TKI and Interferon Alpha Evaluation Initiated by the German Chronic Myeloid Leukemia Study Group - the TIGER Study

Chronic Myeloid Leukemia Clinical Trial

— TIGER  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01657604
• Other study ID #: CML V
• Secondary ID: 2010-024262-22
• Status: Completed
• Phase: Phase 3
• Start date: August 24, 2012
• Est. completion date: May 31, 2022

Study information

• Verified date: May 2023
• Source: University of Jena
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 717
• Est. completion date: May 31, 2022
• Est. primary completion date: May 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• Peginterferon a2b
Patients will receive nilotinib 300 mg BID given as two 150 mg capsules twice daily with at a starting target dose of 30µg/week. After confirmed MMR or at least 24 mo. after start of therapy, maintenance therapy (nilotinib will be discontinued) will start for a study duration of up to 5 years.
• Nilotinib
Patients will receive nilotinib 300 mg BID given as two 150 mg capsules twice daily for a study duration of up to 5 years.

Locations

Country	Name	City	State
Czechia	University Hospital and Masaryk University Brno	Brno
Germany	Universitätsklinikum Aachen Medizinische Klinik IV	Aachen
Germany	Gesundheitszentrum St. Marien GmbH, Onkologie/ Hämatologie Onkologisches Zentrum	Amberg
Germany	MVZ am Klinikum Arnsberg GmbH, Hämatologie - Internistische Onkologie	Arnsberg
Germany	Studienzentrum Drs. Klausmann	Aschaffenburg
Germany	Klinikum Augsburg	Augsburg
Germany	Klinikum Bayreuth GmbH	Bayreuth
Germany	Charité CVK, CC14, Klinik für Hämatologie und Onkologie	Berlin
Germany	Vivantes Netzwerk für Gesundheit GmbH, Klinikum Neukölln, Klinik für Innere Medizin - Hämatologie und Onkologie	Berlin
Germany	Evangelisches Klinikum Bethel	Bielefeld
Germany	Universitätsklinikum Bonn Med. Klinik und Poliklinik III, Hämatologie	Bonn
Germany	Zentrum für Ambulante Hämatologie und Onkologie	Bonn
Germany	Städtisches Klinikum Braunschweig gGmbh, Medizinische Klinik III - Hämatologie	Braunschweig
Germany	DIAKO Ev. Diakonie-Krankenhaus gGmbH, Medizinische Klinik II	Bremen
Germany	Klinikum Bremen-Mitte gGmbH	Bremen
Germany	Klinikum Chemnitz gGmbH Klinik für Innere Medizin III	Chemnitz
Germany	Onkologische Schwerpunktpraxis	Dresden
Germany	Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden	Dresden
Germany	Onkologisch-Hämatologische Schwerpunktpraxis	Eisenach
Germany	Dr. med. Ulrich Hauch	Erfurt
Germany	Onkologische Schwerpunktpraxis Erlangen, Onkologie, Hämatologie	Erlangen
Germany	Universitätsklinikum Erlangen Medizinische Klinik 5 - Hämatologie und int. Onkologie	Erlangen
Germany	St.-Antonius-Hospital, Klinik für Hämatologie Onkologie	Eschweiler
Germany	Klinik für Hämatologie Universitätsklinikum Essen	Essen
Germany	Klinikum der Goethe Universität	Frankfurt
Germany	Universitätsklinikum Freiburg Abteilung Innere Medizin I - Hämatologie und Onkologie	Freiburg
Germany	MVZ-Osthessen GmbH Klinikum Fulda Tumorklinik	Fulda
Germany	Praxis Dr. med. Schmitt	Gerlingen
Germany	Dr. med. Hans Werner Tessen, Facharzt für Innere Medizin	Goslar
Germany	Georg-August Universität Göttingen Abteilung Hämatologie und Onkologie	Göttingen
Germany	Universitätsmedizin Greifswald, Klinik und Poliklinik für Innere	Greifswald
Germany	Internistische Gemeinschaftspraxis	Güstrow
Germany	Katholisches Krankenhaus Hagen gem. GmbH, Klinik für Hämatologie und	Hagen
Germany	Gemeinschaftspraxis Hämatologie und internistische	Halle
Germany	Universitätsklinikum Halle (Saale)	Halle (Saale)
Germany	Asklepios Klinik St. Georg, Abteilung Hämatologie, Onkologie, Stammzelltransplantation	Hamburg
Germany	Universitätsklinikum Hamburg- Eppendorf, Medizinische Klinik 2	Hamburg
Germany	Evangelisches Krankenhaus Hamm	Hamm
Germany	St. Barbara-Klinik, Standort St. Josef	Hamm
Germany	Mediprojekt, Gesellschaft für Medizinstatistik und Projektentwicklung	Hannover
Germany	Medizinische Hochschule Hannover, Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation	Hannover
Germany	Universitätsklinikum Heidelberg Innere Medizin V: Hämatologie, Onkologie und Rheumatologie	Heidelberg
Germany	Internistische Gemeinschaftspraxis Heilbronn	Heilbronn
Germany	St. Bernward Krankenhaus Hildesheim	Hildesheim
Germany	Universitätsklinikum des Saarlandes Klinik für Innere Medizin I	Homburg/ Saar
Germany	Klinikum Idar-Oberstein GmbH, Innere Medizin I (Hämatologie/Onkologie)	Idar-Oberstein
Germany	MVZ Onkologie Ingolstadt	Ingolstadt
Germany	Universitätsklinikum Jena, Klinik für Innere Medizin II, Abt. Hämatologie und internistische Onkologie	Jena
Germany	Westpfalz-Klinikum GmbH Innere 1	Kaiserslautern
Germany	St. Vincentius-Kliniken Karlsruhe	Karlsruhe
Germany	Städtisches Klinikum Karlsruhe gGmbH, Medizinische Klinik III: Hämatologie/Onkologie	Karlsruhe
Germany	Klinikum Kempten Oberallgäu gGmbH	Kempten
Germany	Universitätsklinikum Schleswig-Holstein, II. Medizinische Klinik und Poliklinik im Städtischen Krankenhaus Kiel	Kiel
Germany	InVO, Institut für Versorgungsforschung in der Onkologie	Koblenz
Germany	Universitätsklinikum Köln	Köln
Germany	Onkologische Gemeinschaftspraxis Dr. M. Neise u. Dr. A. Lollert	Krefeld
Germany	Onkologische Schwerpunktpraxis	Kronach
Germany	Onkologisches Zentrum Gemeinschaftspraxis für Hämato-/ Onkologie, Abt. für Hämato-/ Onkologie im Caritas Krankenhaus	Lebach
Germany	Onkologisches Schwerpunktpraxis	Leer
Germany	Dr. Aldaoud - Dr. Schwarzer Forschungsgesellschaft mbH	Leipzig
Germany	Universitätsklinikum Leipzig, Department für Innere Medizin	Leipzig
Germany	Krankenhausgesellschaft St. Vincenz mbH Limburg	Limburg An Der Lahn
Germany	Gemeinschaftspraxis Uhle, Müller, Kröning, Jentsch-Ullrich	Magdeburg
Germany	Internistische Gemeinschaftspraxis Onkologie/Hämatologie	Mainz
Germany	Universitätsmedizin der Johannes- Gutenberg Universität Mainz, III. Medizinische Klinik und Poliklinik, Hämatologie, internistische Onkologie und Pneumologie	Mainz
Germany	Mannheimer Onkologie Praxis	Mannheim
Germany	Universitätsmedizin Mannheim III. Medizinische Klinik	Mannheim
Germany	Klinikum der Philipps-Universität Marburg, Klinik für Innere Medizin, Schwerpunkt Hämatologie, Onkologie und Immunologie	Marburg
Germany	Johannes Wesling Klinikum Minden, Mühlenkreikliniken (AöR), Hämatologie/Onkologie	Minden
Germany	Drs. Schmidt/Schauenberg Onkologie	Muhr am See
Germany	Gemeinschaftspraxis Hämatologie/ Onkologie	München
Germany	Hämatologisch-Onkologische Gemeinschaftspraxis	München
Germany	Hämatologisch-Onkologische Schwerpunktpraxis	München
Germany	Klinikum rechts der Isar, III. Medizinische Klinik und Poliklinik	München
Germany	MHP Münchener Hämatologie Praxis	München
Germany	Universitätsklinikum Grosshadern LMU München	München
Germany	Stauferklinikum Schwäbisch Gmünd, Zentrum Innere Medizin	Mutlangen
Germany	Onkologische und hämatologische Schwerpunktpraxis	Neumarkt
Germany	MVZ I des Klinikums Nürnberg	Nürnberg
Germany	Klinikum Oldenburg Klinik für Onkologie und Hämatologie / Innere Medizin II	Oldenburg
Germany	Brüderkrankenhaus St. Josef Paderborn	Paderborn
Germany	Klinikum Passau, II. Medizinische Klinik	Passau
Germany	MVZ für Blut- und Krebserkrankungen	Potsdam
Germany	Klinikum Vest, Behandlungszentrum Recklinghausen, Medizinische Klinik III	Recklinghausen
Germany	Krankenhaus Barmherzige Brüder Regensburg, Klinik für Onkologie und Hämatologie	Regensburg
Germany	Universitätsklinikum Regensburg Abteilung für Hämatologie und internistische Onkologie	Regensburg
Germany	Kreiskliniken Reutlingen GmbH, Klinikum am Steinenberg, Medizinische Klinik I	Reutlingen
Germany	Universitätsmedizin Rostock, ZIM II Klinik für Hämatologie, Onkologie und	Rostock
Germany	Agaplesion Diakonieklinikum Rotenburg	Rotenburg
Germany	Diakonie-Klinikum Schwäbisch Hall gGmbH, Innere Medizin III: Sektion für Onkologie und Hämatologie	Schwäbisch Hall
Germany	Leopoldina-Krankenhaus	Schweinfurt
Germany	Klinikverbund Südwest, Kliniken Sindelfingen-Böblingen gGmbH	Sindelfingen
Germany	Diakonie Klinikum Stuttgart, Medizinische Klinik	Stuttgart
Germany	Klinikum Mutterhaus der Borromäerinnen	Trier
Germany	Medizinische Universitätsklinik, Department für Innere Medizin GCP Studienzentrale der Abteilung 2	Tübingen
Germany	Universitätsklinikum Ulm Klinik für Innere Medizin III	Ulm
Germany	Medizinisches Versorgungszentrum GmbH	Weiden
Germany	Dres. med. T. Kamp - R. Eckert Innere/Hämatologie/Onkologie	Wendlingen
Germany	Rems-Murr-Klinik Winnenden	Winnenden
Germany	Onkologische Gemeinschaftspraxis Würselen und Stolberg	Würselen
Germany	Universitätsklinikum Würzburg Medizinische Klinik und Poliklinik II	Würzburg
Germany	Heinrich-Braun-Klinikum gGmbH	Zwickau
Switzerland	Kantonspital Aarau AG	Aarau
Switzerland	Kantonspital Baden	Baden
Switzerland	Universitätsspital Basel	Basel
Switzerland	IOSI; Oncology Institute of Southern Switzerland	Bellinzona
Switzerland	Inselspital Bern	Bern
Switzerland	Hopitaux Universitaires de Genève	Geneve
Switzerland	Département d'oncologie UNIL-CHUV	Lausanne
Switzerland	Kantonsspital Baselland	Liestal
Switzerland	Luzerner Kantonsspital	Luzern
Switzerland	Universitätsspital Zürich	Zürich

