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JOURNAL ONKOLOGIE – STUDIE

Ruxo-BEAT The Ruxo-BEAT Trial in Patients With High-risk Polycythemia Vera or High-risk Essential Thrombocythemia

Rekrutierend

NCT-Nummer:
NCT02577926

Studienbeginn:
Oktober 2015

Letztes Update:
08.06.2018

Wirkstoff:
Ruxolitinib, BAT

Indikation (Clinical Trials):
Polycythemia, Polycythemia Vera, Thrombocytosis, Thrombocythemia, Essential

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
RWTH Aachen University

Collaborator:
Novartis Pharmaceuticals

Studienleiter

Steffen Koschmieder, Prof. Dr.
Principal Investigator
RWTH University Hospital MK4

Kontakt

Studienlocations (3 von 24)

Universitätsmedizin Mannheim III. Medizinische Klinik Hämatologie und Internistische Onkologie
68167 Mannheim
(Baden-Württemberg)
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Ansprechpartner:
Eva Langfelder, Prof. Dr.
Phone: +49 (0)621 383 41 31
E-Mail: eva.lengfelder@umm.de
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Universitätsklinikum Ulm Klinik für Innere Medizin III
89081 Ulm
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Konstanz Döhner, Prof. Dr.
Phone: +49 (0)731 500 45543
E-Mail: konstanze.doehner@uniklinik-ulm.de
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Rems-Murr Klinikum Winnenden
71364 Winnenden
(Baden-Württemberg)
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Ansprechpartner:
Stefani Parmentier, Dr.
E-Mail: stefani.parmentier@rems-murr-kliniken.de

Markus Schaich, Dr.
E-Mail: markus.schaich@rems-murr-kliniken.de
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III. Medizinischen Klinik des Klinikums rechts der Isar der TU München
81675 Müchen
(Bayern)
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Ansprechpartner:
Philipp Jost, Dr. med.
E-Mail: philipp.jost@tum.de
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Klinikum Nürnberg Nord Medizinische Klinik 5
90419 Nürnberg
(Bayern)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Marinela Augustin, Dr.
Phone: +49 (0) 911 398 3085
E-Mail: Marinela.Augustin@klinikum-nuernberg.de
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Universitätsmedizin Mainz III. Medizinische Klinik und Poliklinik
55131 Mainz
(Rheinland-Pfalz)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Thomas Kindler, PD Dr.
Phone: +49 (0)6131 17-5046
E-Mail: thomas.kindler@unimedizin-mainz.de
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Universitätsklinikum Bonn Medizinische Klinik und Poliklinik III
53105 Bonn
(Nordrhein-Westfalen)
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Ansprechpartner:
Dominik Wolf, Prof. Dr.
Phone: +49 (0)228 287 17233
E-Mail: dominik.wolf@ukb.uni-bonn.de
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Johanniter-Krankenhaus Rheinhausen GmbH Hämatologie / Internistische Onkologie / Tagesklinik
47228 Duisburg
(Nordrhein-Westfalen)
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Ansprechpartner:
Jan Sebastian Balleisen, Dr. med.
E-Mail: s.balleisen@johanniter-rheinhausen.de
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Universitätsklinikum Düsseldorf Klinik für Hämatologie, Onkologie und Klinische Immunologie
40225 Düsseldorf
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Norbert Gattermann, Prof. Dr.
E-Mail: gattermann@med.uni-duesseldorf.de
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Universitätsklinikum Essen Klinik für Hämatologie
45122 Essen
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Göthert Joachim, Dr.
E-Mail: joachim.goethert@uk-essen.de
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Mühlenkreiskliniken Johannes Wesling Klinikum Minden Klinik für Hämatologie, Onkologie und Palliativmedizin
32429 Minden
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Martin Griesshammer, Prof. Dr.
Phone: +49 (0)571 790 4201
E-Mail: Martin.Griesshammer@muehlenkreiskliniken.de
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Zentralklinikum Medizinische Klinik A Hämatologie, Hämostaseologie, Onkologie und Pneumologie
48149 Münster
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Tim Sauer, Dr.
Phone: +49 (0) 251 83 52818
E-Mail: tim.sauer@ukmuenster.de
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Brustzentrum Stuttgart am Marienhospital
Böheimstraße 37
70199 Stuttgart
DeutschlandRekrutierend» Google-Maps
Ansprechpartner:
Aristoteles Giagounidis, Prof
Phone: +49 2 11 44 00 -25 01
E-Mail: aristoteles.giagounidis@vkkd-kliniken.de
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Zentrum für ambulante Hämatologie und Onkologie (ZAHO)
53721 Siegburg
(Nordrhein-Westfalen)
GermanyNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Stefan Fronhoffs, Dr.
Phone: +49 2241/59540
E-Mail: SFronhoffs@zaho-rheinland.de
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Leberkarzinomzentrum an der Uniklinik RWTH Aachen
Pauwelsstraße 30
52074 Aachen
(Nordrhein-Westfalen)
DeutschlandRekrutierend» Google-Maps
Ansprechpartner:
Steffen Koschmieder, Prof. Dr.
Phone: 00492418036102
E-Mail: skoschmieder@ukaachen.de

Susanne Isfort, Dr.
Phone: 00492418037411
E-Mail: sisfort@ukaachen.de
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Universitätsklinikum Magdeburg
39120 Magdeburg
(Sachsen-Anhalt)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Denise Wolleschak, Dr.
Phone: 0049 391 6713271
E-Mail: denise.wolleschak@med.ovgu.de
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Universitätsklinikum Halle (Saale)
06120 Halle (Saale)
(Sachsen-Anhalt)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Haifa K. Al-Ali, PD Dr. med.
Phone: 0345 5574959
E-Mail: innere4@uk-halle.de
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Klinikum Chemnitz gGmbH Klinik für Innere Medizin III
09113 Chemnitz
(Sachsen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Hänel Mathias, PD Dr.
Phone: +49 (0)371 333 43045
E-Mail: m.haenel@skc.de
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Universitätsklinikum Dresden Medizinische Klinik und Poliklinik I
01307 Dresden
(Sachsen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Uwe Platzbecker, Prof. Dr.
Phone: +49 (0)351 - 458 2583
E-Mail: uwe.platzbecker@uniklinikum-dresden.de
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Charité Universitätsmedizin Berlin Med. Klinik m.S. Hämatologie, Onkologie und Tumorimmunologie
13353 Berlin
(Berlin)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Philipp LeCoutre, PD Dr.
Phone: +49 30 450 665 307
E-Mail: philipp.lecoutre@charite.de
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Universitätsklinikum Freiburg - Klinik für Innere Medizin I
79106 Freiburg
(Baden-Württemberg)
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Ansprechpartner:
Nikolas von Bubnoff, Prof. Dr.
Phone: +49 (0) 761 270-33210
E-Mail: nikolas.bubnoff@uniklinik-freiburg.de
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Universitätsklinikum Hamburg Eppendorf Klinik und Poliklinik für Onkologie, Hämatologie und KMT mit Sektion Pneumologie
20246 Hamburg
(Hamburg)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Philippe Schafhausen, PD Dr.
Phone: +49n (0)40 7410 57122
E-Mail: schafhausen@uke.de
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Universitätsklinik Jena - Klinik für Innere Medizin II
07705 Jena
(Thüringen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Florian Heidel, Prof. Dr.
Phone: +49 3641 9-324210
E-Mail: Florian.Heidel@med.uni-jena.de
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Alle anzeigen

Studien-Informationen

Detailed Description:

Polycythemia vera (PV) and essential thrombocythemia (ET) are classical Philadelphia-negative myeloproliferative neoplasms (MPN) that are characterized by an excess of cells in the peripheral blood, clonal bone marrow hyperplasia, and extramedullary hematopoiesis. The symptoms of these patients may range from asymptomatic disease to symptomatic disease that may significantly affect their activities of daily living, such as severe generalized pruritus, night sweats and fevers, erythromelalgia, bone and muscle pain, weight loss, and fatigue. Moreover, the patients may develop thromboembolic and hemorrhagic complications, transition to myelofibrosis (MF), and transformation to acute leukemia. In principle, the only potentially curative therapy for MPNs is allogenic stem cell transplantation (allo-SCT). However, due to significant transplant-associated morbidity and mortality, this therapeutic option is only applied in exceptional cases of ET or PV. The majority of patients do not qualify for allo-SCT since the risks of this treatment clearly outweigh the potential benefits. Moreover, even with a non-transplantation approach, patients with ET and PV have a life expectancy comparable to or close to healthy age-matched control persons. For patients with standard risk PV, phlebotomy and acetylsalicylic acid are standard of care (target hematocrit below 45 %), while patients with standard risk ET should receive either no specific treatment or acetylsalicylic acid (provided that no microvascular symptoms or secondary acquired von Willebrand syndrome are present).

However, in patients who are at high risk to develop thromboembolic or hemorrhagic complications (high-risk patients), cytoreductive treatment is generally indicated to prevent these potentially life-threatening complications. In PV and ET, high risk patients are characterized by advanced age (> 60 years) and / or a history of thromboembolic or hemorrhagic events {1,2,3}. In ET, a platelet count > 1500 x 109/l is associated with an increased risk of bleeding, and thus should result in a platelet lowering treatment {2}. In PV, in addition to the risk-score based therapy, cytoreduction is also required in patients with progressive or marked myeloproliferation (leukocytosis, thrombocytosis, symptomatic splenomegaly, increase of frequency of phlebotomy requirement), or devastating constitutional symptoms {1,2,4}. In Germany, best available therapy (BAT) includes approved drugs such as hydroxyurea (HU; approved for both PV and ET) and anagrelide (approved for second-line treatment of ET) and non-approved options such as alpha-interferon, pipobroman, busulfan (in elderly patients), and radioactive phosphorus (32P). In rare cases, patients may also benefit from splenic irradiation or splenectomy.

Ruxolitinib is a JAK1/2-specific tyrosine kinase inhibitor (TKI) which has been approved for the treatment of symptomatic myelofibrosis. The compound was shown to be superior to hydroxyurea in reducing splenomegaly and constitutional symptoms. Ruxolitinib is currently studied in phase 2 and phase 3 clinical trials for HU-resistant or HU-intolerant PV and ET. The aim of the present study is to assess the feasibility, efficacy, and safety of ruxolitinib treatment vs. BAT in patients with high-risk PV or -ET.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. written informed consent and willing to comply with treatment and to follow up assessments and procedures

2. >18 years old

3. Patient´s ECOG performance status: 0-2

4. Patient must fulfill WHO 2008 diagnostic criteria for either PV or ET. PV- and ET-patients have to be classified as high risk according to defined criteria.

For patients with high risk PV OR PV with indication for cytoreductive therapy due to progressive myeloproliferation, AT LEAST ONE of the following must be fulfilled:

- Age >60 years

- Previous documented thrombosis or thromboembolism

- Platelet count > 1500 x 10^9/L

- Poor tolerance of phlebotomy or frequent phlebotomy requirement

- Symptomatic or progressive splenomegaly

- Severe disease-related symptoms

- Progressive leukocytosis with leukocyte count > 20 x 10^9/L

For patients with high risk ET, AT LEAST ONE of the following must be fulfilled:

- Age > 60 years

- Platelet count> 1500 x 10^9/L

- Previous thrombosis or thromboembolism

- Previous severe hemorrhage related to ET.

5. Patients must fulfill the following criteria regarding prior therapy:

PV patients: Never treated with cytoreductive drugs except short- term therapy (up to 6 weeks maximum) with ONE of the following drugs: hydroxyurea, anagrelide, or interferon (phlebotomy and/or aspirin are allowed) ET patients: Naïve and pretreated patients may be entered in this trial 7. adequate liver function, AST, and ALT ≤ 2 the institutional ULN value, unless directly attributable to the patient's MPN 8. creatinine clearance >40ml/min calculated according to the modified formula of Cockcroft and Gault, eGFR, or directly measured after 24h-urine collection 9. ability to swallow and retain oral medication

Exclusion Criteria:

1. criteria for post PV-MF or post ET-MF are met

2. previous ruxolitinib treatment

3. history of anaphylaxis following exposure to the BAT drug of choice

4. inadequate bone marrow reserve as demonstrated by ANC ≤ 1 x 10^9/l OR platelet count <50 x 10^9/l

