelfingen-Böblingen gGmbH
city: Stuttgart
country: Germany
facility: Diakonie Klinikum Stuttgart, Medizinische Klinik
city: Trier
country: Germany
facility: Klinikum Mutterhaus der Borromäerinnen
city: Tübingen
country: Germany
facility: Medizinische Universitätsklinik, Department für Innere Medizin GCP Studienzentrale der Abteilung 2
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm Klinik für Innere Medizin III
city: Weiden
country: Germany
facility: Medizinisches Versorgungszentrum GmbH
city: Wendlingen
country: Germany
facility: Dres. med. T. Kamp - R. Eckert Innere/Hämatologie/Onkologie
city: Winnenden
country: Germany
facility: Rems-Murr-Klinik Winnenden
city: Würselen
country: Germany
facility: Onkologische Gemeinschaftspraxis Würselen und Stolberg
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg Medizinische Klinik und Poliklinik II
city: Zwickau
country: Germany
facility: Heinrich-Braun-Klinikum gGmbH
city: Aarau
country: Switzerland
facility: Kantonspital Aarau AG
city: Baden
country: Switzerland
facility: Kantonspital Baden
city: Basel
country: Switzerland
facility: Universitätsspital Basel
city: Bellinzona
country: Switzerland
facility: IOSI; Oncology Institute of Southern Switzerland
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Geneve
country: Switzerland
facility: Hopitaux Universitaires de Genève
city: Lausanne
country: Switzerland
facility: Département d'oncologie UNIL-CHUV
city: Liestal
country: Switzerland
facility: Kantonsspital Baselland
city: Luzern
country: Switzerland
facility: Luzerner Kantonsspital
city: Zürich
country: Switzerland
facility: Universitätsspital Zürich
Study officials:
affiliation: Jena University Hospital
name: Andreas Hochhaus, Prof. MD
role: PRINCIPAL_INVESTIGATOR
References: