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Evaluation of Efficacy and Safety of Nilotinib in Combination With Chemotherapy in Elderly Patients With Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

29 juli 2020 uppdaterad av: Heike Pfeifer MD, Goethe University

An Open Label Phase II Study to Evaluate the Efficacy and Safety of Induction and Consolidation Therapy With Nilotinib in Combination With Chemotherapy in Patients Aged 55 Years and Over With Philadelphia Chromosome Positive (Ph+ or BCR-ABL+) Acute Lymphoblastic Leukemia (ALL)

The goal of this trial is to evaluate the efficacy and the tolerance of the combination of nilotinib with chemotherapy in the front-line setting as induction and consolidation therapy in Ph+ ALL patient aged 55 years and over. A European consensus has been reached to adopt a common chemotherapeutic schedule for patients aged 55 years and over. This schedule will be used in this trial with the addition of nilotinib as concomitant therapy during induction, consolidation and maintenance. The patients will be prospectively monitored for minimal residual disease and bcr-abl tyrosine kinase domain mutations.

Studieöversikt

Status

Avslutad

Betingelser

Philadelphia Chromsome Positive Acute Lymphoblastic Leukemia

Intervention / Behandling

Läkemedel: Nilotinib

Studietyp

Interventionell

Inskrivning (Faktisk)

Fas

Fas 2

Kontakter och platser

Det här avsnittet innehåller kontaktuppgifter för dem som genomför studien och information om var denna studie genomförs.

Studieorter

Frankrike
- - AMIENS Cedex 1, Frankrike, 80054
    - CHU d'Amiens - Hôpital Sud
  - ANGERS Cedex 09, Frankrike, 49933
    - CHU Angers
  - Aix-en-Provence cedex 1, Frankrike, 13616
    - Centre Hospitalier du Pays d'Aix
  - Argenteuil Cedex, Frankrike, 95107
    - Centre Hospitalier Victor Dupouy
  - BESANÇON Cedex, Frankrike, 25030
    - CHU de Besançon - Hôpital Jean Minjoz
  - BREST Cedex, Frankrike, 29609
    - Chu de Brest - Hopital Morvan
  - Bayonne, Frankrike, 64100
    - Centre Hospitalier de la Côte Basque
  - Caen, Frankrike, 14000
    - "CHU Cote de nacre "
  - Clermont Ferrand, Frankrike, 63003
    - CHU Estaing
  - Creteil, Frankrike, 94010
    - AP-HP - Hôpital Henri Mondor
  - DIJON Cedex, Frankrike, 21079
    - CHRU de Dijon
  - Grenoble cedex 9, Frankrike, 38043
    - CHU de GRENOBLE
  - LE CHESNAY Cedex, Frankrike, 78157
    - Ch de Versailles - Hopital Andre Mignot
  - LILLE Cedex, Frankrike, 59037
    - CHRU de Lille
  - LIMOGES Cedex, Frankrike, 87042
    - C H U de Limoges - Hôpital Dupuytren
  - Lille Cedex, Frankrike, 59020
    - Groupe Hospitalier de l'Institut Catholique de Lille, hôpital Saint-Vincent
  - MEAUX Cedex, Frankrike, 77104
    - CH de Meaux
  - MONTPELLIER Cedex 5, Frankrike, 34295
    - Hôpital Saint-Eloi
  - MULHOUSE Cedex, Frankrike, 68070
    - CH de Mulhouse - Hôpital Emile Muller
  - Marseille cedex 9, Frankrike, 13273
    - Institut Paoli-Calmettes
  - Nantes, Frankrike, 44000
    - CHU Hôtel Dieu, Nantes
  - Nice, Frankrike, 06200
    - Chu de Nice - Hôpital L'Archet 1
  - ORLEANS Cedex, Frankrike, 45032
    - CHR d'Orléans - hôpital La Source
  - PARIS Cedex 10, Frankrike, 75010
    - AP-HP - Hôpital Saint Louis
  - PARIS Cedex 15, Frankrike, 75743
    - AP-HP - Hôpital Necker
  - PARIS cedex 12, Frankrike, 75571
    - AP-HP - hôpital Saint-Antoine
  - PERPIGNAN cedex 09, Frankrike, 66046
    - CH de Perpignan - Hôpital Saint-Jean
  - PESSAC Cedex, Frankrike, 33604
    - CHU de Bordeaux - Hôpital Haut-Lévêque
  - POITIERS Cedex, Frankrike, 86021
    - CHU de Poitiers - Hôpital la Milétrie
  - Pierre-Bénite Cedex, Frankrike, 69495
    - Centre Hospitalier LYON SUD
  - Pringy Cedex, Frankrike, 74374
    - CH de la Region d'Annecy
  - REIMS Cedex, Frankrike, 51092
    - CHU de Reims - Hôpital Robert Debré
  - RENNES Cedex 9, Frankrike, 35033
    - CHU de Rennes, Hopital Pontchaillou
  - Rouen Cedex 1, Frankrike, 76038
    - Centre Henri Becquerel, ROUEN
  - SAINT DENIS Cedex, Frankrike, 97405
    - CHU de la Réunion - Hôpital Felix Guyon
  - STRASBOURG Cedex, Frankrike, 67098
    - CHRU de Strasbourg - Hôpital Hautepierre
  - TOULON Cedex 9, Frankrike, 83041
    - Hia Sainte Anne
  - TOURS Cedex 9, Frankrike, 37044
    - CHRU de Tours - Hopital Bretonneau
  - Toulouse, Frankrike, 31100
    - "Institut Universitaire du Cancer (CHU de Toulouse - Hôpital Purpan)"
  - VALENCIENNES Cedex, Frankrike, 59322
    - Centre Hospitalier de Valenciennes
  - Vandoeuvre Les Nancy, Frankrike, 54511
    - CHU de Nancy - Hôpital Brabois
Spanien
- - Barcelona, Spanien, 08036
    - Hospital Clinic de Barcelona
  - Barcelona, Spanien, 08916
    - Hospital Universitario Germans Trias i Pujol (ICO - Badalona)
  - Madrid, Spanien, 28041
    - Hospital Universitario 12 De Octubre (Madrid)
  - Salamanca, Spanien, 37007
    - Hospital Clinico Universitario de Salamanca
  - Sevilla, Spanien, 41013
    - Hospital Universitario Virgen del Rocío (Sevilla)
  - Valencia, Spanien, 46026
    - Hospital Universitario y Politécnico La Fe (Valencia)
Tyskland
- - Aachen, Tyskland, 52074
    - Uniklinik Aachen
  - Berlin, Tyskland, 13353
    - Charité Universitätsmedizin Berlin
  - Düsseldorf, Tyskland, 40225
    - University Hospital Düsseldorf
  - Göttingen, Tyskland, 37075
    - Universitätsklinikum Göttingen
  - Hamburg, Tyskland, 20099
    - Asklepios Klinik St. Georg
  - Kiel, Tyskland, 24116
    - Universitätsklinikum Schleswig-Holstein Campus Kiel
  - Leipzig, Tyskland, 04103
    - Universität Leipzig, José-Carreras-Haus
  - Mainz, Tyskland, 55101
    - Universitätskliniken Mainz
  - Mannheim, Tyskland, 68167
    - Klinikum Mannheim
  - München, Tyskland, 81377
    - Universitätsklinikum Großhadern
  - Nürnberg, Tyskland, 90419
    - Klinikum Nürnberg Nord
  - Oldenburg, Tyskland, 26133
    - Klinikum Oldenburg
  - Rostock, Tyskland, 18055
    - Universität Rostock
  - Ulm, Tyskland, 89070
    - Medizinische Universitätsklinik Ulm
  - Würzburg, Tyskland, 97080
    - Universität Würzburg
- Baden-Württemberg
  - Stuttgart, Baden-Württemberg, Tyskland, 70376
    - Robert Bosch Krankenhaus
- Bayern
  - Regensburg, Bayern, Tyskland, 93042
    - Klinikum der Universität Regensburg
- Hessen
  - Frankfurt, Hessen, Tyskland, 60590
    - University Hospital of Frankfurt, Medical Dept. II
- NRW
  - Essen, NRW, Tyskland, 45147
    - Universitätsklinikum Essen
  - Münster, NRW, Tyskland, 48149
    - Universitätsklinik Münster
- Niedersachsen
  - Hannover, Niedersachsen, Tyskland, 30625
    - Medizinische Hochschule Hannover
- Sachsen
  - Dresden, Sachsen, Tyskland, 01307
    - Universitatsklinik Dresden

Deltagandekriterier

Forskare letar efter personer som passar en viss beskrivning, så kallade behörighetskriterier. Några exempel på dessa kriterier är en persons allmänna hälsotillstånd eller tidigare behandlingar.

Urvalskriterier

Åldrar som är berättigade till studier

55 år och äldre (Vuxen, Äldre vuxen)

Tar emot friska volontärer

Nej

Kön som är behöriga för studier

Allt

Beskrivning

Inclusion Criteria:

Male or female patients > 55 years
Philadelphia chromosome- or BCR-ABL positive acute lymphoblastic leukemia
Not previously treated except with corticosteroids or single dose vincristine (three doses cyclophosphamide accepted)
With or without documented CNS involvement
WHO performance status < 2
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, prior to the first dose of study medication
Signed written inform consent
Molecular evaluation for BCR-ABL performed
Willingness of male subjects whose sexual partners are women of child-bearing potential (WOCBP), to use an effective form of contraception (pearl index < 1%), such as complete sexual abstinence, combined oral contraceptive, hormone IUCD, vaginal hormone ring, transdermal contraceptive patch, contraceptive implant or depot contraceptive injection in combination with a second method of contraception like a condom or a cervical cap / diaphragm with spermicide or surgical sterilisation (vasectomy) in male patients during the study and at least 6 months thereafter. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or surgical sterilization or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months).

Exclusion Criteria:

Patient previously treated with tyrosine kinase inhibitors
Known impaired cardiac function, including any of the following:
- LVEF < 45%
- Complete left bundle branch block
- Right bundle branch block plus left anterior hemiblock, bifascicular block
- Use of a ventricular-paced pacemaker
- Congenital long QT syndrome
- History of or presence of clinically significant ventricular or atrial tachyarrhythmias
- Clinically significant resting bradycardia (< 50 beats per minute)
- QTcF>450 msec on screening ECG. If QTc > 450 msec and electrolytes are not within normal ranges before nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion.
- Myocardial infarction with 12 months prior to starting nilotinib
- Other clinical significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)
Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or known infection with Hepatitis B or C
Treatment with any, other investigational agent or participating in another trial within 30 days prior to entering this study
Inadequate hepatic functions defined as ASAT or ALAT > 2,5 times the institutional upper limit of normal or > 5 times ULN if considered due to leukemia
Total bilirubin > 2 fold the institutional upper limit unless considered to be due to organ involvement by the leukemia or to M. Gilbert / M. Meulengracht
Concurrent severe diseases which exclude the administration of therapy
Past history of acute or chronic pancreatits
Patients unwilling or unable to comply with the protocol.e branch block; Right bundle branch block plus left anterior hemiblock, bifascicular block; Use of a ventricular-paced pacemaker; congenital long QT syndrome
- History of or presence of clinically significant ventricular or atrial tachyarrhythmias
- Clinically significant resting bradycardia (< 50 beats per minute)
- QTcF>450 msec on screening ECG. If QTc > 450 msec and electrolytes are not within normal ranges before nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion.
- Myocardial infarction with 12 months prior to starting nilotinib
- Other clinical significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)
  - Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
  - Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or known infection with Hepatitis B or C
  - Treatment with any, other investigational agent or participating in another trial within 30 days prior to entering this study
  - Inadequate hepatic functions defined as ASAT or ALAT > 2,5 times the institutional upper limit of normal or > 5 times ULN if considered due to leukemia
  - Total bilirubin > 2 fold the institutional upper limit unless considered to be due to organ involvement by the leukemia or to M. Gilbert / M. Meulengracht
  - Concurrent severe diseases which exclude the administration of therapy
  - Past history of acute or chronic pancreatits
  - Patients unwilling or unable to comply with the protocol.

Studieplan

Det här avsnittet ger detaljer om studieplanen, inklusive hur studien är utformad och vad studien mäter.

Hur är studien utformad?

Designdetaljer

Primärt syfte: Behandling
Tilldelning: N/A
Interventionsmodell: Enskild gruppuppgift
Maskning: Ingen (Open Label)

Vad mäter studien?

Primära resultatmått

Resultatmått	Åtgärdsbeskrivning	Tidsram
Evaluation of efficacy of a nilotinib-based induction and consolidation therapy Tidsram: after 12 months	rate of patients without event	after 12 months

Sekundära resultatmått

Resultatmått	Åtgärdsbeskrivning	Tidsram
Total överlevnad
Progressionsfri överlevnad
Eventfri överlevnad
Återfallsfri överlevnad
complete haematological remission Tidsram: after induction treatment (week 5)	The rate of complete haematological remission after induction treatment	after induction treatment (week 5)
major molecular response in bone marrow	major molecular response defined by a BCR-ABL/ABL < 0.1% in bone marrow
complete molecular response	complete molecular response defined by a BCR-ABL/ABL < 0.001% in bone marrow
undetectable BCR-ABL level	The proportion of patients with confirmed undetectable BCR-ABL level with a test sensitivity of at least 4.5 log.
T315I or p-loop Mutations	Detection of a T315I or p-loop BCR-ABL TK domain mutation
molecular relapse or progression	The proportion of patients with molecular relapse or progression
Tolerability	Tolerability as determined by descriptive assessment of adverse events and discontinuation due to treatment-related SAEs
Death during induction Tidsram: End of induction (week 5)	(all patients who started treatment)	End of induction (week 5)
Death in complete remission

Samarbetspartners och utredare

Det är här du hittar personer och organisationer som är involverade i denna studie.

Sponsor

Goethe University

Utredare

Huvudutredare: Heike Pfeifer, Dr.med., Johann Wolfgang Goethe University Hospital

Publikationer och användbara länkar

Den som ansvarar för att lägga in information om studien tillhandahåller frivilligt dessa publikationer. Dessa kan handla om allt som har med studien att göra.

Användbara länkar

Trial register of University Cancer Center Frankfurt, additional trial information

Studieavstämningsdatum

Dessa datum spårar framstegen för inlämningar av studieposter och sammanfattande resultat till ClinicalTrials.gov. Studieposter och rapporterade resultat granskas av National Library of Medicine (NLM) för att säkerställa att de uppfyller specifika kvalitetskontrollstandarder innan de publiceras på den offentliga webbplatsen.

Studera stora datum

Studiestart

1 januari 2012

Primärt slutförande (Faktisk)

10 mars 2020

Avslutad studie (Faktisk)

10 mars 2020

Studieregistreringsdatum

Först inskickad

3 februari 2012

Först inskickad som uppfyllde QC-kriterierna