5. known hepatitis B or C or HIV infection

6. other severe, concurrent diseases, including tuberculosis, serious cardiac functional dysfunction (class III or IV), uncontrolled diabetes, uncontrolled hypertension, severe pulmonary disease, or major organ malfunction

7. history of active substance or alcohol abuse within the last year

8. Female patients who are pregnant or nursing

9. participation in another interventional trial and/or used investigational agents or concurrent anticancer treatment for concomitant disease within the last 4 weeks of registration

10. Any circumstances at the time the study entry that would preclude completion of the study or the required follow-up prohibits inclusion into this study

11. active malignancy during the previous 3 years except for treated cervical intraepithelial neoplasia, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin, each with no evidence for recurrence in the past 3 years

12. active bacterial, viral, or fungal infection

13. medical condition requiring prolonged use of oral corticosteroids with a dose of more than 20 mg per day (> 1 month)

14. severe cerebral dysfunction and/or legal incapacity

15. history of active splanchnic vein thrombosis within the last 3 months (includes Budd-Chiari, portal vein, splenic and mesenteric thrombosis)

16. thyroid dysfunction which is not adequately controlled

17. Fertile men or women of childbearing potential cannot be included unless they are: surgically sterile or >2 years after the onset of menopause and/or willing to use a highly effective contraceptive method (Pearl Index <1)

18. patients who are taking any of the following prohibited medication: clarithromycin, telithromycin, troleandomycin, ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir -itraconazole, ketoconazole, voriconazole, fluconazole

19. Patients who suffer from galactose intolerance, lack of lactose or a glucose-galactose-malabsortion

Studien-Rationale

Primary outcome:

1. The rate of complete clinicohematologic response rate (CHR) as defined by Barosi et al Blood 2009 (Time Frame - at month 6):
The rate of complete clinicohematologic response rate (CHR) as defined by Barosi et al Blood 2009



Secondary outcome:

1. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 (Time Frame - at month 6 and 12)

2. The complete response rate (CR) at month 6 as defined by Barosi et al Blood 2013 (revised ELN response criteria) (Time Frame - month 6)

3. The rate of complete responses (CHR) at month 12 as defined by Barosi et al Blood 2009 (Time Frame - month 12)

4. The efficacy as assessed by the absence of phlebotomy (Hct <45%) (Time Frame - through study completion, an average of 2 years)

5. The efficacy as assessed by the reduction in spleen size (palpable spleen that is reduced by > 50% from baseline measured by palpation and ultrasound) OR platelet count < 600 x 10^9/l (ET) (Time Frame - through study completion, an average of 2 years)

6. Proportion of subjects achieving both durable absence of phlebotomy eligibility AND durable spleen volume reduction measured by palpation and ultrasound (PV) OR durable platelet count <600 x 10^9/l (ET) (durable defined as >3 months) {Barosi et al 2013) (Time Frame - through study completion, an average of 2 years)

7. The rate of overall clinicohematologic remissions (CR + PR) according to both guidelines (Barosi et al 2009 and 2013) (Time Frame - through study completion, an average of 2 years)

Studien-Arme

  • Experimental: Ruxolitinib
    Ruxolitinib will be administered orally at a dose of 10 mg twice daily (both PV and ET) for two consecutive years.
  • Active Comparator: Best available therapy (BAT)
    BAT may include all currently used treatment options. BAT is at the choice of the investigator (monotherapy with i.e. hydroxyurea, anagrelide, interferon, busulfan, immunomodulators etc). BAT will be administrated for two consecutive years.

Geprüfte Regime

  • Ruxolitinib (Study drug / Jakavi / ):
    Ruxolitinib is a JAK1/2-specific tyrosine kinase inhibitor (TKI) which has been approved for the treatment of symptomatic myelofibrosis. The compound was shown to be superior to hydroxyurea in reducing splenomegaly and constitutional symptoms.
  • BAT (Control Treatment):
    BAT is at the choice of the investigator (monotherapy with i.e. hydroxyurea, anagrelide, interferon, busulfan, immunomodulators etc).

Quelle: ClinicalTrials.gov


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