Sponsors (1)

Lead Sponsor	Collaborator
University of Jena

Countries where clinical trial is conducted

Czechia,  Germany,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MMR rate at 18 months of nilotinib monotherapy versus nilotinib+pegylated interferon alpha	rate of MMR 18 months after randomization for each study treatment	at least 18 months after start of study treatment
Primary	rate of continuous MMR after discontinuation of nilotinib versus pegylated interferon alpha	rate of patients with molecular relapse (loss of MMR) 12 months after discontinuation of any treatment for CML	at least 12 months after stopping all therapy
Secondary	rate of CCyR and MMR		at 12, 18 and 24 months after start of treatment
Secondary	Time to CCyR, MMR, MR4 and MR4.5	this time to-event endpoints give an impression of the velocity of drug response and of the time until a certain remission should be waited for	date of randomization until time to endpoints or end of study duration (at least 36 months)
Secondary	rate of MR4 and MR4.5 during maintenance therapy and after discontinuation		start of maintenance therapy (after at least 24 months of treatment) until end of study duration (at least 36 months)
Secondary	Progression-Free Survival (PFS)		at 12, 24 and 60 months after start of treatment
Secondary	Rate of patients off treatment for at least 6 months	all patients and comparison of treatment arms	at 60 months after start of treatment
Secondary	safety and tolerability profile of nilotinib in comparison with nilotinib+pegylated interferon alpha and pegylated interferon alpha	the time of risk is the time while receiving the therapy plus 28 days thereafter	time of first study treatment until 28 days after stop of study treatment (expected 36 months)
Secondary	patients compliance to nilotinib based therapies		until stop of study treatment (at least 36 months)
Secondary	quality of life during induction therapy with ilotinib versus nilotinib+pegylated interferon alpha and during maintenance therapy with nilotinib versus pegylated interferon alpha		during induction therapy (until at least 24 months), during maintenance therapy (until at least 36 months)
Secondary	pharmacoeconomics of the treatment strategies		after end of study (expected in December 2020) (up to 8 years)
Secondary	Overall Survival (OS)		at 12, 24 and 60 months after start of treatment